WO2023002362A1 - Treatment of hematological malignancy - Google Patents

Treatment of hematological malignancy Download PDF

Info

Publication number
WO2023002362A1
WO2023002362A1 PCT/IB2022/056635 IB2022056635W WO2023002362A1 WO 2023002362 A1 WO2023002362 A1 WO 2023002362A1 IB 2022056635 W IB2022056635 W IB 2022056635W WO 2023002362 A1 WO2023002362 A1 WO 2023002362A1
Authority
WO
WIPO (PCT)
Prior art keywords
patient
mutation
pharmaceutically acceptable
acceptable salt
azacitidine
Prior art date
Application number
PCT/IB2022/056635
Other languages
French (fr)
Inventor
Keith Anthony CHING
Thomas Paul O'BRIEN
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Publication of WO2023002362A1 publication Critical patent/WO2023002362A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • This invention relates to methods for the treatment and selection of patients having a hematological malignancy, particularly acute myeloid leukemia (AML), who may benefit from administration of a smoothened (SMO) inhibitor, or a pharmaceutically acceptable salt thereof, optionally glasdegib, or a pharmaceutically acceptable salt thereof, more particularly who may benefit from administration of a smoothened (SMO) inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, such as a hypomethylating agent, for example azacitidine.
  • AML acute myeloid leukemia
  • AML Acute myeloid leukemia
  • MDS myelodysplastic syndromes
  • CMML chronic myelomonocytic leukemia
  • Rollinson D.E. et al. Epidemiology of myelodysplastic syndromes and chorinci myeloproliferative disorders in the United States, 2001-2004, using data from the NAACR and SEER programs. Blood. 2008, 112(1 ):45-52; Thein M.S. et al., Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades. Cancer.
  • the smoothened receptor (SMO), a component of the hedgehog (Hh) signaling pathway is a potential therapeutic target in a number of human cancers, including hematologic malignancies for example acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), myelofibrosis (MF) and myelodysplastic syndrome (MDS).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • CMML chronic myelomonocytic leukemia
  • MF myelofibrosis
  • MDS myelodysplastic syndrome
  • the hedgehog (Hh) signaling pathway is aberrantly activated in AML and MDS promoting leukemic stem cell maintenance (Campbell et al., Stem Cell Cloning (2015); 8:27-38, the contents of which are incorporated herein by reference in their entirety).
  • Hedgehog pathway inhibitors are emerging as a new therapeutic class for the treatment of acute myeloid leukemia (Jamieson C, et al., Hedgehog pathway inhibitors: a new therapeutic class for the treatment of acute myeloid leukemia. Blood Cancer Discovery 2020; 1(2): 134-145 the contents of which are incorporated herein by reference in their entirety).
  • the compound 1 -((2F?,4F?)-2-(1 /-/-benzo[d]imidazol-2-yl)-1 -methylpiperidin-4-yl)- 3-(4-cyanophenyl)urea (also known as PF-04449913) has been assigned the International Nonproprietary Name (INN) glasdegib ⁇ WHO Drug Information, Vol. 29, No. 1, page 89 (2015), referencing the alternative chemical name A/-[(2F?,4F?)-2-(1/-/- benzoimidazol-2-yl)-1-methylpiperidin-4-yl]-/V-(4-cyanophenyl)urea, the contents of which are incorporated herein by reference in their entirety). It is an orally available, small molecule inhibitor of the Hh pathway component Smoothened (SMO), and is also referred to as a smoothened inhibitor.
  • SMO Smoothened
  • the monomaleate salt of 1-((2R,4R)-2-(1/-/-benzo[d]imidazol-2-yl)-1- methylpiperidin-4-yl)-3-(4-cyanophenyl)urea which may also be referred to as 1- ((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate or glasdegib maleate, has the structure of Formula (I):
  • DAURISMOTM (glasdegib), is indicated, in combination with low dose cytarabine (LDAC), for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are > 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy (United States Prescribing Information, 2018, New York, Pfizer Inc., the contents of which are incorporated herein by reference in their entirety).
  • LDAC low dose cytarabine
  • glasdegib The efficacy of glasdegib was evaluated in a phase 1 b/2 study which included patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) (ClinicalTrials.gov reference NCT01546038, the contents of which are incorporated herein by reference in their entirety, BRIGHT AML & MDS 1003 study).
  • hypomethylating agents decitabine and azacitidine are used to treat patients with AML and higher-risk MDS who are deemed ineligible for intensive chemotherapy (Sabattini E, et al., “WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview” Pathologica. 2010;102(3):83-7, the contents of which are incorporated herein by reference in their entirety).
  • the median overall survival for azacitidine was 10.4 months and the rate of complete remission (CR) was 19.5% after a median follow up of 24 months (Dombret H, et at.
  • the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention in another aspect, relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
  • AML acute myeloid leukemia
  • the invention in another aspect, relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
  • AML acute myeloid leukemia
  • the invention in another aspect, relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
  • AML acute myeloid leukemia
  • the invention in another aspect, relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby increasing the overall survival of the patient.
  • AML acute myeloid leukemia
  • a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • a method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • a method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • a method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • a method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine if the biological sample is positive for at least one mutation of the FLT3 gene.
  • a method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • a method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic, or a pharmaceutically acceptable salt thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • a method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • a method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • the patient is a human.
  • the patient is ineligible for first line treatment with standard induction chemotherapy.
  • the patient is eligible for first line treatment with standard induction chemotherapy.
  • the patient is aged at least 75 years old.
  • the patient has no known active central nervous system (CNS) leukemia.
  • CNS central nervous system
  • the patient has received no prior treatment with a smoothened inhibitor.
  • the patient has received no prior treatment with a hypomethylating agent.
  • the patient has received no prior treatment with a FLT3 inhibitor.
  • the acute myeloid leukemia is newly diagnosed.
  • the acute myeloid leukemia is de novo acute myeloid leukemia. In a preferred embodiment of the inventions described, the acute myeloid leukemia is secondary acute myeloid leukemia.
  • the acute myeloid leukemia is previously untreated.
  • the patient has been previously determined to be positive for at least one mutation of the FLT3 gene.
  • the at least one mutation of the FLT3 gene is selected from the group consisting of an insertion, a point mutation, an internal tandem duplication mutation, and combinations thereof.
  • the at least one mutation of the FLT3 gene is a point mutation, which point mutation is in the tyrosine kinase domain of the FLT3 gene.
  • the at least one mutation of the FLT3 gene is a point mutation, which point mutation is selected from the group consisting of a point mutation at codon D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation at codon 1836 in the tyrosine kinase domain of the FLT3 gene, and combinations thereof.
  • the at least one mutation of the FLT3 gene is an internal tandem duplication (ITD) mutation.
  • the at least one mutation of the FLT3 gene is selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605- P606ins12), ITD(E598-Y599ins5 E589-F590ins12) and combinations thereof.
  • the at least one mutation of the FLT3 gene comprises mutation D835Y.
  • the at least one mutation of the FLT3 gene comprises mutation K565E.
  • the at least one mutation of the FLT3 gene comprises mutation Q575R.
  • the at least one mutation of the FLT3 gene comprises mutation D835FI.
  • the at least one mutation of the FLT3 gene comprises mutation D839G. In a preferred embodiment of the inventions described, the at least one mutation of the FL 73 gene comprises mutation V491 L.
  • the at least one mutation of the FLT3 gene comprises mutation V194M.
  • the at least one mutation of the FLT3 gene comprises mutation N841 Y.
  • the at least one mutation of the FLT3 gene comprises mutation N676S.
  • the at least one mutation of the FLT3 gene comprises mutation A680V.
  • the at least one mutation of the FLT3 gene comprises mutation ITD(F605-P606ins12).
  • the at least one mutation of the FLT3 gene comprises mutation ITD(E598-Y599ins5 E589-F590ins12).
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered daily.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally on a continuous daily dosage schedule.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally at a dose of about 100 mg per day, glasdegib free base equivalent.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally as glasdegib maleate, at a does of about 131 mg glasdegib maleate per day.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally in a solid dosage form.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally in a solid dosage form, which solid dosage form is formulated as a tablet.
  • the further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof is a hypomethylating agent, or a pharmaceutically acceptable salt thereof.
  • the further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof is a hypomethylating agent, or a pharmaceutically acceptable salt thereof, which hypomethylating agent is azacitidine.
  • hypomethylating agent or a pharmaceutically acceptable salt thereof, is azacitidine.
  • azacitidine is administered subcutaneously.
  • azacitidine is administered intravenously.
  • azacitidine is administered on a 28-day cycle.
  • azacitidine is administered on a 28-day cycle and for more than one 28-day cycle.
  • azacitidine is administered on a 28-day cycle and for at least 428-day cycles.
  • azacitidine is administered on a 28-day cycle and for at least 628-day cycles.
  • azacitidine is administered on days 1 to 7 of a 28-day cycle.
  • azacitidine is administered on days 1 to 7 of a 28-day cycle and for more than one 28-day cycle.
  • azacitidine is administered on days 1 to 7 of a 28-day cycle and for at least 428-day cycles. In a preferred embodiment of the inventions described, azacitidine is administered on days 1 to 7 of a 28-day cycle and for at least 628-day cycles.
  • azacitidine is administered at a dose of about 75 mg/m 2 .
  • azacitidine is administered at a dose of about 75 mg/m 2 on days 1 to 7 of a 28-day cycle and for at least 1 28-day cycle.
  • azacitidine is administered at a dose of about 75 mg/m 2 on days 1 to 7 of a 28-day cycle and for at least 428-day cycles.
  • azacitidine is administered at a dose of about 75 mg/m 2 on days 1 to 7 of a 28-day cycle and for at least 628-day cycles.
  • azacitidine is administered at a dose of about 75 mg/m 2 of body surface area.
  • azacitidine is administered at a dose of about 75 mg/m 2 of body surface area on days 1 to 7 of a 28- day cycle and for at least 1 28-day cycle.
  • azacitidine is administered at a dose of about 75 mg/m 2 of body surface area on days 1 to 7 of a 28- day cycle and for at least 428-day cycles.
  • azacitidine is administered at a dose of about 75 mg/m 2 of body surface area on days 1 to 7 of a 28- day cycle and for at least 628-day cycles.
  • the thereby treating said acute myeloid leukemia results in an increase in overall survival of said patient.
  • the thereby treating said acute myeloid leukemia results in an increase in overall survival of said patient as compared to a control group.
  • the thereby treating said acute myeloid leukemia results in an increase in overall survival of said patient as compared to a control group wherein the control group comprises one or more acute myeloid leukemia patients wherein said one or more acute myeloid leukemia patients in the control group are not FLT3 mutant positive.
  • the biological sample is selected from the group consisting of a blood sample or a bone marrow sample.
  • the biological sample is a blood sample.
  • the biological sample is a bone marrow sample.
  • each of the embodiments of the inventions described may be combined with one or more other embodiments of the inventions which is not inconsistent with the embodiment(s) with which it is combined.
  • each of the embodiments describing the inventions envisions within its scope the pharmaceutically acceptable salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof of the compounds described for use in the methods or treatments described therein. Accordingly, the phrase “or a pharmaceutically acceptable salt thereof is implicit in the description of all compounds described herein.
  • Figure 1 is a Kaplan-Meier plot illustrating the estimated overall survival (OS) in the AML expansion cohort (A-B) from Example 1.
  • Figure 2 is a Kaplan-Meier plot illustrating the estimated overall survival (OS) in the MDS expansion cohort (A-B) from Example 1.
  • Figure 3 illustrates the baseline mutations occuring in >10% of patients with AML and MDS from Example 1.
  • Figure 4 is a Kaplan-Meier plot illustrating the correlation of FLT3 biomarker with overall survival in patients with AML and the correlation of TP53 biomarker with overall survival in patients with MDS from Example 1.
  • Figure 5 illustrates the gene mutations with >3-fold decrease in VAF at CR (or better) compared to baseline in 6 patients with AML from Example 1.
  • Figure 6 illustrates the gene mutations with with >3-fold decrease in VAF at CR (or better) compared to baseline in 3 patients with MDS from Example 1.
  • Figure 7 illustrates the variant allele fraction of key AML and Hh pathway genes in 3 patients with AML who experienced a CR and subsequently relapsed (increase in the percentage of bone marrow blast following CR) from Example 1.
  • a numerically defined parameter e.g., the dose of a smoothened inhibitor, the dose of azacitidine and the like
  • the parameter may vary by as much as 10% above or below the stated numerical value for that parameter ( ⁇ 10%).
  • a dose of about 5 mg/kg should be understood to mean that the dose may vary between 4.5 mg/kg and 5.5 mg/kg.
  • patient refers to any single subject for which therapy is desired or that is participating in a clinical trial, epidemiological study or used as a control, including humans and mammalian veterinary patients such as cattle, horses, dogs and cats. In certain preferred embodiments, the patient or subject is a human.
  • diagnosis or “diagnosis” and “prognosticating” or “prognosis,” as used herein, are used in the broadest sense, and are commonly used and are well- understood in medical and clinical practice.
  • diagnosis or “diagnosis” refers to a clinical or other assessment of the condition of a subject based on observation, testing, or circumstances for identifying a subject having a disease, disorder, or condition based on the presence of at least one sign or symptom of the disease, disorder, or condition.
  • diagnosing using the method of the invention includes the observation of the subject for other signs or symptoms of the disease, disorder, or condition in addition to detection of a mutation of a gene, such as, but not limited to, a loss-of-function mutation, that makes the subject susceptible to a particular disease or condition or treatment.
  • a mutation of a gene such as, but not limited to, a loss-of-function mutation, that makes the subject susceptible to a particular disease or condition or treatment.
  • prognosticating refers to the determination of probability, risk or possibility of developing a disease, disorder, or condition, such as cancer, in a subject.
  • treat or “treating” a hematological malignancy as used herein means to administer a therapy according to the present invention to a subject or patient having hematological malignancy, or diagnosed with hematological malignancy, to achieve at least one positive therapeutic effect, such as, for example, complete response, complete remission, partial response, partial remission, improved overall survival, improved overall response, hematologic improvement, marrow complete response, marrow complete remission, complete remission with incomplete hematologic recovery, complete remission with partial hematologic recovery, morphologic leukemia free state, partial remission, partial cytogenetic response, complete cytogenic response, cytogenic complete response, stable disease, transfusion independence, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, and the like.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • treating also includes adjuvant and neo adjuvant treatment of a subject.
  • the treatment regimen for a combination of the invention that is effective to treat a subject may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject.
  • treatment also encompasses in vitro and ex vivo treatment, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • treatment regimen “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in the invention.
  • treating may also encompass the term “ameliorating” which, as used herein, means a lessening or improvement of one or more symptoms as compared to not administering a therapeutic agent of a method or regimen of the invention. “Ameliorating” also includes shortening or reduction in duration of a symptom.
  • control population refers to a population of individuals who are matched to the subject but who differ in some aspect, such as disease state.
  • a control group may be matched to the subject by diagnosis and treatment regimen but may differ in disease state.
  • a control group may be matched to the subject by diagnosis and treatment regimen, but may have a different disease profile, for example a different mutation status. The skilled person will be able to select an appropriate control population to provide the requisite reference value.
  • OS all survival
  • stable disease or “SD”, unless otherwise defined, refers to a cancer that is neither decreasing nor increasing in extent or severity.
  • an “effective dosage” or “effective amount” of drug, compound, therapeutic regimen, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired, including biochemical, histological and / or behavioral symptoms, of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • a “therapeutically effective amount” refers to that amount of a drug, compound, therapeutic regimen, or pharmaceutical composition being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • An effective dosage can be administered in one or more administrations.
  • an effective dosage of drug, compound, therapeutic regimen, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective dosage of drug, compound, therapeutic regimen, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.
  • therapeutic regimen treatment regimen
  • dosing protocol dosing regimen
  • dosing regimen may be used interchangeably to refer to the dose and timing of administration of each therapeutic agent administered in a treatment regimen comprising more than one therapeutic agent according to the invention herein.
  • additive is used to mean that the result of the combination of two compounds, components or targeted agents is no greater than the sum of each compound, component or targeted agent individually.
  • the term “synergy” or “synergistic” are used to mean that the result of the combination of two compounds, components or targeted agents is greater than the sum of each compound, component or targeted agent individually. This improvement in the disease, condition or disorder being treated is a “synergistic” effect.
  • a “synergistic amount” is an amount of the combination of the two compounds, components or targeted agents that results in a synergistic effect, as “synergistic” is defined herein.
  • the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different dose ranges, and / or dose ratios to patients in need of treatment.
  • the observation of synergy in in vitro models or in vivo models can be predictive of the effect in humans and other species and in vitro models or in vivo models exist, as described herein, to measure a synergistic effect.
  • the results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and the absolute doses and plasma concentrations required in humans and other species such as by the application of pharmacokinetic and / or pharmacodynamics methods.
  • a “functional assay” is a method to detect the activity of a gene, protein, or cell in response to a stimulus.
  • the specific functional assay performed depends on the specific mutation or mutations incorporated into the genome of the cell.
  • Functional assays include, but are not limited to, kinase assays, transcription assays using, for example, reporter constructs, proliferation assays, apoptosis assays, migration/chemotaxis assays, nutrient sensitivity assay, agent (e.g., drug, chemotherapeutic agent, mutagen) or radiation sensitivity assays, nucleic acid-binding assay or protein-binding assay, all of which are within the ability of those of skill in the art.
  • agent e.g., drug, chemotherapeutic agent, mutagen
  • radiation sensitivity assays nucleic acid-binding assay or protein-binding assay, all of which are within the ability of those of skill in the art.
  • nucleic acid sequence refers to a DNA or RNA molecule in single or double stranded form, particularly a DNA encoding a protein or protein fragment according to the invention.
  • isolated nucleic acid sequence refers to a nucleic acid sequence which is no longer in the natural environment from which it was isolated, e.g., the nucleic acid sequence in a bacterial host cell or in the plant nuclear or plastid genome.
  • protein or “polypeptide” is used interchangeably and refer to molecules consisting of a chain of amino acids, without reference to a specific mode of action, size, 3-dimensional structure or origin. A “fragment” or “portion” of a particular protein may thus still be referred to as a “protein”.
  • isolated protein is used to refer to a protein which is no longer in its natural environment, for example in vitro or in a recombinant bacterial or plant host cell.
  • the term "gene” refers to a nucleic acid sequence that comprises control and coding sequences necessary for the production of a polypeptide or precursor.
  • the polypeptide can be encoded by a full-length coding sequence or by any portion of the coding sequence. It may include regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons).
  • a gene may thus comprise several operably linked sequences, such as a promoter, a 5' leader sequence comprising e.g., sequences involved in translation initiation, a (protein) coding region (cDNA or genomic DNA) and a 3' non-translated sequence comprising e.g., transcription termination sites.
  • a gene may contain one or more modifications in either the coding or the untranslated regions which could affect the biological activity or the chemical structure of the expression product, the rate of expression, or the manner of expression control. Such modifications are referred to collectively as mutations.
  • the gene may constitute an uninterrupted coding sequence, or it may include one or more introns, bound by the appropriate splice junctions.
  • a cDNA is a copy of the mRNA which is translated into the protein after splicing and other post-transcriptional processing events.
  • exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule after a) portions of a precursor RNA, introns, have been removed by cis-splicing or b) two or more precursor RNA molecules have been ligated by trans-splicing.
  • the mature RNA molecule can be a messenger RNA or a functional form of a non-coding RNA such as rRNA or tRNA.
  • exon can refer to the sequence in the DNA or its RNA transcript.
  • UTR which stands for “untranslated region,” refers to either of two sections on each side of a coding sequence on a strand of mRNA. If it is found on the 5' end, it is called the 5' UTR, or if it is found on the 3' end, it is called the 3' UTR.
  • the untranslated regions typically include control regions involved in translation, RNA targeting, and post-transcriptional processing.
  • the term “intron,” derived from the term “intragenic region” and also called intervening sequence (IVS), are DNA regions in a gene that are not translated into proteins. These non-coding sections are present in precursor mRNA (pre-mRNA) and some other RNAs and removed by splicing during the processing to mature RNA. After intron splicing, the mRNA consists only of exons, which are translated into a protein. Mutations present in introns are often silent. However, intronic mutations can result in aberrant or alternative splicing.
  • level of expression refers to the level of mRNA, as well as pre-mRNA nascent transcript(s), transcript processing intermediates, mature mRNA(s), and degradation products, encoded by a gene in the cell.
  • level of expression also refers to the level of protein or polypeptide in a cell.
  • RNA which is biologically active, i.e., which is capable of being translated into a biologically active protein or peptide (or active peptide fragment) or which is active itself (e.g., in posttranscriptional gene silencing or RNAi).
  • the coding sequence may be in sense-orientation and encodes a desired, biologically active protein or peptide, or an active peptide fragment.
  • the DNA sequence is preferably present in the form of an antisense DNA or an inverted repeat DNA, comprising a short sequence of the target gene in antisense or in sense and antisense orientation (inverted repeat).
  • “Ectopic expression” refers to expression in a tissue in which the gene is normally not expressed.
  • differential expression refers to both quantitative as well as qualitative differences in the genes' expression patterns depending on differential development and/or tumor growth. Differentially expressed genes may represent "marker genes," and/or “target genes”. The expression pattern of a differentially expressed gene disclosed herein may be utilized as part of a prognostic or diagnostic cancer evaluation. Alternatively, a differentially expressed gene disclosed herein may be used in methods for identifying reagents and compounds and uses of these reagents and compounds for the treatment of breast cancer as well as methods of treatment. As used herein, a “reference gene” or “normalization gene” refers to a gene, expression of which remains consistent in individual cells, even under different conditions, as well as among cells from different samples and origins.
  • the term “genome” refers to the total genetic information or hereditary material possessed by an organism (including viruses), i.e., the entire genetic complement of an organism or virus.
  • the genome generally refers to all of the genetic material in an organism's chromosome (s), and in addition, extra chromosomal, genetic information that is stably transmitted to daughter cells (e.g., the mitochondrial genome).
  • a genome can comprise RNA or DNA.
  • mutation refers to alterations in one or more nucleic acids in a genomic sequence, compared to the wild type sequence, including, but not limited to, one or more base changes, point mutations, amplifications, deletions, insertions, including multi-nucleotide insertion mutations such as an internal tandem duplication mutations, of one or more nucleotides, and / or substitutions that may result in silent mutations, non-sense mutations, mis-sense mutations, mutations that result in premature stop codons, aberrant splicing, transcription or translation and the like.
  • a “mutant gene” has undergone a change, such as the loss, gain, or exchange of genetic material, such as a change which may affect the normal function and / or expression of the gene.
  • a “disrupted gene” as used herein refers to a mutant gene that has a mutation that causes a premature stop codon. The disrupted gene product is truncated relative to a full-length undisrupted gene product.
  • a gene comprising a mutation can have more than one mutation.
  • the term “point mutation” is a genetic mutation where a single nucleotide base is changed, inserted, or deleted from a DNA or RNA sequence.
  • the term “positive for at least one mutation”, or “mutant positive” refers to genes that comprise at least one mutation including, but not limited to, a single nucleotide variant, protein altering mutation, a mutant sequence and / or variant sequency, when compared to a primary sequence for example a control sequence or a wild type sequence. Methodology for identifying such mutations are well known to one of ordinary skill in the art.
  • insertion refers to the addition of one or more amino acids in the related protein.
  • INS refers to the addition of one or more amino acids in the related protein.
  • amino acid “position” ”new_amino_acid”“fs” “*” “position_termination_site”, e.g., (A309Sfs*25) and
  • fs* means that a frame-shift results in a stop codon.
  • C443* means amino acid C is changed into a stop codon.
  • a minus sign means the mutation occurs upstream of the translational start site. For example, in “-301 fs,” the mutation occurs upstream of position 301.
  • missense mutation or missense variant refers to a (point) mutation in a nucleic acid sequence encoding a protein, whereby a codon is changed to code for a different amino acid.
  • the resulting protein may have reduced function or loss of function.
  • locus is herein defined to be a specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map. Gene mapping is the process of determining the locus for a particular biological trait.
  • polymorphism is herein defined to be the occurrence of genetic variations that account for alternative DNA sequences and/or alleles among individuals in a population.
  • polymorphic site is herein defined to be a genetic locus wherein one or more particular sequence variations occur.
  • a polymorphic site can be one or more base pairs.
  • a "single nucleotide polymorphism (SNP)" is a polymorphism that occurs at a single nucleotide.
  • a “cluster” of SNPs refers to three or more SNPs that occur within 100 kilobases of each other in a particular polymorphic site, wherein all of the SNPs have a p-value e ⁇ "4> (i.e. ⁇ 1 x 10 ⁇ "4>).
  • nonsynonymous refers to mutations that result in changes to the encoded amino acid.
  • synonymous refers to mutations that do not result in changes to the encoded amino acids.
  • somatic mutation or “somatic variation” refers to a mutation in the DNA of somatic cells (i.e., not germ cells), occurring after conception. “Somatic mutagenesis” therefore refers to the process by which somatic mutations occur.
  • variant sequence or “mutant sequence” means a nucleotide or amino acid sequence that contains one or more differences with respect to a primary sequence. These differences may include alternative residues, modified residues, deletions, insertions, and substitutions.
  • a “mutant polynucleotide,” “mutant nucleic acid,” “variant nucleic acid,” and “nucleic acid with variant nucleotides,” refers to a polynucleotide which has a nucleotide sequence that is different from the nucleotide sequence of the corresponding wild-type polynucleotide.
  • Deletions may be of a single nucleotide base, a portion or a region of the nucleotide sequence of the gene, or of the entire gene sequence. Insertions may be of one or more nucleotide bases.
  • the variants may occur in transcriptional regulatory regions, untranslated regions of mRNA, exons, introns, or exon/intron junctions.
  • variant nucleotide may or may not result in stop codons, frame shifts, deletions of amino acids, altered gene transcript splice forms or altered amino acid sequence.
  • variant nucleotide also refers to one or more nucleotide(s) substitution, deletion, insertion, methylation, and/or modification changes.
  • splice-site mutation is a mutation in a nucleic acid sequence encoding a protein, whereby RNA splicing of the pre-mRNA is changed, resulting in an mRNA having a different nucleotide sequence and a protein having a different amino acid sequence than the wild type.
  • the resulting protein may have reduced function or loss of function.
  • a protein altering mutation refers to a genetic mutation that (a) results in a change in the amino acid sequence of the corresponding protein; or (b) otherwise results in a disruption of the expression, or function of the protein which the gene encodes.
  • a protein altering genetic mutation includes but is not limited to disruptive in-frame deletion, disruptive in-frame insertion, frame-shift variant, in-frame deletion, in-frame insertion, initiator codon variant, intron variant, missense variant, non-canonical start codon, splice acceptor variant, splice donor variant, splice region variant, start lost, stop gained, stop lost, and stop retained variant.
  • the insertions can include from 1 to 21 nucleotides, 1 to 12 nucleotides, 1 to 6 nucleotides or 1 to 3 nucleotides.
  • deletions can be of one or more exonic or intronic regions, or about 1 to 21 nucleotides, 1 to 12 nucleotides, 1 to 6 nucleotides or 1 to 3 nucleotides.
  • the mutations are found at the intron exon splice sites, within introns, or within exons.
  • single nucleotide variant refers to a substitution of one nucleotide to a different nucleotide at a position (e.g., site) of a nucleotide sequence, e.g., a sequence read from a sample.
  • a substitution from a first nucleobase X to a second nucleobase Y may be denoted as "X>Y.”
  • a cytosine to thymine SNV may be denoted as "OT.”
  • mutation type refers to the specific nucleotide substitution that comprises the mutation, and is selected from among OT, C>A, C>G, G>T, G>A, G>C, A>T, A>C, A>G, T>A, T>C and T>G mutations.
  • a mutation type of OT refers to a mutation in which the targeted or mutated nucleotide cytosine is replaced with the substituting nucleotide thymine.
  • a mutation in a regulatory sequence is a change of one or more nucleotides compared to the wild type sequence, e.g., by replacement, deletion or insertion of one or more nucleotides, leading for example to reduced or no mRNA transcript of the gene being made.
  • the term “silencing” refers to a down-regulation or complete inhibition of gene expression of the target gene or gene family.
  • point mutation is the replacement of a single nucleotide, or the insertion or deletion of a single nucleotide.
  • target gene in gene silencing approaches is the gene or gene family (or one or more specific alleles of the gene) of which the endogenous gene expression is down-regulated or completely inhibited (silenced) when a chimeric silencing gene (or “chimeric RNAi gene”) is expressed and for example produces a silencing RNA transcript (e.g., a dsRNA or hairpin RNA capable of silencing the endogenous target gene expression).
  • a target gene is the endogenous gene which is to be mutated, leading to a change in (reduction or loss of) gene expression or a change in (reduction or loss of) function of the encoded protein.
  • “Expression level,” “level of expression” and the like refers to the amount of a biomarker in a biological sample. “Expression” generally refers to the process by which information (e.g., gene-encoded and/or epigenetic information) is converted into the structures present and operating in the cell. Therefore, as used herein, “expression” may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and/or polypeptide modifications (e.g., posttranslational modification of a polypeptide).
  • Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and/or polypeptide modifications shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a posttranslational processing of the polypeptide, e.g., by proteolysis.
  • "Expressed genes” include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs).
  • “Increased expression,” “increased expression level,” “increased levels,” “elevated expression,” “elevated expression levels,” or “elevated levels” refers to an increased expression or increased levels of a biomarker in an individual relative to a reference level or control, such as an individual or individuals who do not have the disease or disorder (e.g., cancer), an internal control e.g., a housekeeping biomarker), or a median expression level of the biomarker in samples from a group/population of patients.
  • a reference level or control such as an individual or individuals who do not have the disease or disorder (e.g., cancer), an internal control e.g., a housekeeping biomarker), or a median expression level of the biomarker in samples from a group/population of patients.
  • “Decreased expression,” “decreased expression level,” “decreased levels,” “reduced expression,” “reduced expression levels,” or “reduced levels” refers to a decrease expression or decreased levels of a biomarker in an individual relative to a reference level or control, such as an individual or individuals who do not have the disease or disorder (e.g., cancer), an internal control (e.g., a housekeeping biomarker), or a median expression level of the biomarker in samples from a group/population of patients. In some embodiments, reduced expression is little or no expression.
  • Bioactivity or “bioactivity” or “activity” or “biological function,” which are used interchangeably, herein mean an effector or antigenic function that is directly or indirectly performed by a polypeptide (whether in its native or denatured conformation), or by any fragment thereof in vivo or in vitro.
  • Biological activities include but are not limited to binding to polypeptides, binding to other proteins or molecules, enzymatic activity, signal transduction, activity as a DNA binding protein, as a transcription regulator, ability to bind damaged DNA, etc.
  • a bioactivity can be modulated by directly affecting the subject polypeptide.
  • a bioactivity can be altered by modulating the level of the polypeptide, such as by modulating expression of the corresponding gene.
  • biological sample refers to a material or mixture of materials obtained from a subject (such as a patient), cell line, tissue culture, or other source which may contain cells or cellular products such as extracellular matrix.
  • the biological sample comprises cancer tissue, cancer cells, blast cells or circulating tumor DNA.
  • the sample may be of any biological tissue or bodily fluid.
  • the sample is typically, although not necessarily, in fluid form, containing one or more components of interest. Frequently the sample will be a "clinical sample” which is a sample derived from a patient.
  • Such samples include, but are not limited to, sputum, bone marrow aspirate, blood, peripheral blood, blood cells (e.g., white cells), organs, cells, tissue or fine needle biopsy samples, cell-containing bodily fluid, free floating nucleic acids, urine, peritoneal fluid, and pleural fluid, or cells therefrom, lymph, urine, saliva, fluid from ductal lavage, and nipple aspirate.
  • samples may include a tumor sample which includes one or more premalignant or malignant cells.
  • the sample e.g., tumor sample, includes one or more circulating tumor cells (CTC) (e.g., a CTC acquired from a blood sample).
  • CTC circulating tumor cells
  • Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.
  • the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • the invention in another aspect, relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
  • AML acute myeloid leukemia
  • the invention in another aspect relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
  • the invention relates to a method of treating acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof.
  • AML acute myeloid leukemia
  • the invention relates to a method of improving overall survival a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
  • AML acute myeloid leukemia
  • the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof.
  • AML acute myeloid leukemia
  • a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • a method of treating acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention in another aspect relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said treatment comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
  • AML acute myeloid leukemia
  • the invention in another aspect relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said treatment comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; and d.
  • AML acute myeloid leukemia
  • a method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • a method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
  • FLT3 gene refers to the gene which codes for FLT3 protein, which protein is also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or FLK-2 (fetal liver kinase 2).
  • FLT3 protein is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation (Kiyoi H., et at., “FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development”, Cancer Sci. , 2020, 111:312-322, the contents of which are incorporated herein by reference in their entirety).
  • JM juxtamembrane
  • TK tyrosine kinase
  • C-terminal domain in the intracellular region. It has a transmembrane region in the middle part, flanked by a tyrosine kinase region on the carboxyl-terminal side and an extracellular region on the amino-terminal side.
  • the patient is a human.
  • the patient is ineligible for first line treatment with standard induction chemotherapy including, but not limited to, in view of their age, comorbidities that preclude the use of intensive induction chemotherapy, disease characteristics, performance status, organ dysfunction, combinations thereof and the like.
  • the patient is eligible for first line treatment with standard induction chemotherapy.
  • the patient is aged at least 75 years old.
  • the patient has no known active central nervous system (CNS) leukemia.
  • CNS central nervous system
  • the patient has received no prior treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
  • the patient has received no prior treatment with a hypomethylating agent, or a pharmaceutically acceptable salt thereof.
  • the patient has received no prior treatment with a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the patient has received no prior treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, or a hypomethylating inhibitor, or a pharmaceutically acceptable salt thereof.
  • the patient has received no prior treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, or a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the patient has received no prior treatment with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, or a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the patient has received no prior treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, or a hypomethylating agent, or a pharmaceutically acceptable salt thereof, or a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the patient has received no prior treatment with glasdegib, or a pharmaceutically acceptable salt thereof.
  • the patient has received no prior treatment with azacitidine.
  • the acute myeloid leukemia is newly diagnosed.
  • the acute myeloid leukemia is de novo acute myeloid leukemia (AML).
  • the acute myeloid leukemia is secondary acute myeloid leukemia (AML).
  • the acute myeloid leukemia is previously untreated.
  • the patient has been previously determined to be positive for at least one mutation of the FLT3 gene.
  • the patient is relapsed.
  • the patient is relapsed or refractory following prior treatment with a FLT3 inhibitor.
  • the patient is positive for at least one mutation of the FLT3 gene or the patient has acute myeloid leukemia with at least one mutation of the FLT3 gene.
  • the patient is positive for at least one mutation of the FLT3 gene at diagnosis.
  • the patient is positive for at least one mutation of the FLT3 gene at initial diagnosis.
  • the patient is positive for at least one mutation of the FLT3 gene at relapse.
  • the patient has a newly detected FLT3 mutation at relapse.
  • at least one mutation of the FLT3 gene results in a constitutively active FLT3 kinase.
  • the mutation status can be determined using genomic DNA extracted from mononuclear cells obtained from a biological sample from the patient including, but not limited to, a bone marrow aspirate sample, a blood sample, or a peripheral blood sample.
  • a biological sample is a bone marrow aspirate sample.
  • the biological sample is a blood sample.
  • the biological sample is a peripheral blood sample.
  • the FLT3 gene mutation status can be determined by a companion diagnostic.
  • the FLT3 gene mutation status can be determined by a PCR based in vitro diagnostic test, for example a PCR based in vitro diagnostic test designed to detect internal tandem duplication mutations and tyrosine kinase domain mutations D835 and I836 in the FLT3 gene in genomic DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates of patients, for example LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies, Inc, San Diego, USA).
  • a PCR based in vitro diagnostic test designed to detect internal tandem duplication mutations and tyrosine kinase domain mutations D835 and I836 in the FLT3 gene in genomic DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates of patients, for example LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies, Inc, San Diego, USA).
  • a standard PCR assay using for example, primers that straddle the internal tandem duplication mutation or primers that overlap within the expected region of mutation, can be used to detect mutations of internal tandem duplication, where, for example, amplicons with a size greater than that of wild-type and labeled with both 6-FAM and HEX are interpreted as positive for internal tandem duplication mutation.
  • an assay such as Agilent SureSelect capture-based, targeted re-sequencing assay (Santa Clara, USA) can be used as the primary assay.
  • FLT3 genes are captured by hybridization from genomic DNA using a custom RNA probe set, and then amplified, purified and sequenced on an instrument such as an lllumina MiSeq instrument.
  • An applicanton-based supplement assay can also be used to characterize FLT3 gene for internal tandem duplication mutations by methods well known to one of ordinary skill.
  • the FLT3 gene mutation status can be determined by whole exome sequencing.
  • the FLT3 gene mutation status can be determined by a FISH assay.
  • the at least one mutation of the FLT3 gene is a somatic mutation.
  • the at least one mutation of the FLT3 gene is selected from the group consisting of an insertion, a point mutation, an internal tandem duplication mutation, and combinations thereof.
  • the at least one mutation of the FLT3 gene is an insertion.
  • the at least one mutation of the FLT3 gene is a point mutation.
  • the at least one mutation of the FLT3 gene is a point mutation, which point mutation is in the tyrosine kinase domain of the FLT3 gene.
  • the at least one mutation of the FLT3 gene is a point mutation, which point mutation is at codon D835 in the tyrosine kinase domain of the FLT3 gene. In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is a point mutation, which point mutation is in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene.
  • the at least one mutation of the FLT3 gene is a point mutation, which point mutation is at codon 1836 in the tyrosine kinase domain of the FLT3 gene.
  • the at least one mutation of the FLT3 gene is more than one point mutation, which point mutations are at codon D385 and at codon 1836 in the tyrosine kinase domain of the FLT3 gene.
  • the mutation of the FLT3 gene is an internal tandem duplication mutation.
  • the mutation of the FLT3 gene is an internal tandem duplication with a mutant to wild type allelic ratio of greater than about 0.05.
  • the mutation of the FLT3 gene comprises one or more of a point mutation at codon D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation at codon 1836 in the tyrosine kinase domain of the FLT3 gene; an internal tandem duplication mutation; and combinations thereof.
  • the mutation of the FLT3 gene comprises one or more of a point mutation at codon D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation at codon 1836 in the tyrosine kinase domain of the FLT3 gene; and an internal tandem duplication mutation.
  • the mutation of the FLT3 gene is selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), and ITD(E598-Y599, ins5; E589-F590ins12).
  • the mutation of the FLT3 gene comprises at least one mutation selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), and ITD(E598-Y599, ins5; E589-F590ins12), and combinations thereof.
  • the mutation of the FLT3 gene comprises at least two mutations selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), and ITD(E598-Y599, ins5; E589-F590ins12).
  • the mutation of the FLT3 gene comprises three mutations selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), and ITD(E598-Y599, ins5; E589-F590ins12).
  • the mutation of the FLT3 gene is V194M.
  • the mutation of the FLT3 gene is N841Y.
  • the mutation of the FLT3 gene is N676S.
  • the mutation of the FLT3 gene is A680V.
  • the mutation of the FLT3 gene is ITD(F605-P606ins12) mutation.
  • the mutation of the FLT3 gene is ITD(E598-Y599, ins5; E589-F590ins12) mutation.
  • the method comprises administering the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof. In some embodiments of each of the inventions described herein, the method comprises administering the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof. In some embodiments of each of the inventions described herein, the method comprises administering the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine.
  • administering to said patient the therapeutic regimen increases the overall survival of said patient. In one embodiment of the inventions described herein administering to said patient the therapeutic regimen increases the overall survival of said patient as compared to the overall survival of a control group.
  • the control group comprises one or more patients, where said one or more patients are not FLT3 mutant positive, for example which comprises acute myeloid leukemia patients who are not positive for at least one mutation of the FLT3 gene; or comprises patients with acute myeloid leukemia which does not have at least one mutation of the FLT3 gene; or which comprises acute myeloid leukemia patients, where said patients have wild type FLT3 gene; or which comprises patients with acute myeloid leukemia which is wild-type for the FLT3 gene.
  • control group comprises patients who have received the same therapeutic regimen.
  • therapeutic regimen administered to the control group is a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, and a further chemotherapeutic agent.
  • therapeutic regimen administered to the control group is glasdegib, or a pharmaceutically acceptable salt thereof, in combination with azacitidine.
  • Each therapeutic agent of the methods of the present invention may be administered either alone, or in a medicament (also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically acceptable excipients, including carriers, excipients, or diluents, according to pharmaceutical practice.
  • a medicament also referred to herein as a pharmaceutical composition
  • pharmaceutically acceptable excipients including carriers, excipients, or diluents
  • Each therapeutic agent of the methods of the present invention may also be administered in combination with a further therapeutic agent as described herein.
  • Such combination therapy may optionally be described as a therapeutic regimen.
  • combination therapy or administration “in combination” refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in a medicament, either sequentially, concurrently or simultaneously.
  • sequential refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in a medicament, one after the other, wherein each therapeutic agent can be administered in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and / or are administered according to different dosing schedules, for example, one agent is administered daily, and the second agent is administered less frequently such as weekly.
  • the term “concurrently” refers to the administration of each therapeutic agent in the combination therapy of the invention, either alone or in separate medicaments, wherein the second therapeutic agent is administered immediately after the first therapeutic agent, but that the therapeutic agents can be administered in any order. In a preferred embodiment the therapeutic agents are administered concurrently.
  • the term “simultaneous” refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in separately medicaments, wherein the second therapeutic agent is administered at the same time as the first therapeutic agent, optionally where the therapeutic agents are administered in the same medicament.
  • the method comprises administering a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof.
  • the amounts of the smoothened inhibitor, or pharmaceutically acceptable salt thereof, and the further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof are together effective in treating the acute myeloid leukemia.
  • the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention relates to a method of treating acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • the invention relates to a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in combination with, a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with a further chemotherapeutic agent, for the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof.
  • AML acute myeloid leukemia
  • the invention relates to a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in combination with a smoothened inhibitor, for the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof.
  • AML acute myeloid leukemia
  • the invention relates to a combination of a smoothened inhibitor or a pharmaceutically acceptable salt thereof, and a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • the invention relates to a combination of a smoothened inhibitor or a pharmaceutically acceptable salt thereof, and a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof.
  • AML acute myeloid leukemia
  • the invention in another aspect, relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation in the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
  • AML acute myeloid leukemia
  • the invention relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
  • AML acute myeloid leukemia
  • the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof.
  • AML acute myeloid leukemia
  • the invention relates to a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in combination with a smoothened inhibitor, for improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • the invention relates to a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in combination with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof.
  • AML acute myeloid leukemia
  • the invention relates to a combination of a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
  • AML acute myeloid leukemia
  • the invention relates to a combination of a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof.
  • the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation in the FLT3 gene, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation in the FLT3 gene; c.
  • the invention in another aspect relates to a method of treating acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient has acute myeloid leukemia (AML) with at least one mutation in the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, if the patient has acute myeloid leukemia (AML) with at least one mutation in the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention in another aspect relates to a smoothened inhibitor for use in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for the treatment of acute myeloid leukemia (AML) in a patient, wherein the patient is positive for at least one mutation in the FLT3 gene, said treatment comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine the patient is positive for at least one mutation in the FLT3 gene; c. selecting the patient for treatment if the patient is positive for at least one mutation in the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
  • AML acute myeloid leukemia
  • the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said treatment comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; c.
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • Embodiments of the present invention comprise a smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
  • the smoothened inhibitor, or a pharmaceutically acceptable salt thereof is glasdegib, or a pharmaceutically acceptable salt thereof.
  • the smoothened inhibitor, or a pharmaceutically acceptable salt thereof is vismodegib, or a pharmaceutically acceptable salt thereof.
  • the smoothened inhibitor, or a pharmaceutically acceptable salt thereof is sonidegib, or a pharmaceutically acceptable salt thereof.
  • Chemotherapeutic agent Embodiments of the present invention comprise a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof.
  • the chemotherapeutic agent is a hypomethylating agent, or a pharmaceutically acceptable salt thereof.
  • hypomethylating agent or “demethylating agent” shall be taken to me a drug that inhibits methylation of DNA, i.e. the modification of DAN nucleotides by the addition of a methyl group.
  • Hypomethylating agents include, but are not limited to, azacitidine and decitabine.
  • the hypomethylating agent is azacitidine.
  • Azacitidine is also known by several alternative names such as 5- azacytidine, azacytidine, ladakamycin, or 4-aminio-1-p-D-ribofuranosyl-s-trianin-2(1 H)- one.
  • hypomethylating agent is decitabine.
  • the chemotherapeutic agent is cytarabine.
  • Cytarabine is also known as cytosine arabinoside (ara-C).
  • the chemotherapeutic agent is daunorubicin.
  • the chemotherapeutic agent is doxorubicin.
  • the chemotherapeutic agent is epirubicin.
  • the chemotherapeutic agent is idarubicin.
  • the smoothened inhibitor, or a pharmaceutically acceptable salt thereof is administered before the administration of the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
  • the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof is administered before administration of the smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
  • the smoothened inhibitor, or a pharmaceutically acceptable salt thereof is administered concurrently with the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
  • the smoothened inhibitor, or a pharmaceutically acceptable salt thereof is administered simultaneously with the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
  • the smoothened inhibitor, or a pharmaceutically acceptable salt thereof is administered before the administration of the azacitidine.
  • the azacitidine is administered before administration of the smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
  • the smoothened inhibitor or a pharmaceutically acceptable salt thereof, is administered concurrently with the azacitidine.
  • the smoothened inhibitor or a pharmaceutically acceptable salt thereof, is administered simultaneously with the azacitidine.
  • glasdegib or a pharmaceutically acceptable salt thereof, is administered before the administration of the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
  • the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof is administered before administration of glasdegib, or a pharmaceutically acceptable salt thereof.
  • glasdegib or a pharmaceutically acceptable salt thereof, is administered concurrently with the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
  • glasdegib or a pharmaceutically acceptable salt thereof, is administered simultaneously with the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof. In one embodiment of the inventions described herein glasdegib, or a pharmaceutically acceptable salt thereof, is administered before the administration of the azacitidine.
  • the azacitidine is administered before administration of glasdegib, or a pharmaceutically acceptable salt thereof.
  • glasdegib or a pharmaceutically acceptable salt thereof, is administered concurrently with the azacitidine.
  • glasdegib or a pharmaceutically acceptable salt thereof, is administered simultaneously with the azacitidine.
  • Administration of compounds of the invention may be undertaken by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
  • Dosage regimens may be adjusted to provide the optimum desired response.
  • a therapeutic agent of the combination therapy of the present invention may be administered as a single bolus, as several divided doses administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be particularly advantageous to formulate a therapeutic agent in a dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention may be dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the dose and dosing regimen is adjusted in accordance with methods well- known in the therapeutic arts. That is, the maximum tolerable dose may be readily established, and the effective amount providing a detectable therapeutic benefit to a subject may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the subject. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a subject in practicing the present invention.
  • dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, taking into consideration factors such as the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
  • At least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as a monotherapy for treating the same cancer.
  • the subject received a lower total amount of at least one of the therapeutic agents in the combination therapy than when the same agent is used as a monotherapy, for example a lower dose of therapeutic agent, a reduced frequency of dosing and / or a shorter duration of dosing.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered daily. In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally on a continuous daily dosage schedule.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally at a dose of about 100 mg per day, glasdegib free base equivalent.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally as glasdegib maleate at a dose of about 131 mg glasdegib maleate per day.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered in a solid dosage form, optionally formulated as a tablet.
  • the further chemotherapeutic agent is azacitidine which is administered subcutaneously.
  • the further chemotherapeutic agent is azacitidine which is administered intravenously.
  • the further chemotherapeutic agent is azacitidine which is administered for days 1 to 10 of a 28-day cycle.
  • the further chemotherapeutic agent is azacitidine which is administered for days 1 to 7 of a 28-day cycle.
  • the further chemotherapeutic agent is azacitidine which is administered for greater than one 28-day cycle, optionally for at least 4 28-day cycles, or optionally for at least 628-day cycles.
  • the further chemotherapeutic agent is azacitidine which is administered at a dose of about 75 mg/m 2 .
  • the further chemotherapeutic agent is azacitidine which is administered at a dose of about 75 mg/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered intravenously.
  • the further chemotherapeutic agent is cytarabine which is administered subcutaneously.
  • the further chemotherapeutic agent is cytarabine which is administered by infusion into the cerebrospinal fluid. In one embodiment the further chemotherapeutic agent is cytarabine which is administered for days 1 to 10 of a 28-day cycle.
  • the further chemotherapeutic agent is cytarabine which is administered for days 1 to 7 of a 28-day cycle.
  • the further chemotherapeutic agent is cytarabine which is administered for greater than one 28-day cycle, optionally for at least 428-day cycles, or optionally for at least 628-day cycles.
  • the further chemotherapeutic agent is cytarabine which is administered at a dose of about 20 mg/m 2 .
  • the further chemotherapeutic agent is cytarabine which is administered at a dose of about 20 mg/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered at a dose of about 20 mg/m 2 twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered at a dose of about 20 mg/m 2 of body surface area twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered at a dose of about 100 mg/m 2 .
  • the further chemotherapeutic agent is cytarabine which is administered at a dose of about 100 mg/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered at a dose of about 100 mg/m 2 once daily.
  • the further chemotherapeutic agent is cytarabine which is administered at a dose of about 100 mg/m 2 of body surface area once daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least 4 further 28-day cycles.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least 6 further 28-day cycles.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 3g/m 2 . In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 3g/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 3g/m 2 .
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 3g/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 3g/m 2 .
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 3g/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 3g/m 2 twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 3g/m 2 of body surface area twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 3g/m 2 twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 3g/m 2 of body surface area twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 3g/m 2 twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 3g/m 2 of body surface area twice daily. In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 1 g/m 2
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 1 g/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 1 g/m 2 .
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 1 g/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 1 g/m 2 .
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 1 g/m 2 of body surface area.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 1g/m 2 twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 1g/m 2 of body surface area twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 1g/m 2 twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 1g/m 2 of body surface area twice daily.
  • the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 1g/m 2 twice daily. In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 1g/m 2 of body surface area twice daily.
  • the regimen optionally comprises daunorubicin, which daunorubicin is administered on days 1 to 3 of a 28-day cycle.
  • the regimen optionally comprises daunorubicin, which is administered for greater than one 28-day cycle, optionally for at least 4 28-day cycles, or optionally for at least 628-day cycles.
  • the regimen optionally comprises daunorubicin, which is administered about 60mg/m 2 .
  • the regimen optionally comprises daunorubicin, which is administered about 60mg/m 2 of body surface area.
  • the regimen optionally comprises daunorubicin, which is administered about 60mg/m 2 once daily.
  • the regimen optionally comprises daunorubicin, which is administered about 60mg/m 2 of body surface area once daily.
  • a “continuous dosing schedule” as used herein is an administration or dosing regimen without dose interruptions, e.g. without days off treatment. Repetition of 21 or 28 day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule.
  • the compounds of the combination of the present invention can be administered in a continuous dosing schedule.
  • a “pharmaceutical composition” refers to a mixture of one or more of the therapeutic agents described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, including, but not limited to a carrier or excipient or diluent.
  • the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients and/or diluents.
  • a “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the active compound or therapeutic agent.
  • the pharmaceutically acceptable carrier may comprise any conventional pharmaceutical carrier or excipient.
  • the choice of carrier and/or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • Suitable pharmaceutically acceptable carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates).
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Non-limiting examples of materials therefore, include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream, or for rectal administration as a suppository.
  • Exemplary parenteral administration forms include solutions or suspensions of an active compound in a sterile aqueous solution, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise amounts.
  • Pharmaceutical compositions suitable for the delivery of the therapeutic agents of the combination therapies of the present invention, and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in ‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the contents of which are incorporated herein by reference in their entirety.
  • Therapeutic agents of the combination therapies of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the therapeutic agent enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the therapeutic agent enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid- filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agents and/or suspending agents may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • Therapeutic agents of the combination therapies of the present invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001), the contents of which are incorporated herein by reference in their entirety.
  • the therapeutic agent may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant may comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • compositions include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
  • Exemplary tablets may contain up to about 80 wt% active agent, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting.
  • the final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles may be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The contents of each of these references are incorporated herein by reference in their entireties.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally.
  • the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered in a solid dosage form, optionally formulated as a tablet.
  • the solid dosage form comprises a dose of about 100 mg per day, glasdegib free base equivalent.
  • the solid dosage form is a tablet, which tablet comprises a dose of about 100 mg per day, glasdegib free base equivalent.
  • the solid dosage form comprises a dose of glasdegib maleate at a dose of about 131 mg glasdegib maleate per day.
  • the solid dosage form is a tablet, which tablet comprises a dose of glasdegib maleate at a dose of about 131 mg glasdegib maleate per day.
  • the daily dose of glasdegib, or a pharmaceutically acceptable salt thereof is divided into several sub-doses.
  • the solid dosage form comprises a dose of about 25 mg per day, glasdegib free base equivalent.
  • the solid dosage form is a tablet, which tablet comprises a dose of about 25 mg per day, glasdegib free base equivalent.
  • the solid dosage form comprises a dose of glasdegib maleate at a dose of about 33 mg glasdegib maleate per day.
  • the solid dosage form is a tablet, which tablet comprises a dose of glasdegib maleate at a dose of about 33 mg glasdegib maleate per day.
  • azacitidine is administered subcutaneously.
  • azacitidine is administered intravenously.
  • azacitidine is administered at a dose of about 75 mg/m 2 .
  • azacitidine is administered subcutaneously at a dose of about 75 mg/m 2 .
  • azacitidine is administered intravenously at a dose of about 75 mg/m 2 . In one embodiment azacitidine is administered at a dose of about 75 mg/m 2 of body surface area.
  • azacitidine is administered subcutaneously at a dose of about 75 mg/m 2 of body surface area.
  • azacitidine is administered intravenously at a dose of about 75 mg/m 2 of body surface area.
  • the methods and combination therapies of the present invention may additionally comprise administering further therapeutic agents suitable for treating hematological malignancies, which amounts are together effective in treating said malignancy.
  • the further therapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti hormones, androgen deprivation therapy and anti-androgens.
  • the further therapeutic agent is a FLT3 inhibitor.
  • the further therapeutic agent is midostaurin (available as, for example, RydaptTM).
  • midostaurin is administered orally.
  • midostaurin is administered daily.
  • midostaurin is administered orally on a continuous daily dosing schedule.
  • midostaurin is administered orally at a dose of about 50mg per day, midostaurin free base or midostaurin free base equivalent.
  • midostaurin is administered in a solid dosage form.
  • midostaurin is administered in a solid dosage form, which solid dosage form is formulated as a capsule.
  • midostaurin is administered daily, which daily dose is sub-divided.
  • midostaurin is administered daily at a dose of about 50mg per day midostaurin free base or midostaurin free base equivalent, which dose is sub-divided into two doses, each dose comprising about 25mg midostaurin free base or midostaurin free base equivalent.
  • the further therapeutic agent is gilteritinib (available as, form example, XospataTM).
  • gilteritinib is administered orally.
  • gilteritinib is administered daily.
  • gilteritinib is administered orally on a continuous daily dosing schedule.
  • gilteritinib is administered orally at a dose of about 120mg per day, gilteritinib free base or gilteritinib free base equivalent.
  • gilteritinib is administered in a solid dosage form.
  • gilteritinib is administered in a solid dosage form, which solid dosage form is formulated as a tablet.
  • gilteritinib is administered daily, which daily dose is sub-divided. In one embodiment, gilteritinib is administered daily at a dose of about 120mg per day gilteritinib free base or gilteritinib free base equivalent, which dose is sub-divided into three doses each comprising about 40mg gilteritinib free base or gilteritinib free base equivalent. In one embodiment, gilteritnib is administered as gilteritinib fumarate. In one embodiment, gilteritinib is administered as a solid dosage form comprising gilteritinib fumarate. In one embodiment, gilteritinib is administered as a solid dosage form, which solid dosage form is a tablet comprising gilteritinib fumarate.
  • the further therapeutic agent is quizartinib, or a pharmaceutically acceptable salt thereof. In one embodiment, the further therapeutic agent is quizartinib.
  • the further therapeutic agent is sorafenib, or a pharmaceutically acceptable salt thereof. In one embodiment, the further therapeutic agent is sorafenib.
  • the further therapeutic agent is sunitinib or a pharmaceutically acceptable salt thereof. In one embodiment, the further therapeutic agent is sunitinib.
  • the therapeutic agents of the combination therapies of the present invention may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the present invention relates to a kit which comprises a first container, a second container and a package insert, wherein the first container comprises at least one dose of a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, the second container comprises at least one dose of azacitidine, and the package insert comprises instructions for treating a patient with acute myeloid leukemia, wherein said patient is positive for at least one mutation of the FLT3 gene using the medicaments.
  • the present invention relates to a kit which comprises a first container, a second container and a package insert, wherein the first container comprises at least one dose of glasdegib, or a pharmaceutically acceptable salt thereof, the second container comprises at least one dose of azacitidine, and the package insert comprises instructions for treating for treating a patient with acute myeloid leukemia, wherein said patient is positive for at least one mutation of the FLT3 gene using the medicaments.
  • the kit of the present invention may comprise one or both of the active agents in the form of a pharmaceutical composition, which pharmaceutical composition comprises an active agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the kit may contain means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit may be particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically includes directions for administration and may be provided with a memory aid.
  • the kit may further comprise other materials that may be useful in administering the medicaments, such as diluents, filters, IV bags and lines, needles and syringes, and the like.
  • Example 1 A combination study of PF-04449913 (glasdegib) and azacitidine in untreated MDS, AML and CMML Patients (Bright 1012)
  • Phase 1 b study was designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of glasdegib (PF- 04449913) combined with azacitidine in newly diagnosed patients with Acute Myeloid Leukemia (AML), Higher Risk Myelodysplastic Syndrome (MDS), or Chronic Myelomonocytic Leukemia (CMML) who were not candidates for intensive induction chemotherapy (ClinicalTrials.gov reference NCT02367456, the contents of which are incorporated herein by reference in their entirety).
  • This clinical study included two cohorts: (a) a lead in safety cohort (LIC) and (b) an expansion phase with an AML cohort and an MDS (including CMML) cohort.
  • LIC lead in safety cohort
  • MDS including CMML
  • CR rate defined as percentage of patients achieving CR as defined by modified IWG criteria (2006) for MDS;
  • CR rate defined as percentage of patients achieving CR as defined by ELN (2017) for AML;
  • MDS expansion cohort [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by modified IWG criteria (2006) (MDS expansion cohort);
  • MDS expansion cohort [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by modified IWG criteria (2006);
  • MDS expansion cohort [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by modified IWG criteria (2006);
  • AML expansion cohort [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by ELN criteria (2017); - complete remission with partial hematologic recovery (AML expansion cohort)
  • CRh is defined as CR but with absolute neutrophil count >500/uL, platelets >50,000/uL, and not qualifying for CR;
  • AML expansion cohort [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by ELN criteria (2017);
  • AML expansion cohort [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by ELN criteria (2017);
  • duration of CR defined as duration from date of first achieving CR to date of disease progression after CR, or death due to any cause, whichever occurs first CR (expansion cohorts) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - duration from date of first dose of study drug to date of CR; and
  • the 100mg glasdegib daily dose could be temporarily interrupted or reduced to 50 mg to manage toxicity (see Table 1). Dose re-escalations were not permitted. Azacitidine dose modifications were permitted in line with the prescribing information. If one drug was permanently discontinued for reasons other than disease progression or withdrawal of consent, the other treatment could be continued at the investigator’s discretion.
  • Non-hematologic toxicities excluding QTc prolongation, muscle spasms, and myalgia
  • glasdegib may be reduced below 50 mg once daily following sponsor approval.
  • MDS patients Patients aged 18 years of older who had previously untreated MDS, AML or CMML according to the WHO 2016 classification. AML patients had de novo or secondary AML. MDS patients must have Intermediate risk (>3 to 4.5 points), high risk (>4.5 to 6 points) or very high risk (>6 points) disease according to the Revised International prognostic Scoring System 2012 (IPSS-R) or CMML. Patients should also have clinical indication for treatment with azacitidine for MDS or AML.
  • IPS-R Revised International prognostic Scoring System 2012
  • samples for bone marrow evaluation were collected at screening, on Day 1 of Cycle 4, on Day 1 of every third cycle thereafter, at end of treatment, and at the investigator’s discretion ( ⁇ 7 days of nominal time).
  • samples for bone marrow evaluation were collected at screening, Cycle 7 Day 1, Cycle 13 Day 1, on Day 1 every 12 cycles thereafter, and at the investigator’s discretion if CR was suspected.
  • Time to response was calcuated as the time from the first dose of study drug to the first date of any improvement in disease status; duration of response was calculated as the time from the first date of improvement in diesase status to the investigator-reported date of progressive disease.
  • improved disease was defined as an increase from baseline in platelets (if ⁇ 100x10 9 /L at baseline) without transfusions or neutrophils (if ⁇ 1x10 9 /L at baseline) and/or a decrease from baseline in peripheral blood blasts or bone marrow blasts.
  • improved disease was defined as an increase from baseline in hemoglobin (if ⁇ 11 g/dL at baseline) without transfusions or platelets (if ⁇ 100x10 9 / L at baseline) without transfusions or neutrophils (if ⁇ 1x10 9 / L at baseline) and/or a decrease from baseline in peripheral blood blasts or bone marrow blasts.
  • glasdegib treatment started on Cycle 1 Day 2 to permit drug-drug interaction evaluation.
  • a continuous Cox Proportional-Hazards model using overall survival on AML patients was run using gene expression pathway scores from either the HALLMARK pathway gene sets from msigDB or the immune gene sets obtained from REGEV (Jerby-Arnon Let at. “A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.” Cell. 2018;175(4):984-997 e924, the contents of which are incoprorated herein by reference in their entirety).
  • Gene expression data was converted to z-scores.
  • Pathway scores were calculated as the mean of the z-score of the genes in each pathway gene set. Pathways associated with worse OS has negative log2(HR) while pathways with positive log2(HR) scores are associated with better OS.
  • the median (range) age was 72 (59-89), 74 (56-87), and 72 years (55-89); 58.3%, 60.0%, and 80.0% of patients were male.
  • Patient demographic and baseline characteristics are summarized in Table 2 below.
  • AML acute myeloid leukemia
  • ANC absolute neutrophil count
  • BM bone marrow
  • CMML chronic myelomonocytic leukemia
  • ELN European LeukemiaNet
  • IPSS-R Revised International Prognostic Scoring System
  • MDS myelodysplastic syndromes
  • N/A not applicable
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndromes
  • N/A not applicable
  • AE acute myeloid leukemia
  • MDS myelodysplastic syndromes
  • TEAE treatment-emergent adverse event
  • TEAEs The most frequently (>30%) reported TEAEs were predominantly gastrointestinal, hematologic, and Hh-inhibitor class effects (eg, muscle spasms, dysgeusia, alopecia, weight loss) (Table 5).
  • Electrocardiogram QT 1 (8.3) 0 0 5 (41.7) prolonged
  • Rhinorrhea 0 0 0 4 (33.3)
  • Urinary tract infection 1 (8.3) 0 0 3 (25.0)
  • the median (range) treatment duration was 5.0 months (0.3-20.2) and 4.7 months (0.4-16.4); the median (range) dose of glasdegib and azacitidine was 5 cycles (1-19) and 5 cycles (1-16).
  • Any grade all-causality TEAEs occurred in 100% (maximum Grade 3/4, 66.7%) of patients in the AML cohort and 100% (maximum Grade 3/4, 80.0%) of patients in the MDS cohort (Tables 6, 7 and 8).
  • AE acute myeloid leukemia
  • MDS myelodysplastic syndromes
  • TEAE treatment-emergent adverse event
  • Diarrhea 2 (6.7) 0 0 16 (53.3)
  • Electrocardiogram QT 2 (6.7) 1 (3.3) 0 6 (20.0) prolonged
  • AE acute event
  • AML acute myeloid leukemia
  • TEAE treatment-emergent adverse event
  • AE acute event
  • MDS myeloid dysplastic syndrome
  • TEAE treatment-emergent adverse event
  • the overall response rate was 30.0% in the AML cohort (defined as CR + CRi + PR), and 33.3% in the MDS cohort (defined as CR + PR + hematologic improvement).
  • An additional 3.3% of patients in the AML cohort achieved a morphologic leukemia-free state, and 15.7% of patients in the MDS cohort achieved a marrow CR.
  • Best overall response with other outcomes of interest for patients in the AML and MDS cohorts are summarized in Table 9. Table 9
  • Treatment failure 1 (3.3) 1 (9.1) 0 0
  • CR complete remission
  • CRi complete remission with incomplete hematologic response
  • HI hematologic improvement
  • mCR marrow complete remission
  • MLFS morphologic leukemia-free state
  • PD progressive disease
  • PR partial remission
  • SD stable disease
  • median (range) time to response was 0.5 months (0.23-3.12) and 0.6 months (0.20-2.69); and median (range) duration of response was 5.2 months (0.03-14.13) and 6.24 months (0.03-21.03).
  • the median OS was 15.8 (95% Cl, 9.3-21.9) months, with a 12-month and 18-month survival probability of 65.6% (95%, Cl, 45.5-79.8) and 39.8% (95%, Cl, 16.5-62.5%) respectively (Figure 2A).
  • the median (95% Cl) OS in patients with intermediate, high and very high IPSS-R genetic risk was 21.9 (NE-NE) months, NE (4.7-NE) months, and 12.1 (0.5-17.5) months, and the number of events (n/N, %) in patients with intermediate, high and very high IPSS-R genetic risk was 1/3 (33.3%), 6/15 (40.0%) and 7/9 (77.8%), respectively (Figure 2B).
  • glasdegib plasma concentration data Thirty patients in the acute myeloid leukemia (AML) cohort provided glasdegib plasma concentration data; 25 and 17 patients were considered dose compliant and provided steady-state plasma concentration measured at the end of a dosing interval (Ctrough) parameter data on Cycle 1 Day 15 and Cycle 2 Day 1, respectively.
  • Ctrough dosing interval
  • glasdegib plasma concentration data 22 and 18 patients were considered dose compliant and provided steady-state Ctrough parameter data on Cycle 1 Day 15 and Cycle 2 Day 1, respectively.
  • the observed glasdegib steady-state Ctrough geometric mean (geometric % CV) value for glasdegib was 308 ng/mL (95%) on Cycle 1 Day 15 and 167 ng/mL (52%) on Cycle 2 Day 1.
  • AML acute myeloid leukemia
  • CI confidence interval
  • HR hazard ratio
  • AML acute myeloid leukemia
  • BM bone marrow
  • CR+ complete remission-positive
  • CR- complete remission-negative
  • ELN European LeukemiaNet
  • MRD+ minimal residual disease-positive
  • MRD- minimal residual disease-negative
  • PD progressive disease
  • SD stable disease
  • NPIPB11 4 5.9 17.5 (7.2-21.9) 5.01
  • AML acute myeloid leukemia
  • CR complete remission
  • MDS myelodysplastic syndromes.
  • VAF variant allele frequency Mutations in all of the genes that displayed a >3-fold decrease or increase in VAF when patients achieved CR and when they subsequently relapsed (i.e. bone marrow blast >5%) are shown in Figure 5 and Figure 6.
  • AML patient #6 and MDS patient #3 While mutations detected at baseline were frequently cleared at CR, not all mutations were cleared and in two patients none of the genes associated with AML/MDS or the Hh signaling pathway were cleared (AML patient #6 and MDS patient #3).
  • AML patient #6 only had 24 genes with mutations that changed >3-fold VAF at CR, and of these, the VAF’s of only 8 mutations were decreased.
  • MDS patient #3 only had 1 gene with a VAF that changed at CR, and only 8 genes that showed a decrease in their VAF.
  • the VAFs of BCOR, NUMA, and U2AF1 all decreased at CR, but were still detectable.
  • Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (non-intensive AML population).
  • AML acute myeloid leukemia
  • Glasdegib is being studies in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML).
  • MD Anderson Symptom Inventory measured by the MD Anderson Symptom Inventory (MDASI)- AML/MDS questionnaire [Time Frame: 5 years after last subject randomized, consent withdrawal, or death] - scale is from 0-10 where 0 is not present and 10 is as bad as you can image
  • CR Complete Remission
  • MRD minimal residual disease
  • EPN European LeukemiaNet
  • MLFS morphological leukemia-free state
  • EPN European LeukemiaNet
  • This study is a randomized (1:1), double-blind, multi-center, placebo controlled study of chemotherapy in combination with glasdegib versus chemotherapy in combination with placebo in adult patients with previously untreated AML.
  • Experimental Arm A (glasdegib + azacitidine) - azacitidine 75 mg/m 2 SC or IV daily for 7 days in 28 day cycles for as long as the patient does not meet the criteria for disease progression, unacceptable toxiciity, consent withdrawal or death; glasdegib 100 mg PO QD is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays / modifications in the chemotherapy treatment. Subjects will continue glasdegib until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.
  • Placebo Comparator Arm B placebo + azacitidine
  • Placebo azacitidine 75 mg/m 2 SC or IV daily for 7 days in 28 day cycles for as long as the patient does not meet the criteria for disease progression, unacceptable toxicity, consent withdrawal or death; matching placebo is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays / modifications in the chemotherapy treatment. Subjects will continue placebo until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.
  • Glasdegib is also being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).
  • Experimental Arm A (glasdegib + 7+3’ inductions) - 7+3’ (cytarabine 100 mg/m 2 , IV for 7 days by continuous infusion and daunorubicin 60 mg/m 2 for 3 days), if a second induction is needed
  • Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days (‘5+2’) or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days (7+3’); consolidation with single agent cytarabine 3 g/m 2 IV for adults ⁇ 60 years and 1 g/m 2 for adults 60 years over 3 BID on Days 1 , 3 and 5, every 28 days for up to 4 cycles of alternative single agent cytarabine consolidation schedules may be used per local prescribing information; daily glasdegib (100 mg, PO) beginning on Day 1 and is to continue up to 2 years post randomization, following consolidation therapy, glasdegib or placebo will be administered
  • Placebo Comparator Arm B placebo + 7+3’ inductions
  • Placebo Comparator Arm B placebo + 7+3’ inductions
  • Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days (‘5+2’) or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days (7+3’); consolidation with single agent cytarabine 3g/m 2 IV for adults ⁇ 60 years and 1g/m 2 for adults 60 years over 3 BID on Days 1 , 3 and 5, every 28 days for up to 4 cycles of alternative single agent cytarabine consolidation schedules may be used per local prescribing information; matching placebo (PO) given on Day 1 and is to continue up to 2 years post randomization, following consolidation therapy, placebo will be administered daily for up to 2 years after randomization
  • Inclusion criteria subjects must meet all of the following inclusion criteria to be eligible for enrollment into the Intensive and Non Intensive study (unless where indicated):
  • WHO 2016 Classification2 including those with: o AML arising from MDS or another antecedent hematologic disease (AHD). o AML after previous cytotoxic therapy or radiation (secondary AML).
  • Adequate Organ Function as defined by the following: o Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) 3 x upper limit of normal (ULN), excluding subjects with liver function abnormalities due to underlying malignancy. o Total serum bilirubin 2 x ULN (except subjects with documented Gilbert's syndrome). o Estimated creatinine clearance 30 mL/min as calculated using the standard method for the institution.
  • All anti cancer treatments should be discontinued 2 weeks from study entry, for example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines.
  • All trans retinoic acid (ATRA), hydroxyurea, and/or leukopheresis may be used before and for up to 1 week after the first dose of glasdegib.
  • Serum or urine pregnancy test (for female subjects of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (hCG) negative at screening.
  • hCG human chorionic gonadotropin
  • Female subjects of non childbearing potential must meet at least 1 of the following criteria: a. Flave undergone a documented hysterectomy and/or bilateral oophorectomy; b. Flave medically confirmed ovarian failure; or c. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSFH) level confirming the postmenopausal state.
  • FSFH serum follicle stimulating hormone
  • APL Acute Promyelocytic Leukemia
  • APLwith PML RARA subjects (WHO 2016 classification).
  • Complex genetics may include t(9;22) cytogenetic translocation.
  • LVEF left ventricular ejection fraction

Abstract

This invention relates to therapies useful for the treatment of hematological malignancies. In particular the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby treating said acute myeloid leukemia. The invention also relates to associated combination therapies, pharmaceutical compositions, pharmaceutical uses and kits.

Description

TREATMENT OF HEMATOLOGICAL MALIGNANCY
Field of the Invention
This invention relates to methods for the treatment and selection of patients having a hematological malignancy, particularly acute myeloid leukemia (AML), who may benefit from administration of a smoothened (SMO) inhibitor, or a pharmaceutically acceptable salt thereof, optionally glasdegib, or a pharmaceutically acceptable salt thereof, more particularly who may benefit from administration of a smoothened (SMO) inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, such as a hypomethylating agent, for example azacitidine.
Background of the Invention
Acute myeloid leukemia (AML) in older adults, and higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), are widely recognized to be diagnoses associated with eventual resistance to therapy and severe truncation of life (Rollinson D.E. et al., Epidemiology of myelodysplastic syndromes and chorinci myeloproliferative disorders in the United States, 2001-2004, using data from the NAACR and SEER programs. Blood. 2008, 112(1 ):45-52; Thein M.S. et al., Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades. Cancer. 2013, 119(15): 2720-2727, the contents of each of which are incorporated herein by reference in their entirety). As the typical age at diagnosis for these disorders is 65-75 years, and in patients who frequently have comorbidities, less intensive treatment approaches are commonly adopted, most typically involving hypomethylating agents or low-dose cytarabine (LDAC) (Cortes J.E., et al., Determination of fitness and therapeutic options in older patients with acute myeloid leukemia. Am J Hematol. 2021 ;96(4):493-507; Sekeres M.A., et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv. 2020;4(15):3528-3549; Sekeres MA, et al. How we treat higher-risk myelodysplastic syndromes. Blood. 2014;123(6):829-836; Bewersdorf JP, et al. Risk-adapted, individualized treatment strategies of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Cancers (Basel). 2021 ; 13(7): 1610, the contents of each of which are incoprorated herein by reference in their entirety).
The smoothened receptor (SMO), a component of the hedgehog (Hh) signaling pathway is a potential therapeutic target in a number of human cancers, including hematologic malignancies for example acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), myelofibrosis (MF) and myelodysplastic syndrome (MDS). The hedgehog (Hh) signaling pathway is aberrantly activated in AML and MDS promoting leukemic stem cell maintenance (Campbell et al., Stem Cell Cloning (2015); 8:27-38, the contents of which are incorporated herein by reference in their entirety). Inhibition of Hh signaling has been shown to reduce leukemic stem cell growth and increase sensitivity to chemotherapy (Fukushima et al., Cancer Sci (2016); 107: 1422-1429, the contents of which are incorporated herein by reference in their entirety). Hedgehog pathway inhibitors are emerging as a new therapeutic class for the treatment of acute myeloid leukemia (Jamieson C, et al., Hedgehog pathway inhibitors: a new therapeutic class for the treatment of acute myeloid leukemia. Blood Cancer Discovery 2020; 1(2): 134-145 the contents of which are incorporated herein by reference in their entirety).
The compound 1 -((2F?,4F?)-2-(1 /-/-benzo[d]imidazol-2-yl)-1 -methylpiperidin-4-yl)- 3-(4-cyanophenyl)urea (also known as PF-04449913) has been assigned the International Nonproprietary Name (INN) glasdegib {WHO Drug Information, Vol. 29, No. 1, page 89 (2015), referencing the alternative chemical name A/-[(2F?,4F?)-2-(1/-/- benzoimidazol-2-yl)-1-methylpiperidin-4-yl]-/V-(4-cyanophenyl)urea, the contents of which are incorporated herein by reference in their entirety). It is an orally available, small molecule inhibitor of the Hh pathway component Smoothened (SMO), and is also referred to as a smoothened inhibitor.
Preparation of glasdegib and pharmaceutically acceptable salts thereof, is described in International Patent Application No. PCT/IB2008/001575, which published as WO 2009/004427 on 8th January 2009, and in United States Patent Nos. 8,148,401 and 8,431,597, the contents of each of which are incorporated herein by reference in their entirety. The discovery of glasdegib has been described by Munchhof et al. {Med. Chem., Lett, 2012, 3:106-111, the contents of which are incorporated herein by reference in their entirety). A process for the asymmetric synthesis of glasdegib has been described by Peng et al. {Org. Lett., 2014, 16:860-863, the contents of which are incorporated herein by reference in their entirety). The monomaleate salt of 1-((2R,4R)-2-(1/-/-benzo[d]imidazol-2-yl)-1- methylpiperidin-4-yl)-3-(4-cyanophenyl)urea, which may also be referred to as 1- ((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate or glasdegib maleate, has the structure of Formula (I):
Figure imgf000004_0001
The maleate salt, and methods of its preparation are described in International Patent Application No. PCT/IB2016/052107, which published as WO 2016/170451 on 27th October 2016, the contents of which are incorporated herein by reference in their entirety.
DAURISMO™ (glasdegib), is indicated, in combination with low dose cytarabine (LDAC), for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are > 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy (United States Prescribing Information, 2018, New York, Pfizer Inc., the contents of which are incorporated herein by reference in their entirety).
The efficacy of glasdegib was evaluated in a phase 1 b/2 study which included patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) (ClinicalTrials.gov reference NCT01546038, the contents of which are incorporated herein by reference in their entirety, BRIGHT AML & MDS 1003 study). The study included a randomized Phase 2 study arm in which the efficacy of glasdegib plus low dose cytarabine (LDAC) was evaluated in patients ineligible for intensive chemotherapy. Patients (stratified by cytogenic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight (88) and forty-four (44) patients were randomized to receive glasdegib/LDAC or LDAC, respectively. Median (80% confidence interval [Cl]) overall survival was 8.8 (6.9-9.9) months with glasdegib/LDAC and 4.9 (3.5-6.0) months with LDAC (hazard ratio, 0.51; 80% Cl, 0.39-0.67, P=0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. In summary, the addition of glasdegib to LDAC demonstrated superior overall survival (OS) vs LDAC alone and was well tolerated. The results from this trial were reported in more detail in Cortes et al., “Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome”, Leukemia (2019), 33 (2): 379-389, the contents of which are incorporated herein by reference in their entirety. The study also included a nonrandom ized Phase 2 study arm in which the efficacy of glasdegib plus intensive chemotherapy (cytarabine + daunorubicin on a 7+3 schedule) was evaluated in patients eligible for intensive chemotherapy. The results from this arm were reported in more detail in Cortes et al., “Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study Results”, Am. J. Hematol., (2018), 93: 1301-1310, the contents of which are incorporated herein by reference in their entirety.
Insights into biomarkers in patients with acute myeloid leukemia receiving glasdegib in combination with either intensive or non-intensive chemotherapy have been reported (Merchant A, et al. “Biomarkers Correlating with overall survival (OS) and response to glasdegib and intensive or non-intensive chemotherapy in patients with acute myeloid leukemia (AML)”, Cancer Research., 2019, 79 (13 Suppl): Abstract nr LB-009, the contents of which are incorporated herein by reference in their entirety). The authors conclusions included that expression levels of a select number of biomarkers implicated in AML appeared to correlate with overall survival (OS) and / or overall response (OR) in the non-intensive and intensive arms; that the different observations seen in the intensive and non-intensive arms may reflect underlying biologic differences in the biomarkers that correlate with response to each combination; and that the improved response with FLT3 mutations and high PTCH1 expression levels in the intensive arm, along with the analysis appearing to indicate modulation of select genes and cytokines in both arms while on treatment, deserve further investigation.
In addition to LDAC, the hypomethylating agents decitabine and azacitidine are used to treat patients with AML and higher-risk MDS who are deemed ineligible for intensive chemotherapy (Sabattini E, et al., “WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview” Pathologica. 2010;102(3):83-7, the contents of which are incorporated herein by reference in their entirety). For example, in a phase 3 trial investigating the effects of azacitidine monotherapy in patients with AML the median overall survival for azacitidine was 10.4 months and the rate of complete remission (CR) was 19.5% after a median follow up of 24 months (Dombret H, et at. “International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts.” Blood (2015) 126:291-299, the contents of which are incorporated herein by reference in their entirety). In a study of azacitidine in patients with higher-risk MDS and CMML, the overall response rate (CR + partial remission + hematologic improvement) was 38.0% and the median overall survival (OS) was 15 months after a median follow-up of 23 months (Sekeres M.A., et at. “Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia, North American Intergroup Study SWOG S1117.” J. Clin Oncol. 2017; 35 (24): 2745-53, the contents of which are incorporated herein by reference in their entirety). However, an attempt to improve efficacy with combination therapy resulted in Cycle 2 dose delays due to cytopenic complications as frequently as 33% of the time (DiNardo C. D., etal., Blood (2019) 133: 7-17, the contents of which are incorporated herein by reference in their entirety).
A previous study in patients with AML demonstrated that the expression of GLI2, a signaling component of the Hh signaling pathway, was increased in the bone marrow of patients with FLT3- ITD mutations versus those with wild-type FLT3 (Lim Y, et at., “Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.” Sci. Transl Med. 2015, 7(291): 291ra96, the contents of which are incorporated herein by reference in their entirety). Targeting the hedgehog signaling pathway in acute myeloid leukemia with FLT3 mutation has also been discussed (Bouscary D., “Rational for targeting the hedgehog signaling pathway in acute myeloid leukemia with FLT3 mutation.” Ann Transl Med 2016 Oct; 4(Suppl 1): S53, the contents of which are incorporated herein by reference in their entirety).
There remains a need for further therapies for the treatment of hematologic malignancies, including acute myeloid leukemia and also a need to identify patient sub populations who may benefit from such therapies. There is also a need to identify strategies which may be useful to predict whether an individual patient will be responsive in advance of therapy, methods for identifying such patients and the like. Summary of the Invention
In one aspect the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In one aspect the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In one aspect the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In one aspect the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby treating said acute myeloid leukemia.
In another aspect, the invention relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
In another aspect, the invention relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
In another aspect, the invention relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
In another aspect, the invention relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby increasing the overall survival of the patient.
A method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
A method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
A method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
A method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby treating said acute myeloid leukemia. A method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
A method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
A method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
A method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine if the biological sample is positive for at least one mutation of the FLT3 gene.
A method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
A method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic, or a pharmaceutically acceptable salt thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
A method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
A method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, if the biological sample is positive for at least one mutation of the FLT3 gene.
In a preferred embodiment of the inventions described, the patient is a human.
In a preferred embodiment of the inventions described, the patient is ineligible for first line treatment with standard induction chemotherapy.
In a preferred embodiment of the inventions described, the patient is eligible for first line treatment with standard induction chemotherapy.
In a preferred embodiment of the inventions described, the patient is aged at least 75 years old.
In a preferred embodiment of the inventions described, the patient has no known active central nervous system (CNS) leukemia.
In a preferred embodiment of the inventions described, the patient has received no prior treatment with a smoothened inhibitor.
In a preferred embodiment of the inventions described, the patient has received no prior treatment with a hypomethylating agent.
In a preferred embodiment of the inventions described, the patient has received no prior treatment with a FLT3 inhibitor.
In a preferred embodiment of the inventions described, the acute myeloid leukemia is newly diagnosed.
In a preferred embodiment of the inventions described, the acute myeloid leukemia is de novo acute myeloid leukemia. In a preferred embodiment of the inventions described, the acute myeloid leukemia is secondary acute myeloid leukemia.
In a preferred embodiment of the inventions described, the acute myeloid leukemia is previously untreated.
In a preferred embodiment of the inventions described, the patient has been previously determined to be positive for at least one mutation of the FLT3 gene.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene is selected from the group consisting of an insertion, a point mutation, an internal tandem duplication mutation, and combinations thereof.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene is a point mutation, which point mutation is in the tyrosine kinase domain of the FLT3 gene.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene is a point mutation, which point mutation is selected from the group consisting of a point mutation at codon D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation at codon 1836 in the tyrosine kinase domain of the FLT3 gene, and combinations thereof.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene is an internal tandem duplication (ITD) mutation.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene is selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605- P606ins12), ITD(E598-Y599ins5 E589-F590ins12) and combinations thereof.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation D835Y.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation K565E.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation Q575R.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation D835FI.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation D839G. In a preferred embodiment of the inventions described, the at least one mutation of the FL 73 gene comprises mutation V491 L.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation V194M.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation N841 Y.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation N676S.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation A680V.
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation ITD(F605-P606ins12).
In a preferred embodiment of the inventions described, the at least one mutation of the FLT3 gene comprises mutation ITD(E598-Y599ins5 E589-F590ins12).
In a preferred embodiment of the inventions described, the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the inventions described, the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally.
In a preferred embodiment of the inventions described, the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered daily.
In a preferred embodiment of the inventions described, the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally on a continuous daily dosage schedule.
In a preferred embodiment of the inventions described, the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally at a dose of about 100 mg per day, glasdegib free base equivalent.
In a preferred embodiment of the inventions described, the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally as glasdegib maleate, at a does of about 131 mg glasdegib maleate per day. In a preferred embodiment of the inventions described, the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally in a solid dosage form.
In a preferred embodiment of the inventions described, the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, wherein the glasdegib, or pharmaceutically acceptable salt thereof is administered orally in a solid dosage form, which solid dosage form is formulated as a tablet.
In a preferred embodiment of the inventions described, the further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, is a hypomethylating agent, or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the inventions described, the further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, is a hypomethylating agent, or a pharmaceutically acceptable salt thereof, which hypomethylating agent is azacitidine.
In a preferred embodiment of the inventions described, the hypomethylating agent, or a pharmaceutically acceptable salt thereof, is azacitidine.
In a preferred embodiment of the inventions described, azacitidine is administered subcutaneously.
In a preferred embodiment of the inventions described, azacitidine is administered intravenously.
In a preferred embodiment of the inventions described, azacitidine is administered on a 28-day cycle.
In a preferred embodiment of the inventions described, azacitidine is administered on a 28-day cycle and for more than one 28-day cycle.
In a preferred embodiment of the inventions described, azacitidine is administered on a 28-day cycle and for at least 428-day cycles.
In a preferred embodiment of the inventions described, azacitidine is administered on a 28-day cycle and for at least 628-day cycles.
In a preferred embodiment of the inventions described, azacitidine is administered on days 1 to 7 of a 28-day cycle.
In a preferred embodiment of the inventions described, azacitidine is administered on days 1 to 7 of a 28-day cycle and for more than one 28-day cycle.
In a preferred embodiment of the inventions described, azacitidine is administered on days 1 to 7 of a 28-day cycle and for at least 428-day cycles. In a preferred embodiment of the inventions described, azacitidine is administered on days 1 to 7 of a 28-day cycle and for at least 628-day cycles.
In a preferred embodiment of the inventions described, azacitidine is administered at a dose of about 75 mg/m2.
In a preferred embodiment of the inventions described, azacitidine is administered at a dose of about 75 mg/m2 on days 1 to 7 of a 28-day cycle and for at least 1 28-day cycle.
In a preferred embodiment of the inventions described, azacitidine is administered at a dose of about 75 mg/m2 on days 1 to 7 of a 28-day cycle and for at least 428-day cycles.
In a preferred embodiment of the inventions described, azacitidine is administered at a dose of about 75 mg/m2 on days 1 to 7 of a 28-day cycle and for at least 628-day cycles.
In a preferred embodiment of the inventions described, azacitidine is administered at a dose of about 75 mg/m2 of body surface area.
In a preferred embodiment of the inventions described, azacitidine is administered at a dose of about 75 mg/m2 of body surface area on days 1 to 7 of a 28- day cycle and for at least 1 28-day cycle.
In a preferred embodiment of the inventions described, azacitidine is administered at a dose of about 75 mg/m2 of body surface area on days 1 to 7 of a 28- day cycle and for at least 428-day cycles.
In a preferred embodiment of the inventions described, azacitidine is administered at a dose of about 75 mg/m2 of body surface area on days 1 to 7 of a 28- day cycle and for at least 628-day cycles.
In a preferred embodiment of the inventions described, the thereby treating said acute myeloid leukemia results in an increase in overall survival of said patient.
In a preferred embodiment of the inventions described, the thereby treating said acute myeloid leukemia results in an increase in overall survival of said patient as compared to a control group.
In a preferred embodiment of the inventions described, the thereby treating said acute myeloid leukemia results in an increase in overall survival of said patient as compared to a control group wherein the control group comprises one or more acute myeloid leukemia patients wherein said one or more acute myeloid leukemia patients in the control group are not FLT3 mutant positive. In a preferred embodiment of the inventions described, the biological sample is selected from the group consisting of a blood sample or a bone marrow sample.
In a preferred embodiment of the inventions described, the biological sample is a blood sample.
In a preferred embodiment of the inventions described, the biological sample is a bone marrow sample.
Each of the embodiments of the inventions described may be combined with one or more other embodiments of the inventions which is not inconsistent with the embodiment(s) with which it is combined. In addition, each of the embodiments describing the inventions envisions within its scope the pharmaceutically acceptable salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof of the compounds described for use in the methods or treatments described therein. Accordingly, the phrase “or a pharmaceutically acceptable salt thereof is implicit in the description of all compounds described herein.
Brief Description of the Drawings
Figure 1 is a Kaplan-Meier plot illustrating the estimated overall survival (OS) in the AML expansion cohort (A-B) from Example 1.
Figure 2 is a Kaplan-Meier plot illustrating the estimated overall survival (OS) in the MDS expansion cohort (A-B) from Example 1.
Figure 3 illustrates the baseline mutations occuring in >10% of patients with AML and MDS from Example 1.
Figure 4 is a Kaplan-Meier plot illustrating the correlation of FLT3 biomarker with overall survival in patients with AML and the correlation of TP53 biomarker with overall survival in patients with MDS from Example 1.
Figure 5 illustrates the gene mutations with >3-fold decrease in VAF at CR (or better) compared to baseline in 6 patients with AML from Example 1.
Figure 6 illustrates the gene mutations with with >3-fold decrease in VAF at CR (or better) compared to baseline in 3 patients with MDS from Example 1.
Figure 7 illustrates the variant allele fraction of key AML and Hh pathway genes in 3 patients with AML who experienced a CR and subsequently relapsed (increase in the percentage of bone marrow blast following CR) from Example 1. Detailed Description of the Invention
The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.
As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.
The term “about” when used to modify a numerically defined parameter (e.g., the dose of a smoothened inhibitor, the dose of azacitidine and the like) means that the parameter may vary by as much as 10% above or below the stated numerical value for that parameter (±10%). For example a dose of about 5 mg/kg should be understood to mean that the dose may vary between 4.5 mg/kg and 5.5 mg/kg.
The term “patient” or “subject” refers to any single subject for which therapy is desired or that is participating in a clinical trial, epidemiological study or used as a control, including humans and mammalian veterinary patients such as cattle, horses, dogs and cats. In certain preferred embodiments, the patient or subject is a human.
The terms “diagnosing” or “diagnosis” and “prognosticating” or “prognosis," as used herein, are used in the broadest sense, and are commonly used and are well- understood in medical and clinical practice. As used herein, the term “diagnosing” or “diagnosis” refers to a clinical or other assessment of the condition of a subject based on observation, testing, or circumstances for identifying a subject having a disease, disorder, or condition based on the presence of at least one sign or symptom of the disease, disorder, or condition. Typically, diagnosing using the method of the invention includes the observation of the subject for other signs or symptoms of the disease, disorder, or condition in addition to detection of a mutation of a gene, such as, but not limited to, a loss-of-function mutation, that makes the subject susceptible to a particular disease or condition or treatment. As used herein, the term “prognosticating” or “prognosis” refers to the determination of probability, risk or possibility of developing a disease, disorder, or condition, such as cancer, in a subject.
The term “treat” or “treating” a hematological malignancy as used herein means to administer a therapy according to the present invention to a subject or patient having hematological malignancy, or diagnosed with hematological malignancy, to achieve at least one positive therapeutic effect, such as, for example, complete response, complete remission, partial response, partial remission, improved overall survival, improved overall response, hematologic improvement, marrow complete response, marrow complete remission, complete remission with incomplete hematologic recovery, complete remission with partial hematologic recovery, morphologic leukemia free state, partial remission, partial cytogenetic response, complete cytogenic response, cytogenic complete response, stable disease, transfusion independence, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, and the like. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term “treating” also includes adjuvant and neo adjuvant treatment of a subject. The treatment regimen for a combination of the invention that is effective to treat a subject may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the invention may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi2-test the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrat- testy and the Wilcon on-test. The term “treatment” also encompasses in vitro and ex vivo treatment, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
The terms “treatment regimen”, “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in the invention.
The term “treating” may also encompass the term “ameliorating” which, as used herein, means a lessening or improvement of one or more symptoms as compared to not administering a therapeutic agent of a method or regimen of the invention. “Ameliorating” also includes shortening or reduction in duration of a symptom.
A “control population” or “control group”, used interchangeably herein, refers to a population of individuals who are matched to the subject but who differ in some aspect, such as disease state. For example, a control group may be matched to the subject by diagnosis and treatment regimen but may differ in disease state. As an alternative example, a control group may be matched to the subject by diagnosis and treatment regimen, but may have a different disease profile, for example a different mutation status. The skilled person will be able to select an appropriate control population to provide the requisite reference value.
As used herein, the terms "objective response" and “overall response”, unless otherwise defined, refer to a measurable response, including complete response (CR) or partial response (PR). The term "overall response rate" (ORR), unless otherwise defined, refers to the sum of key response parameters such as the complete response (CR) rate and the partial response (PR) rate.
As used herein, the term “overall survival” (OS) means the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. OS is typically measured as the prolongation in life expectancy in patients who receive a certain treatment as compared to patients in a control group (/.e. , taking either another drug or a placebo or having a different disease profile).
As used herein, the term “stable disease” or “SD”, unless otherwise defined, refers to a cancer that is neither decreasing nor increasing in extent or severity.
As used herein, an “effective dosage” or “effective amount” of drug, compound, therapeutic regimen, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired, including biochemical, histological and / or behavioral symptoms, of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, a “therapeutically effective amount” refers to that amount of a drug, compound, therapeutic regimen, or pharmaceutical composition being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. An effective dosage can be administered in one or more administrations. For the purposes of this invention, an effective dosage of drug, compound, therapeutic regimen, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, compound, therapeutic regimen, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.
The terms “therapeutic regimen”, “treatment regimen,” “dosing protocol” and “dosing regimen” may be used interchangeably to refer to the dose and timing of administration of each therapeutic agent administered in a treatment regimen comprising more than one therapeutic agent according to the invention herein.
The term “additive” is used to mean that the result of the combination of two compounds, components or targeted agents is no greater than the sum of each compound, component or targeted agent individually.
The term “synergy” or “synergistic” are used to mean that the result of the combination of two compounds, components or targeted agents is greater than the sum of each compound, component or targeted agent individually. This improvement in the disease, condition or disorder being treated is a “synergistic” effect. A “synergistic amount” is an amount of the combination of the two compounds, components or targeted agents that results in a synergistic effect, as “synergistic” is defined herein.
Determining a synergistic interaction between one or two components, the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different dose ranges, and / or dose ratios to patients in need of treatment. However, the observation of synergy in in vitro models or in vivo models can be predictive of the effect in humans and other species and in vitro models or in vivo models exist, as described herein, to measure a synergistic effect. The results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and the absolute doses and plasma concentrations required in humans and other species such as by the application of pharmacokinetic and / or pharmacodynamics methods.
A “functional assay” is a method to detect the activity of a gene, protein, or cell in response to a stimulus. The specific functional assay performed depends on the specific mutation or mutations incorporated into the genome of the cell. Functional assays include, but are not limited to, kinase assays, transcription assays using, for example, reporter constructs, proliferation assays, apoptosis assays, migration/chemotaxis assays, nutrient sensitivity assay, agent (e.g., drug, chemotherapeutic agent, mutagen) or radiation sensitivity assays, nucleic acid-binding assay or protein-binding assay, all of which are within the ability of those of skill in the art.
As used herein, the term “nucleic acid sequence” (or nucleic acid molecule) refers to a DNA or RNA molecule in single or double stranded form, particularly a DNA encoding a protein or protein fragment according to the invention. An “isolated nucleic acid sequence” refers to a nucleic acid sequence which is no longer in the natural environment from which it was isolated, e.g., the nucleic acid sequence in a bacterial host cell or in the plant nuclear or plastid genome.
As used herein, the term “protein” or “polypeptide” is used interchangeably and refer to molecules consisting of a chain of amino acids, without reference to a specific mode of action, size, 3-dimensional structure or origin. A “fragment” or “portion” of a particular protein may thus still be referred to as a “protein”. An “isolated protein” is used to refer to a protein which is no longer in its natural environment, for example in vitro or in a recombinant bacterial or plant host cell.
As used herein, the term "gene" refers to a nucleic acid sequence that comprises control and coding sequences necessary for the production of a polypeptide or precursor. The polypeptide can be encoded by a full-length coding sequence or by any portion of the coding sequence. It may include regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). A gene may thus comprise several operably linked sequences, such as a promoter, a 5' leader sequence comprising e.g., sequences involved in translation initiation, a (protein) coding region (cDNA or genomic DNA) and a 3' non-translated sequence comprising e.g., transcription termination sites. A gene may contain one or more modifications in either the coding or the untranslated regions which could affect the biological activity or the chemical structure of the expression product, the rate of expression, or the manner of expression control. Such modifications are referred to collectively as mutations. The gene may constitute an uninterrupted coding sequence, or it may include one or more introns, bound by the appropriate splice junctions.
As used herein, a cDNA is a copy of the mRNA which is translated into the protein after splicing and other post-transcriptional processing events.
As used herein, the term “exon” is a nucleic acid sequence that is represented in the mature form of an RNA molecule after a) portions of a precursor RNA, introns, have been removed by cis-splicing or b) two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA or a functional form of a non-coding RNA such as rRNA or tRNA. Depending on the context, exon can refer to the sequence in the DNA or its RNA transcript.
As used herein, “UTR,” which stands for “untranslated region,” refers to either of two sections on each side of a coding sequence on a strand of mRNA. If it is found on the 5' end, it is called the 5' UTR, or if it is found on the 3' end, it is called the 3' UTR. The untranslated regions typically include control regions involved in translation, RNA targeting, and post-transcriptional processing.
As used herein, the term “intron,” derived from the term “intragenic region” and also called intervening sequence (IVS), are DNA regions in a gene that are not translated into proteins. These non-coding sections are present in precursor mRNA (pre-mRNA) and some other RNAs and removed by splicing during the processing to mature RNA. After intron splicing, the mRNA consists only of exons, which are translated into a protein. Mutations present in introns are often silent. However, intronic mutations can result in aberrant or alternative splicing.
As used herein, the term "level of expression" or “expression level” refers to the level of mRNA, as well as pre-mRNA nascent transcript(s), transcript processing intermediates, mature mRNA(s), and degradation products, encoded by a gene in the cell. The phrase "level of expression" also refers to the level of protein or polypeptide in a cell.
As used herein, “expression of a gene” refers to the process wherein a DNA region, which is operably linked to appropriate regulatory regions, particularly a promoter, is transcribed into an RNA, which is biologically active, i.e., which is capable of being translated into a biologically active protein or peptide (or active peptide fragment) or which is active itself (e.g., in posttranscriptional gene silencing or RNAi). The coding sequence may be in sense-orientation and encodes a desired, biologically active protein or peptide, or an active peptide fragment. In gene silencing approaches, the DNA sequence is preferably present in the form of an antisense DNA or an inverted repeat DNA, comprising a short sequence of the target gene in antisense or in sense and antisense orientation (inverted repeat). “Ectopic expression” refers to expression in a tissue in which the gene is normally not expressed.
As used herein, the term "differential expression" refers to both quantitative as well as qualitative differences in the genes' expression patterns depending on differential development and/or tumor growth. Differentially expressed genes may represent "marker genes," and/or "target genes". The expression pattern of a differentially expressed gene disclosed herein may be utilized as part of a prognostic or diagnostic cancer evaluation. Alternatively, a differentially expressed gene disclosed herein may be used in methods for identifying reagents and compounds and uses of these reagents and compounds for the treatment of breast cancer as well as methods of treatment. As used herein, a “reference gene” or “normalization gene” refers to a gene, expression of which remains consistent in individual cells, even under different conditions, as well as among cells from different samples and origins.
As used herein, the term “genome” refers to the total genetic information or hereditary material possessed by an organism (including viruses), i.e., the entire genetic complement of an organism or virus. The genome generally refers to all of the genetic material in an organism's chromosome (s), and in addition, extra chromosomal, genetic information that is stably transmitted to daughter cells (e.g., the mitochondrial genome). A genome can comprise RNA or DNA.
As used herein, “mutation,” “gene comprising a mutation,” “mutant gene”, “mutant positive” or "mutated gene" as used interchangeably herein refers to alterations in one or more nucleic acids in a genomic sequence, compared to the wild type sequence, including, but not limited to, one or more base changes, point mutations, amplifications, deletions, insertions, including multi-nucleotide insertion mutations such as an internal tandem duplication mutations, of one or more nucleotides, and / or substitutions that may result in silent mutations, non-sense mutations, mis-sense mutations, mutations that result in premature stop codons, aberrant splicing, transcription or translation and the like. A “mutant gene” has undergone a change, such as the loss, gain, or exchange of genetic material, such as a change which may affect the normal function and / or expression of the gene. A "disrupted gene" as used herein refers to a mutant gene that has a mutation that causes a premature stop codon. The disrupted gene product is truncated relative to a full-length undisrupted gene product. A gene comprising a mutation can have more than one mutation. As used herein, the term “point mutation” is a genetic mutation where a single nucleotide base is changed, inserted, or deleted from a DNA or RNA sequence. As used herein, the term “positive for at least one mutation”, or “mutant positive” refers to genes that comprise at least one mutation including, but not limited to, a single nucleotide variant, protein altering mutation, a mutant sequence and / or variant sequency, when compared to a primary sequence for example a control sequence or a wild type sequence. Methodology for identifying such mutations are well known to one of ordinary skill in the art.
As used herein, the term "insertion" or “INS” refers to the addition of one or more amino acids in the related protein. As used herein, some mutations are described as “amino acid” “position” ”new_amino_acid”“fs” “*” “position_termination_site”, e.g., (A309Sfs*25) and
A532Pfs*5. As used herein, “fs*” means that a frame-shift results in a stop codon. For example, in A309Sfs*25, “amino_acid” = first amino acid changed = A, “position” = position = 309, “new_amino_acid” = new amino acid = S, “fs” = type of change is a frame shift = fs, “*” = stop codon = *“position_termination_site” = position new termination site = 25. As used herein, “C443*” means amino acid C is changed into a stop codon. A minus sign means the mutation occurs upstream of the translational start site. For example, in “-301 fs,” the mutation occurs upstream of position 301.
As used herein, the term “missense” mutation or “missense variant” refers to a (point) mutation in a nucleic acid sequence encoding a protein, whereby a codon is changed to code for a different amino acid. The resulting protein may have reduced function or loss of function.
The term "locus" is herein defined to be a specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map. Gene mapping is the process of determining the locus for a particular biological trait.
The term "polymorphism" is herein defined to be the occurrence of genetic variations that account for alternative DNA sequences and/or alleles among individuals in a population.
The term "polymorphic site" is herein defined to be a genetic locus wherein one or more particular sequence variations occur. A polymorphic site can be one or more base pairs. For example, a "single nucleotide polymorphism (SNP)" is a polymorphism that occurs at a single nucleotide. As used herein, a "cluster" of SNPs refers to three or more SNPs that occur within 100 kilobases of each other in a particular polymorphic site, wherein all of the SNPs have a p-value e<"4> (i.e. < 1 x 10<"4>).
As used herein, the term “nonsynonymous” refers to mutations that result in changes to the encoded amino acid. As used herein, the term “synonymous” refers to mutations that do not result in changes to the encoded amino acids.
As used herein, the term “somatic mutation” or “somatic variation” refers to a mutation in the DNA of somatic cells (i.e., not germ cells), occurring after conception. “Somatic mutagenesis” therefore refers to the process by which somatic mutations occur. As used herein, “variant sequence” or “mutant sequence” means a nucleotide or amino acid sequence that contains one or more differences with respect to a primary sequence. These differences may include alternative residues, modified residues, deletions, insertions, and substitutions. For example, a “mutant polynucleotide,” “mutant nucleic acid,” “variant nucleic acid,” and “nucleic acid with variant nucleotides,” refers to a polynucleotide which has a nucleotide sequence that is different from the nucleotide sequence of the corresponding wild-type polynucleotide. The difference in the nucleotide sequence of the mutant polynucleotide as compared to the wild-type polynucleotide is referred to as the nucleotide “mutation,” “variant nucleotide,” “nucleotide variants” or “variation.” Deletions may be of a single nucleotide base, a portion or a region of the nucleotide sequence of the gene, or of the entire gene sequence. Insertions may be of one or more nucleotide bases. The variants may occur in transcriptional regulatory regions, untranslated regions of mRNA, exons, introns, or exon/intron junctions. The “variant nucleotide” may or may not result in stop codons, frame shifts, deletions of amino acids, altered gene transcript splice forms or altered amino acid sequence. The term “variant nucleotide” also refers to one or more nucleotide(s) substitution, deletion, insertion, methylation, and/or modification changes.
As used herein, “splice-site” mutation is a mutation in a nucleic acid sequence encoding a protein, whereby RNA splicing of the pre-mRNA is changed, resulting in an mRNA having a different nucleotide sequence and a protein having a different amino acid sequence than the wild type. The resulting protein may have reduced function or loss of function.
As used herein, “a protein altering mutation” refers to a genetic mutation that (a) results in a change in the amino acid sequence of the corresponding protein; or (b) otherwise results in a disruption of the expression, or function of the protein which the gene encodes. Examples of a protein altering genetic mutation includes but is not limited to disruptive in-frame deletion, disruptive in-frame insertion, frame-shift variant, in-frame deletion, in-frame insertion, initiator codon variant, intron variant, missense variant, non-canonical start codon, splice acceptor variant, splice donor variant, splice region variant, start lost, stop gained, stop lost, and stop retained variant. In some embodiments, the insertions can include from 1 to 21 nucleotides, 1 to 12 nucleotides, 1 to 6 nucleotides or 1 to 3 nucleotides. In some embodiments, deletions can be of one or more exonic or intronic regions, or about 1 to 21 nucleotides, 1 to 12 nucleotides, 1 to 6 nucleotides or 1 to 3 nucleotides. In some embodiments the mutations are found at the intron exon splice sites, within introns, or within exons.
As used herein, the term "single nucleotide variant" or "SNV" refers to a substitution of one nucleotide to a different nucleotide at a position (e.g., site) of a nucleotide sequence, e.g., a sequence read from a sample. A substitution from a first nucleobase X to a second nucleobase Y may be denoted as "X>Y." For example, a cytosine to thymine SNV may be denoted as "OT."
As used herein, “mutation type” refers to the specific nucleotide substitution that comprises the mutation, and is selected from among OT, C>A, C>G, G>T, G>A, G>C, A>T, A>C, A>G, T>A, T>C and T>G mutations. Thus, for example, a mutation type of OT refers to a mutation in which the targeted or mutated nucleotide cytosine is replaced with the substituting nucleotide thymine.
A mutation in a regulatory sequence, e.g., in a promoter of a gene, is a change of one or more nucleotides compared to the wild type sequence, e.g., by replacement, deletion or insertion of one or more nucleotides, leading for example to reduced or no mRNA transcript of the gene being made.
As used herein, the term “silencing” refers to a down-regulation or complete inhibition of gene expression of the target gene or gene family.
As used herein, “point mutation” is the replacement of a single nucleotide, or the insertion or deletion of a single nucleotide.
As used herein, the term “target gene” in gene silencing approaches is the gene or gene family (or one or more specific alleles of the gene) of which the endogenous gene expression is down-regulated or completely inhibited (silenced) when a chimeric silencing gene (or “chimeric RNAi gene”) is expressed and for example produces a silencing RNA transcript (e.g., a dsRNA or hairpin RNA capable of silencing the endogenous target gene expression). In mutagenesis approaches, a target gene is the endogenous gene which is to be mutated, leading to a change in (reduction or loss of) gene expression or a change in (reduction or loss of) function of the encoded protein.
“Expression level,” “level of expression” and the like refers to the amount of a biomarker in a biological sample. "Expression" generally refers to the process by which information (e.g., gene-encoded and/or epigenetic information) is converted into the structures present and operating in the cell. Therefore, as used herein, "expression" may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and/or polypeptide modifications (e.g., posttranslational modification of a polypeptide). Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and/or polypeptide modifications ( e.g ., posttranslational modification of a polypeptide) shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a posttranslational processing of the polypeptide, e.g., by proteolysis. "Expressed genes" include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs).
"Increased expression," "increased expression level," "increased levels," "elevated expression," "elevated expression levels," or "elevated levels" refers to an increased expression or increased levels of a biomarker in an individual relative to a reference level or control, such as an individual or individuals who do not have the disease or disorder (e.g., cancer), an internal control e.g., a housekeeping biomarker), or a median expression level of the biomarker in samples from a group/population of patients.
"Decreased expression," "decreased expression level," "decreased levels," "reduced expression," "reduced expression levels," or "reduced levels" refers to a decrease expression or decreased levels of a biomarker in an individual relative to a reference level or control, such as an individual or individuals who do not have the disease or disorder (e.g., cancer), an internal control (e.g., a housekeeping biomarker), or a median expression level of the biomarker in samples from a group/population of patients. In some embodiments, reduced expression is little or no expression.
"Biological activity" or "bioactivity" or "activity" or "biological function," which are used interchangeably, herein mean an effector or antigenic function that is directly or indirectly performed by a polypeptide (whether in its native or denatured conformation), or by any fragment thereof in vivo or in vitro. Biological activities include but are not limited to binding to polypeptides, binding to other proteins or molecules, enzymatic activity, signal transduction, activity as a DNA binding protein, as a transcription regulator, ability to bind damaged DNA, etc. A bioactivity can be modulated by directly affecting the subject polypeptide. Alternatively, a bioactivity can be altered by modulating the level of the polypeptide, such as by modulating expression of the corresponding gene.
As used herein, the term "biological sample" or “sample” refers to a material or mixture of materials obtained from a subject (such as a patient), cell line, tissue culture, or other source which may contain cells or cellular products such as extracellular matrix. In certain embodiments, the biological sample comprises cancer tissue, cancer cells, blast cells or circulating tumor DNA. The sample may be of any biological tissue or bodily fluid. The sample is typically, although not necessarily, in fluid form, containing one or more components of interest. Frequently the sample will be a "clinical sample" which is a sample derived from a patient. Such samples include, but are not limited to, sputum, bone marrow aspirate, blood, peripheral blood, blood cells (e.g., white cells), organs, cells, tissue or fine needle biopsy samples, cell-containing bodily fluid, free floating nucleic acids, urine, peritoneal fluid, and pleural fluid, or cells therefrom, lymph, urine, saliva, fluid from ductal lavage, and nipple aspirate. Such samples may include a tumor sample which includes one or more premalignant or malignant cells. In one embodiment, the sample, e.g., tumor sample, includes one or more circulating tumor cells (CTC) (e.g., a CTC acquired from a blood sample). Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.
Therapeutic Methods and Uses
In one aspect the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
In another aspect, the invention relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene. In one aspect the invention relates to a method of treating acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof.
In one aspect the invention relates to a method of improving overall survival a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof.
A method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
A method of treating acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said treatment comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said treatment comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof. A method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
A method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, if the biological sample is positive for at least one mutation of the FLT3 gene.
As used herein the term “FLT3 gene” refers to the gene which codes for FLT3 protein, which protein is also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or FLK-2 (fetal liver kinase 2). The FLT3 protein is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation (Kiyoi H., et at., “FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development”, Cancer Sci. , 2020, 111:312-322, the contents of which are incorporated herein by reference in their entirety). It consists of five immunoglobulin-like domains in the extra-cellular region, a juxtamembrane (JM) domain, a tyrosine kinase (TK) domain separated by a kinase insert domain, and a C-terminal domain in the intracellular region. It has a transmembrane region in the middle part, flanked by a tyrosine kinase region on the carboxyl-terminal side and an extracellular region on the amino-terminal side.
In one embodiment of the inventions described herein the patient is a human.
In one embodiment of the inventions described herein the patient is ineligible for first line treatment with standard induction chemotherapy including, but not limited to, in view of their age, comorbidities that preclude the use of intensive induction chemotherapy, disease characteristics, performance status, organ dysfunction, combinations thereof and the like.
In one embodiment of the inventions described herein the patient is eligible for first line treatment with standard induction chemotherapy.
In one embodiment of the inventions described herein the patient is aged at least 75 years old.
In one embodiment of the inventions described herein the patient has no known active central nervous system (CNS) leukemia.
In one embodiment of the inventions described herein the patient has received no prior treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the patient has received no prior treatment with a hypomethylating agent, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the patient has received no prior treatment with a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the patient has received no prior treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, or a hypomethylating inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the patient has received no prior treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, or a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the patient has received no prior treatment with a hypomethylating agent, or a pharmaceutically acceptable salt thereof, or a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the patient has received no prior treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, or a hypomethylating agent, or a pharmaceutically acceptable salt thereof, or a FLT3 inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the patient has received no prior treatment with glasdegib, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the patient has received no prior treatment with azacitidine. In one embodiment of the inventions described herein the acute myeloid leukemia is newly diagnosed.
In one embodiment of the inventions described herein the acute myeloid leukemia is de novo acute myeloid leukemia (AML).
In one embodiment of the inventions described herein the acute myeloid leukemia is secondary acute myeloid leukemia (AML).
In one embodiment of the inventions described herein the acute myeloid leukemia is previously untreated.
In one embodiment of the inventions described herein the patient has been previously determined to be positive for at least one mutation of the FLT3 gene.
In one embodiment of the inventions described herein the patient is relapsed.
In one embodiment of the inventions described herein the patient is relapsed or refractory following prior treatment with a FLT3 inhibitor.
In one embodiment of the inventions described herein, the patient is positive for at least one mutation of the FLT3 gene or the patient has acute myeloid leukemia with at least one mutation of the FLT3 gene. In one embodiment of the inventions described herein, the patient is positive for at least one mutation of the FLT3 gene at diagnosis. In one embodiment of the inventions described herein, the patient is positive for at least one mutation of the FLT3 gene at initial diagnosis. In one embodiment of the inventions described herein, the patient is positive for at least one mutation of the FLT3 gene at relapse. In one embodiment of the inventions described herein, the patient has a newly detected FLT3 mutation at relapse. In one embodiment of the inventions described herein, at least one mutation of the FLT3 gene results in a constitutively active FLT3 kinase.
One of ordinary skill in the art can readily determine whether the patient is positive for at least one mutation of the FLT3 gene or whether the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene. For example, the mutation status can be determined using genomic DNA extracted from mononuclear cells obtained from a biological sample from the patient including, but not limited to, a bone marrow aspirate sample, a blood sample, or a peripheral blood sample. In one embodiment the biological sample is a bone marrow aspirate sample. In one embodiment the biological sample is a blood sample. In one embodiment the biological sample is a peripheral blood sample. In one embodiment the FLT3 gene mutation status can be determined by a companion diagnostic. In one embodiment the FLT3 gene mutation status can be determined by a PCR based in vitro diagnostic test, for example a PCR based in vitro diagnostic test designed to detect internal tandem duplication mutations and tyrosine kinase domain mutations D835 and I836 in the FLT3 gene in genomic DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates of patients, for example LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies, Inc, San Diego, USA). Alternatively, a standard PCR assay using for example, primers that straddle the internal tandem duplication mutation or primers that overlap within the expected region of mutation, can be used to detect mutations of internal tandem duplication, where, for example, amplicons with a size greater than that of wild-type and labeled with both 6-FAM and HEX are interpreted as positive for internal tandem duplication mutation. Alternatively, an assay such as Agilent SureSelect capture-based, targeted re-sequencing assay (Santa Clara, USA) can be used as the primary assay. FLT3 genes are captured by hybridization from genomic DNA using a custom RNA probe set, and then amplified, purified and sequenced on an instrument such as an lllumina MiSeq instrument. An aplicon-based supplement assay can also be used to characterize FLT3 gene for internal tandem duplication mutations by methods well known to one of ordinary skill. Alternatively, the FLT3 gene mutation status can be determined by whole exome sequencing. Alternatively, the FLT3 gene mutation status can be determined by a FISH assay.
In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is a somatic mutation.
In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is selected from the group consisting of an insertion, a point mutation, an internal tandem duplication mutation, and combinations thereof.
In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is an insertion.
In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is a point mutation.
In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is a point mutation, which point mutation is in the tyrosine kinase domain of the FLT3 gene.
In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is a point mutation, which point mutation is at codon D835 in the tyrosine kinase domain of the FLT3 gene. In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is a point mutation, which point mutation is in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene.
In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is a point mutation, which point mutation is at codon 1836 in the tyrosine kinase domain of the FLT3 gene.
In one embodiment of the inventions described herein the at least one mutation of the FLT3 gene is more than one point mutation, which point mutations are at codon D385 and at codon 1836 in the tyrosine kinase domain of the FLT3 gene.
In one embodiment of the inventions described herein the mutation of the FLT3 gene is an internal tandem duplication mutation.
In one embodiment of the inventions described herein the mutation of the FLT3 gene is an internal tandem duplication with a mutant to wild type allelic ratio of greater than about 0.05.
In one embodiment of the inventions described herein the mutation of the FLT3 gene comprises one or more of a point mutation at codon D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation at codon 1836 in the tyrosine kinase domain of the FLT3 gene; an internal tandem duplication mutation; and combinations thereof. In one embodiment of the inventions described herein the mutation of the FLT3 gene comprises one or more of a point mutation at codon D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation at codon 1836 in the tyrosine kinase domain of the FLT3 gene; and an internal tandem duplication mutation.
In one embodiment of the inventions described herein the mutation of the FLT3 gene is selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), and ITD(E598-Y599, ins5; E589-F590ins12).
In one embodiment of the inventions described herein the mutation of the FLT3 gene comprises at least one mutation selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), and ITD(E598-Y599, ins5; E589-F590ins12), and combinations thereof. In one embodiment of the inventions described herein the mutation of the FLT3 gene comprises at least two mutations selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), and ITD(E598-Y599, ins5; E589-F590ins12).
In one embodiment of the inventions described herein the mutation of the FLT3 gene comprises three mutations selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), and ITD(E598-Y599, ins5; E589-F590ins12).
In one embodiment of the inventions described herein the mutation of the FLT3 gene is V194M.
In one embodiment of the inventions described herein the mutation of the FLT3 gene is N841Y.
In one embodiment of the inventions described herein the mutation of the FLT3 gene is N676S.
In one embodiment of the inventions described herein the mutation of the FLT3 gene is A680V.
In one embodiment of the inventions described herein the mutation of the FLT3 gene is ITD(F605-P606ins12) mutation.
In one embodiment of the inventions described herein the mutation of the FLT3 gene is ITD(E598-Y599, ins5; E589-F590ins12) mutation.
In some embodiments of each of the inventions described herein, the method comprises administering the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof. In some embodiments of each of the inventions described herein, the method comprises administering the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a hypomethylating agent, or a pharmaceutically acceptable salt thereof. In some embodiments of each of the inventions described herein, the method comprises administering the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine.
In one embodiment of the inventions described herein administering to said patient the therapeutic regimen increases the overall survival of said patient. In one embodiment of the inventions described herein administering to said patient the therapeutic regimen increases the overall survival of said patient as compared to the overall survival of a control group. In one embodiment the control group comprises one or more patients, where said one or more patients are not FLT3 mutant positive, for example which comprises acute myeloid leukemia patients who are not positive for at least one mutation of the FLT3 gene; or comprises patients with acute myeloid leukemia which does not have at least one mutation of the FLT3 gene; or which comprises acute myeloid leukemia patients, where said patients have wild type FLT3 gene; or which comprises patients with acute myeloid leukemia which is wild-type for the FLT3 gene. In one embodiment the control group comprises patients who have received the same therapeutic regimen. In one embodiment the therapeutic regimen administered to the control group is a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, and a further chemotherapeutic agent. In one embodiment, the therapeutic regimen administered to the control group is glasdegib, or a pharmaceutically acceptable salt thereof, in combination with azacitidine.
Therapeutic Regimens and Agents
Each therapeutic agent of the methods of the present invention may be administered either alone, or in a medicament (also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically acceptable excipients, including carriers, excipients, or diluents, according to pharmaceutical practice.
Each therapeutic agent of the methods of the present invention may also be administered in combination with a further therapeutic agent as described herein. Such combination therapy may optionally be described as a therapeutic regimen.
As used herein, the term “combination therapy” or administration “in combination” refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in a medicament, either sequentially, concurrently or simultaneously.
As used herein, the term “sequential” or “sequentially” refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in a medicament, one after the other, wherein each therapeutic agent can be administered in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and / or are administered according to different dosing schedules, for example, one agent is administered daily, and the second agent is administered less frequently such as weekly.
As used herein, the term “concurrently” refers to the administration of each therapeutic agent in the combination therapy of the invention, either alone or in separate medicaments, wherein the second therapeutic agent is administered immediately after the first therapeutic agent, but that the therapeutic agents can be administered in any order. In a preferred embodiment the therapeutic agents are administered concurrently.
As used herein, the term “simultaneous” refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in separately medicaments, wherein the second therapeutic agent is administered at the same time as the first therapeutic agent, optionally where the therapeutic agents are administered in the same medicament.
In one embodiment of each of the inventions described herein, the method comprises administering a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof. In one embodiment the amounts of the smoothened inhibitor, or pharmaceutically acceptable salt thereof, and the further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, are together effective in treating the acute myeloid leukemia.
In one aspect the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In one aspect the invention relates to a method of treating acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
In another aspect the invention relates to a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in combination with, a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with a further chemotherapeutic agent, for the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof.
In another aspect the invention relates to a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in combination with a smoothened inhibitor, for the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof.
In another aspect the invention relates to a combination of a smoothened inhibitor or a pharmaceutically acceptable salt thereof, and a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
In another aspect the invention relates to a combination of a smoothened inhibitor or a pharmaceutically acceptable salt thereof, and a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof.
In another aspect, the invention relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation in the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
In one aspect the invention relates to a method of improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby increasing the overall survival of the patient.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof.
In another aspect the invention relates to a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in combination with a smoothened inhibitor, for improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
In another aspect the invention relates to a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in combination with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof.
In another aspect the invention relates to a combination of a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene.
In another aspect the invention relates to a combination of a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for improving overall survival in a patient with acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in need thereof. In another aspect the invention relates to a method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation in the FLT3 gene, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation in the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, if the patient is positive for at least one mutation in the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In another aspect the invention relates to a method of treating acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient has acute myeloid leukemia (AML) with at least one mutation in the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, if the patient has acute myeloid leukemia (AML) with at least one mutation in the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In another aspect the invention relates to a smoothened inhibitor for use in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for the treatment of acute myeloid leukemia (AML) in a patient, wherein the patient is positive for at least one mutation in the FLT3 gene, said treatment comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine the patient is positive for at least one mutation in the FLT3 gene; c. selecting the patient for treatment if the patient is positive for at least one mutation in the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
In another aspect the invention relates to a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene in a patient in need thereof, said treatment comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further therapeutic agent, or a pharmaceutically acceptable salt thereof, if the patient has acute myeloid leukemia (AML) with at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, thereby treating said acute myeloid leukemia.
Smoothened Inhibitor Embodiments of the present invention comprise a smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is glasdegib, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is vismodegib, or a pharmaceutically acceptable salt thereof. In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is sonidegib, or a pharmaceutically acceptable salt thereof.
Chemotherapeutic agent Embodiments of the present invention comprise a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the chemotherapeutic agent is a hypomethylating agent, or a pharmaceutically acceptable salt thereof. As used herein the term “hypomethylating agent”, or “demethylating agent” shall be taken to me a drug that inhibits methylation of DNA, i.e. the modification of DAN nucleotides by the addition of a methyl group. Hypomethylating agents include, but are not limited to, azacitidine and decitabine.
In one embodiment of the inventions described herein the hypomethylating agent is azacitidine. Azacitidine is also known by several alternative names such as 5- azacytidine, azacytidine, ladakamycin, or 4-aminio-1-p-D-ribofuranosyl-s-trianin-2(1 H)- one.
In one embodiment of the inventions described herein the hypomethylating agent is decitabine.
In one embodiment of the inventions described herein the chemotherapeutic agent is cytarabine. Cytarabine is also known as cytosine arabinoside (ara-C).
In one embodiment of the inventions described herein the chemotherapeutic agent is daunorubicin.
In one embodiment of the inventions described herein the chemotherapeutic agent is doxorubicin.
In one embodiment of the inventions described herein the chemotherapeutic agent is epirubicin.
In one embodiment of the inventions described herein the chemotherapeutic agent is idarubicin.
In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is administered before the administration of the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof, is administered before administration of the smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is administered concurrently with the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is administered simultaneously with the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is administered before the administration of the azacitidine.
In one embodiment of the inventions described herein the azacitidine, is administered before administration of the smoothened inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is administered concurrently with the azacitidine.
In one embodiment of the inventions described herein the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, is administered simultaneously with the azacitidine.
In one embodiment of the inventions described herein glasdegib, or a pharmaceutically acceptable salt thereof, is administered before the administration of the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof, is administered before administration of glasdegib, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein glasdegib, or a pharmaceutically acceptable salt thereof, is administered concurrently with the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein glasdegib, or a pharmaceutically acceptable salt thereof, is administered simultaneously with the further chemotherapeutic agent, or pharmaceutically acceptable salt thereof. In one embodiment of the inventions described herein glasdegib, or a pharmaceutically acceptable salt thereof, is administered before the administration of the azacitidine.
In one embodiment of the inventions described herein the azacitidine, is administered before administration of glasdegib, or a pharmaceutically acceptable salt thereof.
In one embodiment of the inventions described herein glasdegib, or a pharmaceutically acceptable salt thereof, is administered concurrently with the azacitidine.
In one embodiment of the inventions described herein glasdegib, or a pharmaceutically acceptable salt thereof, is administered simultaneously with the azacitidine.
Administration of compounds of the invention may be undertaken by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a therapeutic agent of the combination therapy of the present invention may be administered as a single bolus, as several divided doses administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be particularly advantageous to formulate a therapeutic agent in a dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention may be dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well- known in the therapeutic arts. That is, the maximum tolerable dose may be readily established, and the effective amount providing a detectable therapeutic benefit to a subject may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the subject. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a subject in practicing the present invention.
It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, taking into consideration factors such as the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. The dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
In some embodiments, at least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as a monotherapy for treating the same cancer. In other embodiments, the subject received a lower total amount of at least one of the therapeutic agents in the combination therapy than when the same agent is used as a monotherapy, for example a lower dose of therapeutic agent, a reduced frequency of dosing and / or a shorter duration of dosing.
In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally.
In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered daily. In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally on a continuous daily dosage schedule.
In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally at a dose of about 100 mg per day, glasdegib free base equivalent.
In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally as glasdegib maleate at a dose of about 131 mg glasdegib maleate per day.
In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered in a solid dosage form, optionally formulated as a tablet.
In one embodiment the further chemotherapeutic agent is azacitidine which is administered subcutaneously.
In one embodiment the further chemotherapeutic agent is azacitidine which is administered intravenously.
In one embodiment the further chemotherapeutic agent is azacitidine which is administered for days 1 to 10 of a 28-day cycle.
In one embodiment the further chemotherapeutic agent is azacitidine which is administered for days 1 to 7 of a 28-day cycle.
In one embodiment the further chemotherapeutic agent is azacitidine which is administered for greater than one 28-day cycle, optionally for at least 4 28-day cycles, or optionally for at least 628-day cycles.
In one embodiment the further chemotherapeutic agent is azacitidine which is administered at a dose of about 75 mg/m2.
In one embodiment the further chemotherapeutic agent is azacitidine which is administered at a dose of about 75 mg/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered intravenously.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered subcutaneously.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered by infusion into the cerebrospinal fluid. In one embodiment the further chemotherapeutic agent is cytarabine which is administered for days 1 to 10 of a 28-day cycle.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered for days 1 to 7 of a 28-day cycle.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered for greater than one 28-day cycle, optionally for at least 428-day cycles, or optionally for at least 628-day cycles.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered at a dose of about 20 mg/m2.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered at a dose of about 20 mg/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered at a dose of about 20 mg/m2 twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered at a dose of about 20 mg/m2 of body surface area twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered at a dose of about 100 mg/m2.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered at a dose of about 100 mg/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered at a dose of about 100 mg/m2 once daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered at a dose of about 100 mg/m2 of body surface area once daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least 4 further 28-day cycles.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least 6 further 28-day cycles.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 3g/m2. In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 3g/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 3g/m2.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 3g/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 3g/m2.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 3g/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 3g/m2 twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 3g/m2 of body surface area twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 3g/m2 twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 3g/m2 of body surface area twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 3g/m2 twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 3g/m2 of body surface area twice daily. In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 1 g/m2
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 1 g/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 1 g/m2.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 1 g/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 1 g/m2.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 1 g/m2 of body surface area.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 1g/m2 twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1 , 3 and 5 of at least one further 28-day cycle at a dose of about 1g/m2 of body surface area twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 1g/m2 twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 4 further 28-day cycles at a dose of about 1g/m2 of body surface area twice daily.
In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 1g/m2 twice daily. In one embodiment the further chemotherapeutic agent is cytarabine which is administered on days 1, 3 and 5 of at least 6 further 28-day cycles at a dose of about 1g/m2 of body surface area twice daily.
In one embodiment the regimen optionally comprises daunorubicin, which daunorubicin is administered on days 1 to 3 of a 28-day cycle.
In one embodiment the regimen optionally comprises daunorubicin, which is administered for greater than one 28-day cycle, optionally for at least 4 28-day cycles, or optionally for at least 628-day cycles.
In one embodiment the regimen optionally comprises daunorubicin, which is administered about 60mg/m2.
In one embodiment the regimen optionally comprises daunorubicin, which is administered about 60mg/m2 of body surface area.
In one embodiment the regimen optionally comprises daunorubicin, which is administered about 60mg/m2 once daily.
In one embodiment the regimen optionally comprises daunorubicin, which is administered about 60mg/m2 of body surface area once daily.
Repetition of the administration or dosing regimens, or adjustment of the administration or dosing regimen may be conducted as necessary to achieve the desired treatment. A “continuous dosing schedule” as used herein is an administration or dosing regimen without dose interruptions, e.g. without days off treatment. Repetition of 21 or 28 day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule. In an embodiment, the compounds of the combination of the present invention can be administered in a continuous dosing schedule.
Pharmaceutical Compositions and Routes of Administration
A "pharmaceutical composition" refers to a mixture of one or more of the therapeutic agents described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, including, but not limited to a carrier or excipient or diluent. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients and/or diluents. As used herein, a "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the active compound or therapeutic agent.
The pharmaceutically acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
Suitable pharmaceutically acceptable carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream, or for rectal administration as a suppository.
Exemplary parenteral administration forms include solutions or suspensions of an active compound in a sterile aqueous solution, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.
The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise amounts. Pharmaceutical compositions suitable for the delivery of the therapeutic agents of the combination therapies of the present invention, and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in ‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the contents of which are incorporated herein by reference in their entirety.
Therapeutic agents of the combination therapies of the invention may be administered orally. Oral administration may involve swallowing, so that the therapeutic agent enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the therapeutic agent enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid- filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
Therapeutic agents of the combination therapies of the present invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001), the contents of which are incorporated herein by reference in their entirety.
For tablet dosage forms, the therapeutic agent may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the active agent, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant may comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
Exemplary tablets may contain up to about 80 wt% active agent, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
The formulation of tablets is discussed in detail in “Pharmaceutical Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the contents of which are incorporated herein by reference in their entirety.
Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles may be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The contents of each of these references are incorporated herein by reference in their entireties.
In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered orally.
In one embodiment the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof, which is administered in a solid dosage form, optionally formulated as a tablet.
In one embodiment the solid dosage form comprises a dose of about 100 mg per day, glasdegib free base equivalent.
In one embodiment the solid dosage form is a tablet, which tablet comprises a dose of about 100 mg per day, glasdegib free base equivalent.
In one embodiment the solid dosage form comprises a dose of glasdegib maleate at a dose of about 131 mg glasdegib maleate per day.
In one embodiment the solid dosage form is a tablet, which tablet comprises a dose of glasdegib maleate at a dose of about 131 mg glasdegib maleate per day.
In one embodiment the daily dose of glasdegib, or a pharmaceutically acceptable salt thereof, is divided into several sub-doses.
In one embodiment the solid dosage form comprises a dose of about 25 mg per day, glasdegib free base equivalent.
In one embodiment the solid dosage form is a tablet, which tablet comprises a dose of about 25 mg per day, glasdegib free base equivalent.
In one embodiment the solid dosage form comprises a dose of glasdegib maleate at a dose of about 33 mg glasdegib maleate per day.
In one embodiment the solid dosage form is a tablet, which tablet comprises a dose of glasdegib maleate at a dose of about 33 mg glasdegib maleate per day.
In one embodiment azacitidine is administered subcutaneously.
In one embodiment azacitidine is administered intravenously.
In one embodiment azacitidine is administered at a dose of about 75 mg/m2.
In one embodiment azacitidine is administered subcutaneously at a dose of about 75 mg/m2.
In one embodiment azacitidine is administered intravenously at a dose of about 75 mg/m2. In one embodiment azacitidine is administered at a dose of about 75 mg/m2 of body surface area.
In one embodiment azacitidine is administered subcutaneously at a dose of about 75 mg/m2 of body surface area.
In one embodiment azacitidine is administered intravenously at a dose of about 75 mg/m2 of body surface area.
Further Therapeutic Agents
In a further aspect, the methods and combination therapies of the present invention may additionally comprise administering further therapeutic agents suitable for treating hematological malignancies, which amounts are together effective in treating said malignancy. In some such embodiments, the further therapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti hormones, androgen deprivation therapy and anti-androgens.
In one embodiment the further therapeutic agent is a FLT3 inhibitor.
In one embodiment the further therapeutic agent is midostaurin (available as, for example, Rydapt™). In one embodiment, midostaurin is administered orally. In one embodiment, midostaurin is administered daily. In one embodiment, midostaurin is administered orally on a continuous daily dosing schedule. In one embodiment, midostaurin is administered orally at a dose of about 50mg per day, midostaurin free base or midostaurin free base equivalent. In one embodiment, midostaurin is administered in a solid dosage form. In one embodiment, midostaurin is administered in a solid dosage form, which solid dosage form is formulated as a capsule. In one embodiment, midostaurin is administered daily, which daily dose is sub-divided. In one embodiment, midostaurin is administered daily at a dose of about 50mg per day midostaurin free base or midostaurin free base equivalent, which dose is sub-divided into two doses, each dose comprising about 25mg midostaurin free base or midostaurin free base equivalent.
In one embodiment the further therapeutic agent is gilteritinib (available as, form example, Xospata™). In one embodiment, gilteritinib is administered orally. In one embodiment, gilteritinib is administered daily. In one embodiment, gilteritinib is administered orally on a continuous daily dosing schedule. In one embodiment, gilteritinib is administered orally at a dose of about 120mg per day, gilteritinib free base or gilteritinib free base equivalent. In one embodiment, gilteritinib is administered in a solid dosage form. In one embodiment, gilteritinib is administered in a solid dosage form, which solid dosage form is formulated as a tablet. In one embodiment, gilteritinib is administered daily, which daily dose is sub-divided. In one embodiment, gilteritinib is administered daily at a dose of about 120mg per day gilteritinib free base or gilteritinib free base equivalent, which dose is sub-divided into three doses each comprising about 40mg gilteritinib free base or gilteritinib free base equivalent. In one embodiment, gilteritnib is administered as gilteritinib fumarate. In one embodiment, gilteritinib is administered as a solid dosage form comprising gilteritinib fumarate. In one embodiment, gilteritinib is administered as a solid dosage form, which solid dosage form is a tablet comprising gilteritinib fumarate.
In one embodiment, the further therapeutic agent is quizartinib, or a pharmaceutically acceptable salt thereof. In one embodiment, the further therapeutic agent is quizartinib.
In one embodiment, the further therapeutic agent is sorafenib, or a pharmaceutically acceptable salt thereof. In one embodiment, the further therapeutic agent is sorafenib.
In one embodiment, the further therapeutic agent is sunitinib or a pharmaceutically acceptable salt thereof. In one embodiment, the further therapeutic agent is sunitinib.
Kits
The therapeutic agents of the combination therapies of the present invention may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
In one aspect, the present invention relates to a kit which comprises a first container, a second container and a package insert, wherein the first container comprises at least one dose of a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, the second container comprises at least one dose of azacitidine, and the package insert comprises instructions for treating a patient with acute myeloid leukemia, wherein said patient is positive for at least one mutation of the FLT3 gene using the medicaments. In one aspect, the present invention relates to a kit which comprises a first container, a second container and a package insert, wherein the first container comprises at least one dose of glasdegib, or a pharmaceutically acceptable salt thereof, the second container comprises at least one dose of azacitidine, and the package insert comprises instructions for treating for treating a patient with acute myeloid leukemia, wherein said patient is positive for at least one mutation of the FLT3 gene using the medicaments.
In one embodiment, the kit of the present invention may comprise one or both of the active agents in the form of a pharmaceutical composition, which pharmaceutical composition comprises an active agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The kit may contain means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
The kit may be particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid. The kit may further comprise other materials that may be useful in administering the medicaments, such as diluents, filters, IV bags and lines, needles and syringes, and the like.
These and other aspects of the invention, including the exemplary specific embodiments listed below, will be apparent from the teachings contained herein.
Examples
Example 1 - A combination study of PF-04449913 (glasdegib) and azacitidine in untreated MDS, AML and CMML Patients (Bright 1012)
Brief Summary
This multi center open label Phase 1 b study was designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of glasdegib (PF- 04449913) combined with azacitidine in newly diagnosed patients with Acute Myeloid Leukemia (AML), Higher Risk Myelodysplastic Syndrome (MDS), or Chronic Myelomonocytic Leukemia (CMML) who were not candidates for intensive induction chemotherapy (ClinicalTrials.gov reference NCT02367456, the contents of which are incorporated herein by reference in their entirety). This clinical study included two cohorts: (a) a lead in safety cohort (LIC) and (b) an expansion phase with an AML cohort and an MDS (including CMML) cohort.
Primary Objectives
To assess the following:
- for the lead in safety cohort to assess the safety and tolerability of glasdegib in combination with azacitidine in patients with intermediate-11 or high-risk MDS per International Prognostic Scoring System (IPSS), AML with 20-30% blasts and multilineage dysplasia, and CMML; diagnoses were determined according to the World Health Organization (WHO) 2008 classification (Sabattini E, Bacci F, Sagramoso C, Pileri SA. WHO classification of tumors of haematopoietic and lymphoid tissues in 2008: an overview. Pathologica. 2010;102(3):83-7, the contents of which are incorporated herein by reference in their entirety);
- for the expansion cohort to determine the rate of complete remission (CR) in patients with previously untreated intermediate, high, or very high risk MDS per Revised IPSS (IPSS-R), for whom the risk/benefit profile of intensive chemotherapy was unacceptable [Time Frame: All cycles until progression or 24 months from first visit of last patient] CR rate defined as percentage of patients achieving CR as defined by modified IWG criteria (2006) for MDS;
- for the expansion cohort to determine the rate of complete remission (CR) for AML, [Time Frame: All cycles until progression or 24 months from first visit of last patient] CR rate defined as percentage of patients achieving CR as defined by ELN (2017) for AML;
- for the expansion cohort to determine the rate of complete remission (CR) for CMML (WHO 2016 classification), [Time Frame: All cycles until progression or 24 months from first visit of last patient]; and
- adverse events (safety lead in phase) [Time Frame: Screening through 28 days following last dose of study drug] as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03), timing, seriousness and relationship to study therapy, and laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03) and timing.
Patients were diagnosed in accordance with WHO 2016 classification, for example as described in Arber D.A., et at. “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.” Blood. 2016;127(20):2391-405 and Greenberg P.L., et at. “Revised international prognostic scoring system for myelodysplastic syndromes.” Blood. 2012;120(12):2454-65, the contents of each of which are incorporated herein by reference in their entirety.
Secondary Objectives
To assess the following:
- response rate (safety lead in phase) [Time Frame: All cycles until progression, a median of 1 year] as defined by percentage of participants achieving complete remission + partial remission as defined by modified IWG criteria (2006);
- hematologic improvement (safety lead in phase) [Time Frame: All cycles until progression, a median of 1 year] as defined by modified IWG criteria (2006);
- marrow complete response (mCR), (safety lead in phase) [Time Frame: All cycles until progression, a median of 1 year] as defined by modified IWG criteria (2006);
- cytogenetic response (safety lead in phase) [Time Frame: All cycles until progression, a median of 1 year] as defined by modified IWG criteria (2006);
- stable disease (safety lead in phase) [Time Frame: All cycles until progression, a median of 1 year] as defined by modified IWG criteria (2006);
- AUC for azacitidine (safety lead in phase) [Time Frame: First 2 weeks of treatment] - Area under the Concentration-Time Curve (ng*h/ml_);
- Cmax for azacitidine (safety lead in phase) [Time Frame: First 2 weeks of treatment] - Maximum Observed Plasma Concentration (ng/mL);
- Tmax for azacitidine (safety lead in phase) [Time Frame: First 2 weeks of treatment] - Time to Reach Maximum Observed Plasma Concentration (hrs);
- AUC for glasdegib (safety lead in phase) [Time Frame: First 5 months of treatment] - Area under the Concentration-Time Curve (ng*h/ml_); - Cmax for glasdegib (safety lead in phase) [Time Frame: First 5 months of treatment] - Maximum Observed Plasma Concentration (ng/mL);
- Tmax for glasdegib (safety lead in phase) [Time Frame: First 5 months of treatment] - Time to Reach Maximum Observed Plasma Concentration (hrs);
- Ctrough for glasdegib (safety lead in phase) [Time Frame: First 1 month of treatment] - Minimum plasma concentration following daily dosing to steady state (ng/mL);
- QTc interval (expansion cohorts) [Time Frame: All cycles through end of treatment, a mediam of 1 year] - QTc interval corrected using Fridericia's Formula (msec) (Safety lead-in phase and Expansion cohorts);
- Overall Survival (OS) (expansion cohorts) [Time Frame: all cycles until death or
24 months from first visit of last patient] - Time from date of first study treatment to date of death due to any cause. Patients last known to be alive without date of death documented will be censored at the date of last contact;
- Marrow complete remission (MDS expansion cohort) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by modified IWG criteria (2006) (MDS expansion cohort);
- partial remission (MDS expansion cohort) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by modified IWG criteria (2006);
- stable disease (MDS expansion cohort) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by modified IWG criteria (2006);
- partial or complete cytogenetic response (MDS expansion cohort) [Time Frame:
All cycles until progression or 24 months from first visit of last patient] - as defined by modified IWG criteria (2006);
- hematologic improvement (MDS expansion cohort) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by modified IWG criteria (2006);
- complete remission with incomplete hematologic recovery (AML expansion cohort) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by ELN criteria (2017); - complete remission with partial hematologic recovery (AML expansion cohort)
[Time Frame: All cycles until progression or 24 months from first visit of last patient] - CRh is defined as CR but with absolute neutrophil count >500/uL, platelets >50,000/uL, and not qualifying for CR;
- morphologic leukemia free state (AML expansion cohort) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by ELN criteria (2017);
- partial remission (AML expansion cohort) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by ELN criteria (2017);
- stable disease (AML expansion cohort) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - as defined by ELN criteria (2017);
- duration of CR (expansion cohorts) [Time Frame: All cycles until progression or
24 months from first visit of last patient] - duration of CR defined as duration from date of first achieving CR to date of disease progression after CR, or death due to any cause, whichever occurs first CR (expansion cohorts) [Time Frame: All cycles until progression or 24 months from first visit of last patient] - duration from date of first dose of study drug to date of CR; and
- adverse events (expansion cohorts) [Time Frame: Date of informed consent through 28 days following last dose of study drug] - type, frequency, severity, timing, and relationship to study therapy of adverse ; and laboratory abnormalities (graded by NCI CTCAE v.4.03).
Exploratory analyses included pharmacodynamics, biomarker assessments, patient-reported outcomes (PROs), and the rate and duration of transfusion independence.
Study Design
This open-label, multicenter, phase 1b trial (BRIGHT MDS & AML 1012; NCT02367456) had a start date, April 2015; analysis based on primary completion date, January 2020. Glasdegib (100 mg once daily) was administered orally in 28-day cycles on a continuous basis, and azacitidine was administered subcutaneously or intravenously (expansion phase only) at a dose of 75 mg/m2/day on Days 1-7 (+ / - 3 days) of a 28-day cycle. Treatment was continued for a minimum of 6 cycles, or until disease progression, unacceptable toxicity, death, or patient refusal. Treatment was continued beyond 6 cycle if a clinical benefit was demonstrated. The 100mg glasdegib daily dose could be temporarily interrupted or reduced to 50 mg to manage toxicity (see Table 1). Dose re-escalations were not permitted. Azacitidine dose modifications were permitted in line with the prescribing information. If one drug was permanently discontinued for reasons other than disease progression or withdrawal of consent, the other treatment could be continued at the investigator’s discretion.
Table 1 Glasdegib dose modifications for toxicities
Hematologic toxicity
Glasdegib does not need to be delayed or dose-reduced for hematologic toxicity deemed unrelated/unlikely related to glasdegib by the investigator
Non-hematologic toxicities (excluding QTc prolongation, muscle spasms, and myalgia)
>Grade 3 toxicity (nausea, vomiting, and/or Hold glasdegib until toxicity has recovered to diarrhea must persist at >Grade 3 (despite maximal <Grade 1 appropriate medical therapy) to require dose First episode: decrease by 1 dose level3 modification) Second episode: decrease by 1 dose level3
Third episode: permanently discontinue
Potential drug-induced liver injury/Hy’s law Interrupt glasdegib dosing. If an alternative cause is found, restarting glasdegib at the same dose may be considered
Confirmed drug-induced liver injury/Hy’s law Glasdegib should be permanently discontinued
3Each dose level is 25 mg. If clinical benefit is observed, glasdegib may be reduced below 50 mg once daily following sponsor approval.
QTc=QT interval corrected for heart rate
Study Population
Patients aged 18 years of older who had previously untreated MDS, AML or CMML according to the WHO 2016 classification. AML patients had de novo or secondary AML. MDS patients must have Intermediate risk (>3 to 4.5 points), high risk (>4.5 to 6 points) or very high risk (>6 points) disease according to the Revised International prognostic Scoring System 2012 (IPSS-R) or CMML. Patients should also have clinical indication for treatment with azacitidine for MDS or AML.
Exclusion criteria
Subjects were not enrolled into the study if:
- patients with AML were candidates for standard induction chemotherapy as first line treatment;
- patients with known active CNS leukemia; or
- prior treatment with a smoothened inhibitor (SMOi) and / or hypomethylating agent.
Assessments
Response to treatment was evaluated using the 2006 International Working Group modified response criteria for all patients in the safety lead-in cohort and in the MDS and CMML expansion cohorts. The 2017 European LeukemiaNet (ELN) response criteria were applied to patients in the AML expansion cohort (Cheson B.D., et al. “Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.” Blood, 2006, 108(2): 419-25; and Dohner H, et al. “Diagnosis and management of AML in aduults, 2017 ENL recommendation from an international expert panel.” Blood, 2017; 129(4): 424-47, the contents of each of which are incorporated herein by reference in their entirety).
In the lead-in safety cohort, samples for bone marrow evaluation were collected at screening, on Day 1 of Cycle 4, on Day 1 of every third cycle thereafter, at end of treatment, and at the investigator’s discretion (±7 days of nominal time). For the expansion cohorts, samples for bone marrow evaluation were collected at screening, Cycle 7 Day 1, Cycle 13 Day 1, on Day 1 every 12 cycles thereafter, and at the investigator’s discretion if CR was suspected. Time to response was calcuated as the time from the first dose of study drug to the first date of any improvement in disease status; duration of response was calculated as the time from the first date of improvement in diesase status to the investigator-reported date of progressive disease. In the AML cohort, improved disease was defined as an increase from baseline in platelets (if <100x109/L at baseline) without transfusions or neutrophils (if <1x109/L at baseline) and/or a decrease from baseline in peripheral blood blasts or bone marrow blasts. In the MDS cohort, improved disease was defined as an increase from baseline in hemoglobin (if <11 g/dL at baseline) without transfusions or platelets (if <100x109 / L at baseline) without transfusions or neutrophils (if <1x109 / L at baseline) and/or a decrease from baseline in peripheral blood blasts or bone marrow blasts.
Transfusion rates and recovery of blood cell lineages (absolute neutrophil count [ANC], hemoglobin, and platelets) were assessed. Treatment-cycle analyses included only remaining patients at risk in that cycle. Transfusion independence was defined as >8 weeks without transfusions.
Patient blood samples were collected for PK analysis of glasdegib at protocol- defined time points. In the lead-in safety cohort, glasdegib treatment started on Cycle 1 Day 2 to permit drug-drug interaction evaluation.
The frequency of baseline mutations examined in evaluable patients in the AML cohort are reported here. Biomarker assessments included whole-exome sequencing, RNA-sequencing analysis of bone marrow aspirate samples, and serum concentrations of 38 circulating cytokines potentially implicated in the Hh signaling pathway and AML. Correlations between baseline biomarkers with OS and response (defined as CR) were determined. On-treatment samples were analyzed to examine changes in gene mutation profiles when patients achieved CR, and for those patients who subsequently relapsed. A continuous Cox Proportional-Hazards model using overall survival on AML patients was run using gene expression pathway scores from either the HALLMARK pathway gene sets from msigDB or the immune gene sets obtained from REGEV (Jerby-Arnon Let at. “A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.” Cell. 2018;175(4):984-997 e924, the contents of which are incoprorated herein by reference in their entirety). Gene expression data was converted to z-scores. Pathway scores were calculated as the mean of the z-score of the genes in each pathway gene set. Pathways associated with worse OS has negative log2(HR) while pathways with positive log2(HR) scores are associated with better OS.
Safety assessments included adverse events (AEs), classified and graded based on the National Cancer Institute Common Terminology Criteria for AEs v4.03, laboratory evaluations, vital signs, physical examinations, and 12-lead electrocardiograms.
Statistical Analysis
Twelve patients were included in the lead-in safety cohort, which provided at least 80% probability to observe at least 1 AE if the true incidence of the AE in the population was at least 15%. In the expansion phase, a total of 30 patients each were enrolled in the MDS and AML cohorts, which provided the maximum width of the exact 2-sided 95% confidence interval (Cl) for CR of <0.374 in each cohort. The full safety and efficacy analysis set included all enrolled patients who received at least 1 dose of study medication. The PK analysis population included all treated patients who had at least 1 PK parameter estimated. The biomarker analysis population included all treated patients evaluable for baseline and post-baseline mutational status. Descriptive statistics were used throughout the study unless otherwise stated. Time-to-event endpoints were summarized using the Kaplan-Meier method. Median event times and 2-sided 95% Cls were included.
Disposition, Demographics and baseline characteristics
A total of 72 patients were treated with glasdegib + azacitidine across the study phases: 12 patients in the lead-in safety cohort, and 30 patients in each of the AML and MDS (including 3 patients with CMML) cohorts of the expansion phase. In the lead-in safety, AML, and MDS cohorts, respectively, the median (range) age was 72 (59-89), 74 (56-87), and 72 years (55-89); 58.3%, 60.0%, and 80.0% of patients were male. Patient demographic and baseline characteristics are summarized in Table 2 below.
Table 2
Safety lead-in
AML cohort MDS cohort
Characteristic cohort N=30 N=30 N=12
Sex
Female 5 (41.7) 12 (40.0) 6 (20.0)
Male 7 (58.3) 18 (60.0) 24 (80.0)
Age, y 72 (59-89) 74 (56-87) 72 (55-89) Race White 11 (91.7) 22 (73.3) 24 (80.0) Black 0 1 (3.3) 0 Asian 1 (8.3) 1 (3.3) 0
Other/unknown 0 6 (20.0) 6 (20.0) Diagnosis3 AML 3 (25.0) 30 (100.0) N/A
MDS 7 (58.3) N/A 27 (90.0) CMML 1 (8.3) N/A 3 (10.0)
Disease history de novo 18 (60.0) 27 (90.0)
Secondary AML/MDS 12 (40.0) 3 (10.0) Prior hematologic disease 11 (36.6) 2 (6.7) C h e mot h e ra py/rad i oth e ra py 1 (3.3) 1 (3.3)
ELN risk stratification for AML1 Favorable 1 (3.3) N/A Intermediate 10 (33.3) N/A Adverse 18 (60.0) N/A Unknown 1 (3.3) N/A
MDS IPSS-R score2 >3-4.5 (intermediate) N/A 3 (11.1)
>4.5-6 (high) N/A 15 (55.6)
>6 (very high) N/A 9 (33.3)
MDS with >5% BM blasts - N/A 22 (73.3)
ANC <500/pL - 10 (33.3) 7 (23.3)
ANC <1000/pL - 14 (46.7) 16 (53.3)
BM blasts - 32 (9-90) 9 (0-22)
Hemoglobin <9 g/dL - 19 (63.3) 16 (53.3)
Platelets <50, 000/pL - 16 (53.3) 7 (23.3)
Data given as n (%) except Age and BM blasts, given as median (range).
3 unknown for one patient in the lead in safety cohort
AML=acute myeloid leukemia; ANC=absolute neutrophil count; BM=bone marrow; CMML=chronic myelomonocytic leukemia; ELN=European LeukemiaNet;
IPSS-R=Revised International Prognostic Scoring System; MDS=myelodysplastic syndromes; N/A=not applicable
1 Rollig C, et at. “Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system.” J Clin Oncol. 2011 ;29(20):2758-2765, the contents of which are incorporated herein by reference in their entirety
2 Greenberg P.L., etal. “Revised international prognostic scoring system for myelodysplastic syndromes.” Blood. 2012;120(12):2454-2465, the contents of which are incorporated herein by reference in their entirety
As of the data cut-off, 100%, 93.3%, and 86.7% of patients in the lead-in safety, AML, and MDS cohorts, respectively, had discontinued glasdegib and/or azacitidine treatment (Table 3). The main reasons for discontinuation from glasdegib and azacitidine, respectively, were AEs (50.0% and 33.3%) in the lead-in safety cohort, AEs (23.3%, each) and insufficient clinical response (23.0%, each) in the AML cohort, and AEs (33.3% and 30.0%) in the MDS cohort. Table 3
Safety lead-in
AML cohort MDS cohort cohort
Assigned to treatment 12 31 30
Treated 12 (100) 30 (96.8) 30 (100)
Glasdegib and/or azacitidine 12 (100) 28 (93.3) 26 (86.7) discontinued
Glasdegib and/or azacitidine treatment 0 2 (6.7) 4 (13.3) ongoing at data cut-off
Study discontinuation 12 (100) 24 (80.0) 15 (50.0) Death 8 (66.7) 21 (70.0) 14 (46.7)
Patient-requested 1 (8.9) 3 (10.0) 1 (3.3)
Other 3 (25.0) 0 0
Study ongoing at data cut-off N/A 6 (20.0) 15 (50.0)
Data given as n (%) except Assigned to treatment, given as n.
AML=acute myeloid leukemia; MDS=myelodysplastic syndromes; N/A=not applicable
Safety Results - Lead-in safety cohort
In the lead-in safety cohort, the safety profile of glasdegib plus azacitidine was determined to be consistent with those of glasdegib or azacitidine alone with no evidence of drug-drug interactions. The median (range) treatment duration was 2.7 months (0.8-14.0); the median (range) exposure to both glasdegib and azacitidine was 3.5 cycles (1-15). Any grade all-causality treatment-emergent AEs (TEAEs) occurred in 100% (maximum Grade 3/4, 66.7 %) of patients in the lead-in safety cohort (Table 4). Table 4
TEAEs (all causalities) in the lead-in safety cohorts
Lead-in safety cohort
N=12
AEs 12 (100)
Serious AEs 9 (75.0)
Grade 3 or 4 AEs 8 (66.7)
Grade 5 AEs 2 (16.7)
Discontinued glasdegib due to AEs 6 (50.0)
Discontinued azacitidine due to AEs 4 (33.3)
Glasdegib dose reduced or temporarily 8 (66.7) discontinued due to AEs
Azacitidine dose reduced or 4 (33.3) temporarily discontinued due to AEs All data given as n (%).
AE=adverse events; AML=acute myeloid leukemia; MDS=myelodysplastic syndromes; TEAE=treatment-emergent adverse event
The most frequently (>30%) reported TEAEs were predominantly gastrointestinal, hematologic, and Hh-inhibitor class effects (eg, muscle spasms, dysgeusia, alopecia, weight loss) (Table 5).
Table 5
TEAEs (all causality) occurring in >20% of patients in the lead-in safety cohort
Grade 3 Grade 4 Grade 5 Any grade
Any AE 3 (25.0) 5 (41.7) 2 (16.7) 12 (100)
Anemia 8 (66.7) 1 (8.3) 0 9 (75.0)
Constipation 0 0 0 9 (75.0)
Nausea 0 0 0 8 (66.7)
Diarrhea 0 0 0 6 (50.0)
Fatigue 1 (8.3) 0 0 6 (50.0)
Neutropenia 1 (8.3) 5 (41.7) 0 6 (50.0)
Dysgeusia 0 0 0 5 (41.7)
Electrocardiogram QT 1 (8.3) 0 0 5 (41.7) prolonged
Weight decreased 0 0 0 5 (41.7)
Alopecia 0 0 0 4 (33.3)
Dyspnea 0 1 (8.3) 0 4 (33.3)
Febrile neutropenia 4 (33.3) 0 0 4 (33.3)
Muscle spasms 1 (8.3) 0 0 4 (33.3)
Pyrexia 1 (8.3) 0 0 4 (33.3)
Rhinorrhea 0 0 0 4 (33.3)
Vomiting 0 0 0 4 (33.3)
Cellulitis 0 1 (8.3) 0 3 (25.0) Cough 0 0 0 3 (25.0)
Folliculitis 0 0 0 3 (25.0)
Hyponatremia 1 (8.3) 0 0 3 (25.0)
Injection site erythema 0 0 0 3 (25.0)
Edema peripheral 0 0 0 3 (25.0)
Pneumonia 0 1 (8.3) 0 3 (25.0)
Pollakiuria 0 0 0 3 (25.0)
Rash 0 0 0 3 (25.0)
Thrombocytopenia 0 3 (25.0) 0 3 (25.0)
Urinary tract infection 1 (8.3) 0 0 3 (25.0)
All data given as n (%).
AE=adverse event; TEAE=treatment-emergent adverse events
Serious AEs were reported by 9 patients (75.0%), 7 patients (58.3%) had serious AEs considered to be treatment-related (per investigator’s assessment), of which none were reported in more than one patient except for febrile neutropenia (4 patients [33.3%]). Six patients (50.0%) permanently discontinued study treatments due to AEs, with 4 patients (33.3%) discontinuing both glasdegib and azacitidine. One patient permanently discontinued glasdegib treatment due to glasdegib-related muscle spasms. Eight patients (66.7%) temporarily discontinued or reduced the dose of glasdegib and/or azacitidine due to AEs. A total of 9 patients (75.0%) died, the major cause of being the disease under study (41.7%). No patients died within 30 days after the first dose of study treatment; one patient (8.3%) died within 60 days of the first dose of study treatment.
Safety Results - Expansion phase
In the AML and MDS cohorts, respectively, the median (range) treatment duration was 5.0 months (0.3-20.2) and 4.7 months (0.4-16.4); the median (range) dose of glasdegib and azacitidine was 5 cycles (1-19) and 5 cycles (1-16). Any grade all-causality TEAEs occurred in 100% (maximum Grade 3/4, 66.7%) of patients in the AML cohort and 100% (maximum Grade 3/4, 80.0%) of patients in the MDS cohort (Tables 6, 7 and 8). Table 6
TEAEs (all causalities) in the AML, and MDS cohorts
AML cohort MDS cohort
N=30 N=30
AEs 30 (100) 30 (100)
Serious AEs 24 (80.0) 18 (60.0) Grade 3 or 4 AEs 20 (66.7) 24 (80.0) Grade 5 AEs 8 (26.7) 4 (13.3)
Discontinued glasdegib due to AEs 10 (33.3) 10 (33.3) Discontinued azacitidine due to AEs 10 (33.3) 9 (30.0) Glasdegib dose reduced or temporarily 19 (63.3) 19 (63.3) discontinued due to AEs Azacitidine dose reduced or temporarily 10 (33.3) 16 (53.3) discontinued due to AEs
All data given as n (%).
AE=adverse events; AML=acute myeloid leukemia; MDS=myelodysplastic syndromes; TEAE=treatment-emergent adverse event
Table 7
TEAEs (all causality) occurring in ³20% of patients in the AML cohort
Grade 3 Grade 4 Grade 5 Any grade
Any AE 10 (33.3) 10 (33.3) 8 (26.7) 30 (100)
Nausea 2 (6.7) 0 0 19 (63.3)
Constipation 1 (3.3) 0 0 18 (60.0)
Decreased appetite 6 (20.0) 0 0 17 (56.7)
Diarrhea 2 (6.7) 0 0 16 (53.3)
Vomiting 2 (6.7) 0 0 14 (46.7)
Pyrexia 0 0 0 10 (33.3)
Muscle spasms 0 0 0 9 (30.0)
Dyspnea 1 (3.3) 0 0 8 (26.7)
Fall 1 (3.3) 0 0 8 (26.7)
Fatigue 0 0 0 8 (26.7)
Febrile neutropenia 8 (26.7) 0 0 8 (26.7)
Hypokalemia 0 0 0 8 (26.7)
Hyponatremia 1 (3.3) 1 (3.3) 0 8 (26.7)
Abdominal pain 1 (3.3) 0 0 7 (23.3)
Anemia 6 (20.0) 1 (3.3) 0 7 (23.3)
Cough 0 0 0 7 (23.3)
White blood cell count 2 (6.7) 5 (16.7) 0 7 (23.3) decreased
Back pain 2 (6.7) 0 0 6 (20.0)
Electrocardiogram QT 2 (6.7) 1 (3.3) 0 6 (20.0) prolonged
Hypomagnesemia 0 0 0 6 (20.0)
Insomnia 0 0 0 6 (20.0)
All data given as n (%).
AE=adverse event; AML=acute myeloid leukemia; TEAE=treatment-emergent adverse event
Table 8
TEAEs (all causality) occurring in >20% of patients in the MDS cohort
Grade 3 Grade 4 Grade 5 Any grade
Any AE 10 (33.3) 14 (46.7) 4 (13.3) 30 (100)
Nausea 2 (6.7) 0 0 20 (66.7)
Constipation 0 0 0 15 (50.0)
Muscle spasms 1 (3.3) 0 0 15 (50.0)
Diarrhea 3 (10.0) 0 0 14 (46.7)
Dysgeusia 0 0 0 13 (43.3)
Anemia 8 (26.7) 0 0 12 (40.0)
Neutrophil count 3 (10.0) 7 (23.3) 0 11 (36.7) decreased
Platelet count decreased 4 (13.3) 6 (20.0) 0 11 (36.7)
Vomiting 0 0 0 10 (33.3)
Decreased appetite 0 0 0 9 (30.0)
Fatigue 2 (6.7) 0 0 9 (30.0)
Hypotension 2 (6.7) 1 (3.3) 0 9 (30.0)
Edema peripheral 0 0 0 8 (26.7)
White blood cell count 5 (16.7) 2 (6.7) 0 8 (26.7) decreased
Alopecia 0 0 0 7 (23.3)
Dizziness 1 (3.3) 0 0 7 (23.3)
Fall 2 (6.7) 0 0 7 (23.3)
Febrile neutropenia 6 (20.0) 1 (3.3) 0 7 (23.3)
Headache 0 0 0 7 (23.3)
Dyspnea 0 0 0 6 (20.0)
Hyperglycemia 3 (10.0) 0 0 6 (20.0)
Hypomagnesemia 0 0 0 6 (20.0)
Hyponatremia 2 (6.7) 0 0 6 (20.0)
Sepsis 1 (3.3) 5 (16.7) 0 6 (20.0)
All data given as n (%).
AE=adverse event; MDS=myeloid dysplastic syndrome; TEAE=treatment-emergent adverse event
The most frequently (>10%) reported non-hematologic Grade >3 TEAEs were decreased appetite (20.0%), electrocardiogram QT prolongation (10.0%), and hypertension (10.0%) in the AML cohort; and sepsis (20.0%), diarrhea (10.0%), hypotension (10.0%), pneumonia (10.0%), and hyperglycemia (10.0%) in the MDS cohort. The most frequently reported (>5%) reported non-hematologic serious AEs were pyrexia (13.3%), electrocardiogram QT prolongation (6.7%) and urinary tract infection (6.7%) in the AML cohort, and sepsis (16.7%) and pyrexia (6.7%) in the MDS cohort.
Eleven patients (36.6%) in the AML cohort and 10 patients (33.3%) in the MDS cohort permanently discontinued study treatments due to AEs, with 9 patients (30.0%) in each cohort discontinuing both glasdegib and azacitidine. No patients in the AML cohort discontinued glasdegib because of AEs associated with the inhibition of the Hh signaling pathway in normal tissues. Two patients in the MDS cohort permanently discontinued both glasdegib and azacitidine due to dysgeusia; both AEs were considered related to glasdegib. In the AML and MDS cohorts, respectively, 19 patients (63.3%) and 21 patients (70.0%) temporarily discontinued or reduced the dose of glasdegib and/or azacitidine due to AEs.
Six (20.0%) and 3 (10.0%) patients in the AML and MDS cohorts, respectively, had electrocardiogram QT prolongation, 5 (16.7%) and 2 (6.7%) of which were considered to be treatment-related and 1 (3.3%) in each cohort was considered to be related to concomitant drug treatment. Glasdegib was temporarily discontinued or the glasdegib dose was reduced due to electrocardiogram QT prolongation in 5 (16.7%) and 2 (6.7%) patients in the AML and MDS cohorts, respectively. None of the electrocardiogram QT prolongations resulted in permanent treatment discontinuation.
Efficacy Results - lead in safety cohort
Of the 12 patients in the lead-in safety cohort, 3 patients with AML (25.0%) achieved CR, 2 patients with MDS (16.7%) achieved marrow CR, and hematologic improvement of at least 1 lineage was observed in 6 patients (50.0%).
Efficacy Results- expansion phase
The overall response rate was 30.0% in the AML cohort (defined as CR + CRi + PR), and 33.3% in the MDS cohort (defined as CR + PR + hematologic improvement). An additional 3.3% of patients in the AML cohort achieved a morphologic leukemia-free state, and 15.7% of patients in the MDS cohort achieved a marrow CR. A total of 6 patients (20.0%) in the AML cohort and 4 patients (13.3%) in the MDS cohort achieved CR. Best overall response with other outcomes of interest for patients in the AML and MDS cohorts are summarized in Table 9. Table 9
Investigator-reported best overall response for patients in the AML and MDS cohorts
Best overall response, n (%)
All patients Favorable/intermediate* Adverse risk* Unknown*
AML cohort N = 30 n = 11 N = 18 N = 1
CR 6 (20.0) 3 (27.3) 3 (16.7) 0
CRi 1 (3.3) 1 (9.1) 0 0
CR + CRi 7 (23.3) 4 (36.4) 3 (16.7) 0
PR 2 (6.7) 1 (9.1) 1 (5.6) 0
MLFS 1 (3.3) 0 1 (5.6) 0
SD 6 (20.0) 3 (27.3) 2 (11.1) 1 (100)
PD 4 (13.3) 1 (9.1) 3 (16.7) 0
Treatment failure 1 (3.3) 1 (9.1) 0 0
Not evaluable 9 (30.0) 1 (9.1) 8 (44.4) 0
All patients Intermediate risk† High risk† Very high risk†
MDS cohort n = 30 n = 3 n = 15 n = 9
CR 4 (13.3) 0 3 (0.0) 0
PR 3 (10.0) 0 1 (6.7) 1 (11.1)
HI without CR or PR 3 (10.0) 0 2 (13.3) 1 (11.1)
CR + PR + HI without 10 (33.3) 0 6 (40.0) 2 (22.2) CR or PR mCR 5 (16.7) 0 2 (13.3) 2 (22.2)
SD 8 (26.7) 2 (66.7) 4 (26.7) 2 (22.2)
CR + PR + mCR + SD 20 (66.7) 2 (66.7) 10 (66.7) 5 (55.6)
Treatment failure 3 (10.0) 0 2 (13.3) 1 (11.1)
Not evaluable 7 (23.3) 1 (33.3) 3 (20.0) 3 (33.3)
CR=complete remission; CRi=complete remission with incomplete hematologic response; HI=hematologic improvement; mCR=marrow complete remission; MLFS=morphologic leukemia-free state; PD=progressive disease; PR=partial remission; SD=stable disease
* ELN risk category - Rollig C, et al. “Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system.” J Clin Oncol. 2011 ;29(20):2758-2765, the contents of which are incorporated herein by reference in their entirety. †IPSS-R risk category for patients with MDS only- Greenberg P.L., et at. “Revised international prognostic scoring system for myelodysplastic syndromes.” Blood. 2012;120(12):2454-2465, the contents of which are incorporated herein by reference in their entirety.
For patients in the AML and MDS cohorts the median (range) time to response was 0.5 months (0.23-3.12) and 0.6 months (0.20-2.69); and median (range) duration of response was 5.2 months (0.03-14.13) and 6.24 months (0.03-21.03).
In the AML and MDS cohorts, median (range) follow-up for OS was 8.5 months (0.8-20.4) and 12.9 months (0.5-22.0), with 22 (77.3%) and 15 (50.0%) patients known to have died by the time of data cut-off. In both cohorts, the main cause of death was the disease under study or complications of the disease related to bleeding or infections. Of the patients in the AML and MDS cohorts respectively, 3 (10.0%) and 1 (3.3%) died within 30 days of the first dose of study treatment, and 6 (20.0%) and 1 (3.3%) died within 60 days. In the AML cohort, median OS was 9.2 (95% Cl, 6.2-14.0) months, with a 12-month and 18-month survival probability of 36.8% (95% Cl, 19.7- 54.2) and 21.5% (95% Cl, 8.5-38.4), respectively (Figure 1A). The median (95% Cl) OS in patients with favorable/intermediate, adverse, and unknown ELN genetic risk was 14.0 (7.7-not evaluable [NE]) months, 5.3 (1.6-10.5) months, and 8.2 (NE-NE) months, respectively and the number of events (n/N, %) in patients with favorable/intermediate, adverse, and unknown ELN genetic risk was 8/11 (72/7%); 13/18 (72.2%), and 1/1 (100%), respectively (Figure 1B). In the MDS cohort, the median OS was 15.8 (95% Cl, 9.3-21.9) months, with a 12-month and 18-month survival probability of 65.6% (95%, Cl, 45.5-79.8) and 39.8% (95%, Cl, 16.5-62.5%) respectively (Figure 2A). The median (95% Cl) OS in patients with intermediate, high and very high IPSS-R genetic risk was 21.9 (NE-NE) months, NE (4.7-NE) months, and 12.1 (0.5-17.5) months, and the number of events (n/N, %) in patients with intermediate, high and very high IPSS-R genetic risk was 1/3 (33.3%), 6/15 (40.0%) and 7/9 (77.8%), respectively (Figure 2B).
In both the AML and MDS cohorts, bone marrow recovery of absolute neutrophil count (ANC), hemoglobin, and platelet counts at 2 thresholds was seen following glasdegib + azacitidine treatment, regardless of baseline counts (Table 10). Recovery occurred as early as Cycle 1 in a meaningful proportion of patients. In the MDS cohort, early platelet recovery correlated with response to treatment; 54.0% (n = 7/13) of patients with platelets >100,000/pL at cycle 2 day 1 achieved complete or partial remission vs 0.0% (n = 0/13) of patients with <100,000/pL, P = .002. Transfusion independence was achieved by 47.4% of patients (n=9/19) in the AML cohort and 46.7% of patients (n-7/15) in the MDS cohort who were transfusion-dependent at baseline (Table 10); the median (range) duration of independence was 5.1 months (1.9-17.4) and 4.8 months (2.0-14.4), respectively.
Table 10
Recovery of ANC, hemoglobin, and platelets, and rates of transfusions in the AML and MDS cohorts
AML cohort MDS cohort
ANC >1000/pL >500/pL >1000/pL ³500/pL n = 30 n = 30 n = 28 n = 28
Recovery in all patients* 19 (63.3) 21 (70.0) 16 (57.1) 22 (78.6)
Achieved recovery during cycle 1 17 (56.7) 21 (70.0) 16 (57.1) 21 (75.0) n = 14 n = 10 n = 15 n = 7
Recovery in patients with baseline ANC <
7 (50.0) 5 (50.0) 5 (33.3) 5 (71.4) threshold*
Achieved recovery during cycle 1 3 (21.4) 3 (30.0) 3 (20.0) 1 (14.3)
Hemoglobin >10 g/dL >9 g/dL >10 g/dL >9 g/dL n = 30 n = 30 n = 29 n = 29
Recovery in all patients* 11 (36.7) 15 (50.0) 13 (44.8) 17 (58.6)
Achieved recovery during cycle 1 7 (23.3) 21 (70.0) 9 (31.0) 18 (62.1) n = 25 n = 19 n = 22 n = 15
Recovery in patients with baseline
6 (24.0) 5 (26.3) 6 (27.3) 6 (40.0) hemoglobin < threshold*
Achieved recovery during cycle 1 4 (16.0) 11 (57.9) 3 (13.6) 6 (40.0)
Platelets ³100,000/pL ³50,000/pL ³100,000/pL ³50,000/pL n = 30 n = 30 n = 29 n = 29
Recovery in all patients* 14 (46.7) 19 (63.3) 15 (51.7) 24 (82.8)
Achieved recovery during cycle 1 11 (36.7) 17 (56.7) 17 (58.6) 24 (82.8) n = 25 n = 16 n = 21 n = 7
Recovery in patients with baseline platelets 4
10 (40.0) 7 (43.8) 9 (42.9) < threshold* (57.1) 3 9
Achieved recovery during cycle 1 7 (28.0) 4 (57.1)
(18.8) (42.9)
Transfusion independence rates† n = 19 n = 15
Patients with transfusion dependence at
9 (47.4) 7 (46.7) baseline
Median duration of independence 154 (58-528) 145 (61-438)
Data given as n (%) except median duration of independence, given as days (range).
'Required measurement at >2 consecutive visits. tRequired no packed red blood cell or platelet transfusions for >8 weeks. Pharmacokinetics results
A summary of PK parameters for glasdegib and azacitidine from the lead in safety cohort, when dosed alone or in combination, are shown (Table 11 and Table 12). There was no evidence of change in area under the concentration-time curve (AUC) or maximum plasma concentration (Cmax) of either glasdegib or azacitidine when dosed in combination.
Table 11
Descriptive summary of glasdegib PK parameters dosed alone or in combination with azacitidine in the lead-in cohort, reported for all patients
Glasdegib alone Glasdegib + azacitidine
(Cycle 1 Day 15) (Cycle 1 Day 7) n=9 n=12
AUCtau , ng-h/mL 14,350 (61) 13,230 (49)
Cmax, ng/mL 991.4 (57) 1013.0 (58)
T max, h 1.50 (1.00-6.02) 1.05 (1.00-5.70)
Data given as geometric mean (geometric % coefficient of variation) except Tmax, given as median (range).
AUCtau=area under the concentration-time curve from time zero to end of dosing interval; Cmax=maximurn plasma concentration; PK=pharmacokinetic; Tmax=tirne to maximum plasma concentration Table 12
Descriptive summary of azacitidine PK parameters dosed alone or in combination with glasdegib in the lead-in cohort, reported for all patients
Azacitidine alone Glasdegib + azacitidine
(Cycle 1 Day 1) (Cycle 1 Day 7) n=12 n=12
AUCinf (ng h/mL) 1319 (19) 1260 (21)
Cmax (ng/mL) 778.5 (23) 716.9 (32)
T max (h) 0.50 (0.00-1.00) 0.50 (0.25-1.08)
Data given as geometric mean (geometric % coefficient of variation) except Tmax, given as median (range).
AUCmf=area under the concentration-time curve from time zero to infinity; Cmax=maximum plasma concentration; PK=pharmacokinetic; Tmax=tirne to maximum plasma concentration
Glasdegib plasma concentration data for patients in the AML and MDS cohorts is summarized as follows.
Thirty patients in the acute myeloid leukemia (AML) cohort provided glasdegib plasma concentration data; 25 and 17 patients were considered dose compliant and provided steady-state plasma concentration measured at the end of a dosing interval (Ctrough) parameter data on Cycle 1 Day 15 and Cycle 2 Day 1, respectively. vThe observed glasdegib steady-state Ctrough geometric mean (geometric % coefficient of variance [CV]) value for glasdegib was 468 ng/mL (88%) on Cycle 1 Day 15 and 463 ng/mL (110%) on Cycle 2 Day1.
In the myelodysplastic syndromes (MDS) cohort, 30 patients provided glasdegib plasma concentration data; 22 and 18 patients were considered dose compliant and provided steady-state Ctrough parameter data on Cycle 1 Day 15 and Cycle 2 Day 1, respectively. The observed glasdegib steady-state Ctrough geometric mean (geometric % CV) value for glasdegib was 308 ng/mL (95%) on Cycle 1 Day 15 and 167 ng/mL (52%) on Cycle 2 Day 1.
Biomarker Assessments
Gene mutations that correlate with overall survival and response
Whole-exome sequencing was performed using bone marrow aspirate samples from 26 patients in the AML cohort and 23 patients in MDS cohort. The primary analysis focused on 115 genes with a known role in AML/MDS or the Hh signaling pathway, although an analysis of all genes was performed. Of the 115 genes of interest, those with a mutation frequency of >10% are shown in Figure 3: the most common (>20.0%) were TET2 (35.0%), ASXL1 (29.0%), SMO (27.0%), TP53 (27.0%), GBP4 (25%), DNMT3A (21.0%), and RUNX1 (21.0%). While 13 patients (27.0%) had a SMO mutation, none of these mutations were in regions previously identified as playing a role in resistance to SMO inhibitors, and it is not clear if these are functionally relevant mutations.
Among patients in the AML cohort, of all the genes identified with a mutation at baseline, only 31 genes (with >4 mutations) showed a significant association with OS (P> 0.05) (Table 13).
Table 13
Baseline gene mutations that correlate with OS in patients with AML
Figure imgf000080_0001
CYP2D6 5 1.3 21 10.5 13.32 <0.001
(19.2) 0 8 6 8 (80.8) (7.7-15.6) (3.42-51.82)
TMPRSS13 6 1.5 20 13.9 6.11 0.001
(23.1) (0.8-10.4) (76.9) (7.7-15.6) (2.06-18.07)
CROCC 6 1.7 20 10.5 4.97 0.002
(23.1) (0.8-13.9) (76.9) (7.7-15.6) (1.76-14.05)
TMEM67 4 1.5 22 10.5 7.49 0.002
(15.4) (0.8-7.7) (84.6) (6.8-15.6) (2.06-27.29)
TTLL10 13 14.0 13 6.8 0.23 0.004
(50.0) (9.2-NE) (50.0) (1.6-8.9) (0.08-0.63)
DMTF1 5 3.8 21 10.5 4.92 0.008
(19.2) (1 .0-9.2) (80.8) (7.7-15.6) (1.51-15.98)
RERE 4 3.9 22 10.5 5.11 0.013
(15.4) (1 .3-7.7) (84.6) (6.8-15.6) (1.41-18.47)
ZNF831 4 3.0 22 10.5 5.49 0.013
(15.4) (1 .7-6.8) (84.6) (7.7-15.6) (1.43-21.12)
LOC338667 7 15.6 19 7.7 0.20 0.014
(26.9) (14.0-NE) (73.1) (1.7-10.2) (0.06-0.72)
SIRT6 4 1.9 22 10.5 4.43 0.015
(15.4) (1.0-10.2) (84.6) (6.8-15.6) (1.34-14.68)
RP1L1 4 1.7 22 10.5 4.17 0.018
(15.4) (1.0-10.4) (84.6) (6.8-15.6) (1.28-13.58)
AK8 4 1.5 22 10.4 4.04 0.019
(15.4) (1.0-10.5) (84.6) (6.8-15.6) (1.26-12.96)
ALS2CR11 4 3.0 22 10.5 4.35 0.022
(15.4) (1 .7-8.9) (84.6) (6.8-15.6) (1.23-15.34)
SPTBN5 10 6.2 16 10.5 2.98 0.023
(38.5) (0.8-14.0) (61 .5) (7.7-NE) (1.16-7.65) CCDC37 5 3.8 21 10.5 4.04 0.026
(19.2) (0.8-9.2) (80.8) (6.8-15.6) (1.18-13.76)
DCHS2 5 2.1 21 10.4 3.34 0.029
(19.2) (0.8-10.5) (80.8) (6.8-15.6) (1.13-9.85)
TIGD5 8 5.0 18 10.5 3.02 0.029
(30.8) (1.3-14.4) (69.2) (7.7-NE) (1.12-8.10)
NBPF1 5 6.8 21 10.5 3.47 0.031
(19.2) (0.8-10.2) (80.8) (6.2-15.6) (1.12-10.75)
LOXHD1 12 5.3 14 13.9 2.71 0.034
(46.2) (1.0-10.4) (53.8) (7.7-NE) (1.08-6.79)
TMEM194B 7 NE 19 9.2 0.20 0.034
(26.9) (3.8-NE) (73.1) (1.7-10.5) (0.05-0.89)
KRTAP9-9 4 4.7 22 10.5 3.56 0.036
(15.4) (1.0-10.2) (84.6) (6.2-15.6) (1.09-11.67)
ANK1 5 3.8 21 10.4 3.10 0.037
(19.2) (1.0-14.0) (80.8) (7.7-15.6) (1.07-8.95)
FAT 2 4 6.5 22 10.5 3.64 0.037
(15.4) (0.8-9.2) (84.6) (3.8-15.6) (1.08-12.27)
FLT3 6 NE 20 8.9 0.20 0.039
(23.1) (1.0-NE) (76.9) (2.1-10.5) (0.04-0.92)
PDE6B 5 1.7 21 10.5 3.47 0.039
(19.2) (0.8-10.4) (80.8) (6.8-15.6) (1.07-11.31)
SLC02B1 4 5.3 22 10.5 3.68 0.040
(15.4) (1.7-8.9) (84.6) (6.2-15.6) (1.06-12.78)
RBBP6 6 8.3 20 13.9 3.08 0.041
(23.1) (1.0-10.4) (76.9) (3.8-15.6) (1.05-9.03)
ANKRD65 5 NE 21 8.3 0.21 0.042
(19.2) (9.2-NE) (80.8) (2.1-10.5) (0.05-0.95)
PRAMEF11 4 4.2 22 10.5 3.31 0.045
(15.4) (1.0-10.4) (84.6) (6.2-15.6) (1.03-10.66)
LOC642643 4 3.0 22 10.4 4.59 0.047
(15.4) (1.3-NE) (84.6) (6.8-14.4) (1.02-20.64)
FAT4 6 NE 20 8.9 0.22 0.048
(23.1) (1.6-NE) (76.9) (2.1-10.5) (0.05-0.99)
Genes with a mutation frequency of >4 mutations and P-value <0.05 are reported. aBased on the Cox proportional hazards model using wild type as the reference group. bP-value from the Cox proportional hazards model.
AML=acute myeloid leukemia; CI=confidence interval; HR=hazard ratio; NE= not evaluable OS=overall survival
Of the 115 genes previously implicated in AML/MDS or the Hh signaling pathway, improved OS was only found to correlate with mutations in FLT3 (mutated vs. wildtype, median OS (95%, Cl) months NE (1.0-NE) and 8.9 (2.1-10.5) respectively, with number of events n/N 2/6 and 17/20 respectively, with a hazard ratio [HR] 0.20 [95% Cl, 0.04-0.93]; P= 0.039; Figure 4A). We detected FLT3 mutations in 6/26 patients (23.1%) in the AML cohort, which is similar to the previously reported rate of 20-30% in patients with AML (Tyner J.W. et at., “Functional genomic landscape of acute myeloid leukemia.” Nature, 2018, 562 (7728): 526-31, the contents of which are incorporated herein by reference in their entirety). Three were tyrosine kinase domain mutations (TKD), and two were FLT3- ITD. Additionally, these patients were classified as adverse (n=3) and intermediate (n=3) ELN risk. Of these 6 patients, with a median age of 77.5 years old, the median OS was not reached even after 20 months, and 2 patients (33%) achieved a CR. Five of the six patients were categorized as de novo AML (see results in Table 14).
Table 14
Listing of FLT3 mutations with clinical characteristics in patients with AML
BM Best overall Transfusion blasts at ELN risk response dependence
Age, AML baseline, stratification (locally/centrall (baseline/on- FLT3 y Sex diagnosis % (25) y determined) treatment) mutation
Patient 84 Male cte novo 39 Adverse CR- MRD- Dependent/ V194M 1 independent
Patient 68 Male Secondary Unknown Intermediate PD Independent/ N841Y
2 AML dependent
Patient 71 Female cte novo 90 Intermediate CR- MRD- Dependent/ N676S 3 independent
Patient 81 Male cte novo 90 Adverse Not evaluable Dependent/ A680V 4 dependent
Patient 80 Female de novo 59 Adverse PD Independent/ ITD 5 dependent (F605-
P606ins1
2)
Patient 75 -Female de novo 60 Intermediate CR-MRD+ Independent/ ITD 6 independent (E598-
Y599, ins5;
E589-
F590ins1
2)
AML=acute myeloid leukemia; BM=bone marrow; CR+=complete remission-positive; CR-=complete remission-negative; ELN=European LeukemiaNet; MRD+=minimal residual disease-positive; MRD-=minimal residual disease-negative; PD=progressive disease; SD=stable disease
Among patients in the MDS cohort, mutations in only 8 genes (with >4 mutations) were found to correlate with OS (Table 15). Of these genes, TP53 was the only gene known to be associated with AML/MDS or the Hh signaling pathway and was associated with worse OS (mutated vs wildtype, HR 4.45 [95% Cl, 1.24-16.01]; P = .022) (Figure 3B). TP53 mutations occurred in 4/22 patients (18.2%) in the MDS cohort, which is similar to the previously reported rate of 13% in patients with MDS (Palomo L., et at. “Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms.” Blood. 2020; 136(16): 1851 -1862, the contents of which are incorporated herein by reference in their entirety).
Table 15
Baseline gene mutations that correlate with OS in patients with MDS
Figure imgf000083_0001
ANKLE1 6 4.4 17.5 (7.2-21.9) 7.34
(27.3) (0.5-12.1) 6 (2.02-26.71) 002
(72.7)
NPIPB11 4 5.9 17.5 (7.2-21.9) 5.01
(18.2) (2.0-9.3) 8 (1.31-19.18) 018
(81.8)
LOXHD1 13 7.2 21.9 (4.4-21.9) 6.00
(59.1) (3.9-17.5) (1.29-27.92) 022
(40.9)
TP53 4 5.8 17.5 (7.2-21.9) 4.45
(18.2) (0.5-12.1) 8 (1.24-16.01) 022
(81.8)
SPATA31A3 4 6.0 17.5 (7.2-21.9) 4.09
(18.2) (2.0-12.1) 8 (1.13-14.74) 032
(81.8)
LOC100653515 6 5.9 17.6 (9.3-21.9) 3.78
(27.3) (0.5-NE) 6 (1.10-12.97) 035
(72.7)
PIEZ02 9 7.2 17.5 (7.2-21.9) 3.59
(40.9) (2.0-NE) 3 (1.04-12.45) 044
(59.1)
ZNF268 9 21.9 7.2 (4.0-17.5) 0.21
(40.9) (3.9-21.9) 3 (0.05-0.97) 046
(59.1)
Genes with a mutation frequency of >4 mutations and P-value < .05 are reported. 'Based on the Cox proportional hazards model using mutation as the reference group.
†P-value from the unstratified log-rank test.
Cl, confidence interval; HR, hazard ratio; MDS, myelodysplastic syndromes; NE, not evaluable; OS, overall survival. Mutations in the Hh signaling pathway did not correlate with OS in patients in the
AML cohort.
The effect of baseline mutations on response (defined as CR) are reported in Table 16; no correlation with any genes associated with the Hh pathway or the development of AML or MDS was determined among these patients.
Table 16 Baseline gene mutation associated with response (CR) to treatment in patients with AML and MDS
Gene No. of mutations P-value*
Patients with AML
PIEZ01 8 (30.8) .004 LEMD1 5 (19.2) .005
LOC101060022 5 (19.2) .005 LOC728728 6 (23.1) .013 B3GNT6 13 (50.0) .015 FAM120C 4 (15.4) .028 GOLGA80 4 (15.4) .028 LTK 4 (15.4) .028 NBPF9 4 (15.4) .028 NLRC5 4 (15.4) .028 SNX29 4 (15.4) .028 SPIRE2 4 (15.4) .028 ZNF804B 4 (15.4) .028
Patients with MDS ALDH4A1 4 (18.2) .026 CDH4 4 (18.2) .026 EIF5AL1 4 (18.2) .026 KRBA1 4 (18.2) .026 ULK4 4 (18.2) .026 PPP1R37 5 (22.7) .043 PRSS41 5 (22.7) .043
Genes with a mutation frequency of >4 mutations and P-value < .05 are reported.
*P-value from the Fisher’s exact test. AML, acute myeloid leukemia; CR, complete remission; MDS, myelodysplastic syndromes. Molecular clearance of mutations in paired samples in patients who achieve CR
Molecular clearance of mutations at CR was analyzed in 6 patients in the AML cohort and 3 patients in the MDS cohort. Of the 115 genes of interest, Table 17 shows mutations that were detected at baseline (variant allele frequency [VAF] > 0.05) in each of these patients and that were found to be significantly reduced or cleared (VAF <0.05) at CR.
Table 17
Mutations cleared (VAF <0.05) at response in patients with AML
Figure imgf000085_0001
CR=complete remission; mCR=marrow complete remission; MRD+=minimal residual disease-positive; MRD-= minimal residual disease-negative; VAF=variant allele frequency Mutations in all of the genes that displayed a >3-fold decrease or increase in VAF when patients achieved CR and when they subsequently relapsed (i.e. bone marrow blast >5%) are shown in Figure 5 and Figure 6. Three of the four patients with a FLT3 mutation at baseline cleared their FLT3 mutation at CR; the one instance where FLT3 was not cleared was in a patient with AML who had a V194M mutation, and it is not clear if this mutation is functionally relevant to driving FLT3 activation. Additionally, this patient had a well described IDH1 (R143H) mutation that was effectively cleared by glasdegib + azacitidine. In the three cases where FLT3 mutations were cleared, these mutations were a N676S, a FLT3- ITD, and a D835E mutation.
While mutations detected at baseline were frequently cleared at CR, not all mutations were cleared and in two patients none of the genes associated with AML/MDS or the Hh signaling pathway were cleared (AML patient #6 and MDS patient #3). AML patient #6 only had 24 genes with mutations that changed >3-fold VAF at CR, and of these, the VAF’s of only 8 mutations were decreased. MDS patient #3 only had 1 gene with a VAF that changed at CR, and only 8 genes that showed a decrease in their VAF. Interestingly, in this patient, the VAFs of BCOR, NUMA, and U2AF1 all decreased at CR, but were still detectable.
Only three patients who achieved a CR and subsequently relapsed (bone marrow blast >5%) had a suitable bone marrow aspirate sample that could be analyzed by whole exome-sequence analysis (Figure 7). Without wishing to be bound by theory, interestingly there is no evidence suggesting that a single mutation is driving relapse in any of these three patients, as mutations that are initially cleared at CR tend to reappear at relapse. VAFs that increase at relapse are frequently mutations that were present at baseline but significantly reduced or cleared at CR, but then re-appear at relapse. Whilst not wishing to be bound by theory, these observations are consistent with glasdegib + azacitidine reducing but not eliminating key mutations implicated in promoting AML.
Summary and Conclusions
This phase 1b study demonstrated that the addition of glasdegib to azacitidine was generally well tolerated and manageable for patients with newly diagnosed AML, higher-risk MDS, or CMML who are not candidates for intensive induction chemotherapy. Clinical efficacy, as reflected by -overall response rate and transfusion independence, was achieved in patients with AML and patients with MDS receiving glasdegib + azacitidine. Furthermore, a clinical benefit was demonstrated across groups when stratified by genetic risk, was associated with molecular mutation clearance, and with a signal for improved outcomes in patients with AML who had a FLT3 mutation.
The safety data were consistent with the known safety profiles of glasdegib, azacitidine monotherapy, and other SMO inhibitors (Cortes et al., “Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome.” Leukemia (2019), 33 (2): 379-389; Savona M.R. et al., “Phase 1b study of glasdegib, a hedgehog pathway inhibtior, in combination with standard chemotherapy in patients with AML or high risk MDS.” Clin Cancer Res. 2018; 24 (14): 2294-303; Bixby D., etai, “Safety and efficacy of vismodegib in relapsed / refractory acute myeloid leukemia: results of a phase 1b trials.” Br J Haematol., 2019, 185(3): 595-598; Villani A., et al., “Sonidegib: safety and efficacy in reatment of advanced basal cell carcinoma.” Dermatolog. Ther (Heidelb). 202, 10(3): 401-412; and Dombret H., et al. “International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts.” Blood (2015) 126:291-299; the contents of each of which are incorporated herein by reference in their entirety). In the current study, treatment discontinuation due to AEs associated with inhibition of the Hh signaling pathway in normal tissues (e.g., muscle spasms, myalgia and dysgeusia) were infrequent. In the lead-in safety cohort, there was no evidence of potential for drug-drug interaction between glasdegib and azacitidine, as the exposure parameters (AUC and Cmax) for both drugs were similar when dosed alone or in combination.
While comparisons between trials should be considered with caution, in the context of the patient population and duration of follow-up, the response rate and median OS in the AML and MDS cohorts were at least comparable with those previously reported for azacitidine monotherapy. In a phase 3 trial investigating the effects of azacitidine monotherapy in patients with AML, the rate of CR was 19.5% and the median OS was 10.4 months after a median follow-up of 24 months (Dombret H., et al. “International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts.” Blood. 2015;126(3):291-299, the contents of which are incorporated herein by reference in their entirety). In a study of patients with higher-risk MDS and CMML, the overall response rate (CR + partial remission + hematologic improvement) was 38.0% and the median OS was 15 months after a median follow-up of 23 months (Sekeres M.A., et al. “Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117.” J Clin Oncol. 2017;35(24):2745-2753, the contents of which are incorporated herein by reference in their entirety). In addition, the median OS for glasdegib + azacitidine is equivalent to or possibly higher than what was reported previously for glasdegib + LDAC (AML, 8.3 months; MDS, 10.9 months) and therefore appears to be a reasonable alternative combination (Cortes J.E., et al. “Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome.” Leukemia. 2019;33(2):379-389, the contents of which are incorporated herein by reference in their entirety).
Mutations in FLT3, which are commonly associated with poor prognosis in patients with AML (Kiyoi H., et al., “FLT3 mutations in acute myeloid leukemia therapeutic paradigm beyond inhibitor development.” Cancer Sci, 2020, 111 (2): 312- 322, the contents of which are incorporated herein by reference in their entirety), were associated in these patients with significantly improved OS following treatment with glasdegib and azacitidine. Together with results from the BRIGHT AML & MDS 1003 study in patients with AML eligible for intensive chemotherapy receiving glasdegib plus cytarabine + daunorubicin on a 7 + 3 schedule, these studies suggest that combining glasdegib with 7+3 or with azacitidine enhances survival of patients with mutations in FLT3 (Merchant A., et al. “Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or non-intensive chemotherapy in patients with acute myeloid leukemia (AML)” [abstract]. Cancer Research. 2019;79(13 Suppl):LB- 009. Abstract LB-009, the contents of which are hereby incorporated herein by reference in their entirety). Due to the small sample sizes and the exploratory nature of the biomarker analyses, additional verification of these findings in larger randomized trials would be of interest. Of the 3 patients in the AML and MDS cohorts who had a FLT3 mutation at baseline and achieved CR, FLT3 mutations were cleared (VAF <0.05) in all the patients at CR, one of these patients subsequently relapsed and had a bone marrow aspirate sample that could be used for analysis and, at relapse, the VAF of the FLT3 mutation increased, suggesting that clones containing this mutation were not fully cleared at CR. A previous study in patients with AML demonstrated that the expression of GLI2, a major signaling component of the Hh signaling pathway, was increased in the bone marrow of patients with FLT3- ITD mutations versus those with wild-type FLT3 (Lim Y., et at. “Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.” Sci Transl Med. 2015;7(291):291ra296. the contents of which are incorporated herein by reference in their entirety). Using a transgenic mouse model, the authors demonstrated that FLT3- ITD expression and constitutive Hh signaling resulted in enhanced STAT5 signaling and the proliferation of bone marrow myeloid progenitors. The combined inhibition of FLT3 and the Hh pathway reduced leukemic growth both in vitro and in vivo. Without wishing to be bound by theory, together these results suggest that FLT3 and Hh signaling cooperate to promote the development of AML, potentially explaining why the inhibition of Hh signaling in the context of FLT3 mutation may improve OS.
Another important finding of this analysis is that patients receiving glasdegib + azacitidine demonstrated early marrow recovery as evidenced by ANC, hemoglobin, and platelet recoveries beginning in Cycle 1. More than half of evaluable patients who were transfusion-dependent at baseline became transfusion-independent. Few patients required Cycle 2 dose delays due to AEs. In contrast, venetoclax + azacitidine is associated with prolonged cytopenias, with thrombocytopenia (45.0% of patients) and neutropenia (42.0% of patients) indicated as the primary toxicities reported with the treatment combination (DiNardo C.D., et at. “Azacitidine and venetoclax in previously untreated acute myeloid leukemia.” N Engl J Med. 2020;383(7):617-629, the contents of which are incorporated herein by reference in their entirety). Dose interruptions, including dose delays between treatment cycles, were frequently required to allow for hematologic recovery in patients with a response following venetoclax + azacitidine.
In conclusion, this analysis of the BRIGHT AML & MDS 1012 study in patients with newly diagnosed AML, higher-risk MDS, or CMML showed glasdegib + azacitidine to be generally well tolerated, with a manageable safety profile consistent with toxicities associated with azacitidine monotherapy and other marketed inhibitors of the Hh signaling pathway. Clinical benefit was observed in patients with AML who received glasdegib + azacitidine. Patients with AML and FLT3 mutations had improved OS compared to patients who were wild-type for FLT3. These data suggest that further studies of glasdegib + azacitidine in patients with higher risk MDS and MAL harboring FLT3 mutations may be warranted. Example 2 - A study evaluating intensive chemotherapy with or without glasdegib or azacitidine with or without glasdegib in patients with previously untreated AML (BRIGHT AML 1019)
Brief Summary
Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (non-intensive AML population). Glasdegib is being studies in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML).
Primary Objectives
Overall survival [Time Frame: 5 years after last subject randomized]
Secondary Objectives
- Fatigue score measured by the MD Anderson Symptom Inventory (MDASI)- AML/MDS questionnaire [Time Frame: 5 years after last subject randomized, consent withdrawal, or death] - scale is from 0-10 where 0 is not present and 10 is as bad as you can image
- rate of Complete Remission (CR) (including CR with minimal residual disease (MRD)-negative as assessed by multiparametric flow cytometry) [Time Frame: 2 years after last dose of study therapy] - response as defined by the 2017 European LeukemiaNet (ELN) recommendations
- duration of response (defined as CR [includes CR-MRD negative]/CRi or CR/CRh as appropriate) [Time Frame: 2 years after last dose of study therapy] - response as defined by the 2017 European LeukemiaNet (ELN) recommendations
- time to response (CR[includes CR-MRD negative)]/CR with partial hematologic rcovery (CRh) as appropriate) [Time Frame: 2 years after last dose of study therapy] - response as defined by the 2017 European LeukemiaNet (ELN) recommendations
- event-free Survival [Time Frame: 5 years after last subject randomized, consent withdrawal, or death]
- patient reported outcomes (PROs) as measured by the M.D. Anderson Symptom Inventory AML/MDS Module (MDASI-AML/MDS) [Time Frame: 5 years after last subject randomized, consent withdrawal, or death] - measurement Scale from 0-10
- adverse events as graded by NCI CTCAE v4.03 [Time Frame: 5 years after last subject randomized, consent withdrawal, or death]
- laboratory abnormalities as graded by NCI CTCAE v4.03 [Time Frame: 5 years after last subject randomized, consent withdrawal, or death]
- for the intensive study, the plasma trough concentration (Ctrough) will be analyzed [Time Frame: PK samples taken on Induction(s) Day 1 (1 and 4 hours post induction); Induction(s) Day 10 (pre-dose, 1 and 4 hours post dose); Day 1 of each Consolidation cycle (pre-dose, 1 and 4 hours post dose)]
- QTc interval [Time Frame: 5 years after last subject randomized, consent withdrawal, or death]
- PROs as measured by Patient Global Impression of Change (PGIC) [Time Frame: 5 years after last patient randomized, withdrawal, or death] - one question asking for description of leukemia symptoms
- patient Reported Outcomes (PROs) as measured by EuroQoL 5 Dimension questionnaire 5-Level version (EQ-5D-5L) [Time Frame: 5 years after last subject randomized, withdrawal, or death] - series of questions that ask for information that best describes health
- patient reported outcomes (PROs) as measured by Patient Global Impression of Symptoms (PGIS) [Time Frame: 5 years after last subject randomized, consent withdrawal, or death] - one question asking for information regarding leukemia symptoms
- complete Remission with incomplete hematologic recovery (CRi) [Time Frame: 5 years after last subject randomized, consent withdrawal, or death] - response as defined by the 2017 European LeukemiaNet (ELN) recommendations
- rate of morphological leukemia-free state (MLFS) [Time Frame: 5 years after last subject randomized, consent withdrawal, or death] - response as defined by the 2017 European LeukemiaNet (ELN) recommendations
- rate of Partial Remission (PR) [Time Frame: 5 years after last subject randomized, consent withdrawal, or death] - response as defined by the 2017 European LeukemiaNet (ELN) recommendations.
- rate of Complete Remission with partial hematological recovery (CRh) for the Non-intensive study only [Time Frame: 5 years after last subject randomized, consent withdrawal, or death] - response as defined by the 2017 European LeukemiaNet (ELN) recommendations
- minimum observed plasma trough concentratrion of glasdegib in the Intensive Study [Time Frame: Day 10 of Induction Cycle and Day 1 of each Consolidation Cycle] - minimum trough concentration in plasma of glasdegib following multiple daily dosing to steady state
- minimum Observed Plasma Trough Concentration of glasdegib in the Non- intensive study [Time Frame: Cycle 1 Day 15 and Cycles 2 and 3 on Day 1] - minimum trough concentration in plasma of glasdegib following multiple daily dosing to steady state.
Study Design
Two separate registration trials are being conducted under one protocol number to adequately and independently evaluate the addition of glasdegib in intensive and non-intensive chemotherapy populations. Each study will have an experimental treatment arm and a placebo arm. Endpoints are the same for each study except where specifically indicated.
Assignment to the Intensive Study or the Non-intensive Study will be made by the Investigator based on the 2017 European LeukemiaNet (ELN) recommendations.
This study is a randomized (1:1), double-blind, multi-center, placebo controlled study of chemotherapy in combination with glasdegib versus chemotherapy in combination with placebo in adult patients with previously untreated AML.
Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (Non-intensive AML population).
Experimental Arm A (glasdegib + azacitidine) - azacitidine 75 mg/m2 SC or IV daily for 7 days in 28 day cycles for as long as the patient does not meet the criteria for disease progression, unacceptable toxiciity, consent withdrawal or death; glasdegib 100 mg PO QD is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays / modifications in the chemotherapy treatment. Subjects will continue glasdegib until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.
Placebo Comparator Arm B (placebo + azacitidine) - azacitidine 75 mg/m2 SC or IV daily for 7 days in 28 day cycles for as long as the patient does not meet the criteria for disease progression, unacceptable toxicity, consent withdrawal or death; matching placebo is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays / modifications in the chemotherapy treatment. Subjects will continue placebo until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.
Glasdegib is also being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).
Experimental Arm A (glasdegib + 7+3’ inductions) - 7+3’ (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days), if a second induction is needed Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days (‘5+2’) or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days (7+3’); consolidation with single agent cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 BID on Days 1 , 3 and 5, every 28 days for up to 4 cycles of alternative single agent cytarabine consolidation schedules may be used per local prescribing information; daily glasdegib (100 mg, PO) beginning on Day 1 and is to continue up to 2 years post randomization, following consolidation therapy, glasdegib or placebo will be administered daily for us to 2 years after randomization or until the patient has minimal residual disease (MRD) negative disease, whichever comes first, daily glasdegib (100 mg, PO) or matching placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications / delays in the chemotherapy.
Placebo Comparator Arm B (placebo + 7+3’ inductions) - 7+3’ (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days), if a second induction is needed Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days (‘5+2’) or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days (7+3’); consolidation with single agent cytarabine 3g/m2 IV for adults <60 years and 1g/m2 for adults 60 years over 3 BID on Days 1 , 3 and 5, every 28 days for up to 4 cycles of alternative single agent cytarabine consolidation schedules may be used per local prescribing information; matching placebo (PO) given on Day 1 and is to continue up to 2 years post randomization, following consolidation therapy, placebo will be administered daily for up to 2 years after randomization or until the patient has minimal residual disease (MRD) negative disease, whichever comes first, matching placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications / delays in the chemotherapy.
Study Population
Inclusion criteria - subjects must meet all of the following inclusion criteria to be eligible for enrollment into the Intensive and Non Intensive study (unless where indicated):
1. Subjects with untreated AML according to the World Health Organization
(WHO) 2016 Classification2, including those with: o AML arising from MDS or another antecedent hematologic disease (AHD). o AML after previous cytotoxic therapy or radiation (secondary AML).
2. 18 years of age (In Japan, 20 years of age).
3. Adequate Organ Function as defined by the following: o Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) 3 x upper limit of normal (ULN), excluding subjects with liver function abnormalities due to underlying malignancy. o Total serum bilirubin 2 x ULN (except subjects with documented Gilbert's syndrome). o Estimated creatinine clearance 30 mL/min as calculated using the standard method for the institution.
4. QTc interval 470 msec using the Fridericia correction (QTcF).
5. All anti cancer treatments (unless specified) should be discontinued 2 weeks from study entry, for example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines. o For control of rapidly progressing leukemia, all trans retinoic acid (ATRA), hydroxyurea, and/or leukopheresis may be used before and for up to 1 week after the first dose of glasdegib.
6. Serum or urine pregnancy test (for female subjects of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (hCG) negative at screening.
7. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use at least one highly effective method of contraception throughout the study and for 180 days after the last dose of azacitidine, cytarabine, or daunorubicin; and the last dose of glasdegib or placebo, whichever occurs later.
8. Female subjects of non childbearing potential must meet at least 1 of the following criteria: a. Flave undergone a documented hysterectomy and/or bilateral oophorectomy; b. Flave medically confirmed ovarian failure; or c. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSFH) level confirming the postmenopausal state.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
9. Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision.
10. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
11. Subjects who are willing and able to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow [BM] assessments).
Exclusion Criteria - subjects with any of the following characteristics / conditions will not be included in the study:
1. Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016 classification).
2. AML with BCR ABL1 or t(9;22)(q34;q11.2) as a sole abnormality. o Complex genetics may include t(9;22) cytogenetic translocation.
3. Subjects with known active CNS leukemia.
4. Participation in other clinical studies involving other investigational drug(s) (Phases 1 4) within 4 weeks prior study entry and/or during study participation.
5. Subjects known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
6. Subjects with another active malignancy on treatment with the exception of basal cell carcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior or concurrent malignancies will be considered on a case by case basis.
7. Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, symptomatic arrhythmias (including sustained ventricular tachyarrhythmia), right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms.
8. Subjects with an active, life threatening or clinically significant uncontrolled systemic infection not related to AML.
9. Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the Intensive Chemotherapy Study only.
10. Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for the Intensive Chemotherapy Study only. 11. Known malabsorption syndrome or other condition that may significantly impair absorption of study medication in the investigator's judgment (eg, gastrectomy, lap band, Crohn's disease) and inability or unwillingness to swallow tablets or capsules.
12. Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers.
13. Concurrent administration of herbal preparations.
14. Major surgery or radiation within 4 weeks of starting study treatment.
15. Documented or suspected hypersensitivity to any one of the following: o For subjects assigned to intensive chemotherapy, documented or suspected hypersensitivity to cytarabine (not including drug fever or exanthema, including known cerebellar side effects) or daunorubicin. o For subjects assigned to non intensive chemotherapy, documented or suspected hypersensitivity to azacitidine or mannitol.
16. Known active drug or alcohol abuse.
17. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
18. Pregnant females or breastfeeding female subjects.
19. Known recent or active suicidal ideation or behavior.
20. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.
Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those of ordinary skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, and yet these modifications and improvements are within the scope and spirit of the invention.

Claims

Claims We Claim:
1. A method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby treating said acute myeloid leukemia.
2. A method of treating acute myeloid leukemia (AML) in a patient in need thereof, wherein said patient is positive for at least one mutation of the FLT3 gene, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether the patient is positive for at least one mutation of the FLT3 gene; c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine if the patient is positive for at least one mutation of the FLT3 gene; and d. where the patient is selected for treatment, administering to said patient a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, thereby treating said acute myeloid leukemia.
3. The method according to claim 1 or claim 2, wherein the patient is a human.
4. The method according to any one of claims 1 to 3 wherein the patient is ineligible for first line treatment with standard induction chemotherapy.
5. The method according to any one of claims 1 to 3, wherein the patient is eligible for first line treatment with standard induction chemotherapy.
6. The method according to any one of claims 1 to 5, wherein the patient is aged at least 75 years old.
7. The method according to any one of claims 1 to 6, wherein the patient has no known active central nervous system (CNS) leukemia.
8. The method according to any one of claims 1 to 7, wherein the patient has received no prior treatment with a smoothened inhibitor.
9. The method according to any one of claims 1 to 8, wherein the patient has received no prior treatment with a hypomethylating agent.
10. The method according to any one of claims 1 to 9, wherein the patient has received no prior treatment with a FLT3 inhibitor.
11. The method according to any one of claims 1 to 10, wherein the acute myeloid leukemia is newly diagnosed.
12. The method according to any one of claims 1 to 11, wherein the acute myeloid leukemia is de novo acute myeloid leukemia.
13. The method according to any one of claims 1 to 11, wherein the acute myeloid leukemia is secondary acute myeloid leukemia.
14. The method according to any one of claims 1 to 13, wherein the acute myeloid leukemia is previously untreated.
15. The method according to any one of claims 1 to 14, wherein the at least one mutation of the FLT3 gene is selected from the group consisting of an insertion, a point mutation, an internal tandem duplication mutation, and combinations thereof.
16. The method according to claim 15, wherein the at least one mutation in the FLT3 gene is a point mutation, which point mutation is in the tyrosine kinase domain of the FLT3 gene.
17. The method according to claim 16, wherein the point mutation is selected from the group consisting of a point mutation at codon D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation in the codons surrounding D835 in the tyrosine kinase domain of the FLT3 gene; a point mutation at codon 1836 in the tyrosine kinase domain of the FLT3 gene; and combinations thereof.
18. The method according to claim 15, wherein the at least one mutation of the FLT3 gene is an internal tandem duplication (ITD) mutation.
19. The method according to any one of claims 1 to 18, wherein the at least one mutation of the FLT3 gene is selected from the group consisting of mutations D835Y, K565E, Q575R, D835H, D839G, V491L, V194M, N841Y, N676S, A680V, ITD(F605-P606ins12), ITD(E598-Y599, ins5; E589-F590ins12) and combinations thereof.
20. The method according to any one of claims 1 to 19, wherein the smoothened inhibitor is glasdegib, or a pharmaceutically acceptable salt thereof.
21. The method according to claim 20, wherein glasdegib is administered orally at a dose of about 100 mg per day, glasdegib free base equivalent.
22. The method according to claim 20, wherein glasdegib is administered orally as glasdegib maleate at a dose of about 131 mg glasdegib maleate per day.
23. The method according to any one of claims 1 to 22, wherein the azacitidine is administered subcutaneously.
24. The method according to any one of claims 1 to 22, wherein azacitidine is administered intravenously.
25. The method according to any one of claims 1 to 24, wherein azacitidine is administered on days 1 to 7 of a 28-day cycle.
26. The method according to claim 25, wherein azacitidine is administered for greater than one 28-day cycle.
27. The method according to claim 25, wherein azacitidine is administered for at least 4 28-day cycles.
28. The method according to any one of claims 1 to 27, wherein azacitidine is administered at a dose of about 75 mg/m2 of body surface area.
29. The method according to any one of claims 1 to 28, wherein administering to said patient the smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine increases the overall survival of said patient.
30. The method according to claim 29, wherein the increase in overall survival of said patient is as compared to the overall survival of a control group.
31. The method according to claim 30, wherein the control group comprises one or more acute myeloid leukemia patients, where said one or more acute myeloid leukemia patients in the control group are not FLT3 mutant positive.
32. The method according to any one of claims 2 to 31, wherein the biological sample is a blood sample.
33. The method according to any one of claims 2 to 31, wherein the biological sample is a bone marrow sample.
34. A method of selecting a patient with acute myeloid leukemia (AML) for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, said method comprising: a. obtaining a biological sample from said patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. selecting the patient for treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine if the biological sample is positive for at least one mutation of the FLT3 gene.
35. A method for predicting whether a patient with acute myeloid leukemia (AML) will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine, said method comprising: a. obtaining a biological sample from the patient; b. assaying the biological sample to determine whether said sample is positive for at least one mutation of the FLT3 gene; and c. predicting the patient will respond to treatment with a smoothened inhibitor, or a pharmaceutically acceptable salt thereof, in combination with azacitidine if the biological sample is positive for at least one mutation of the FLT3 gene.
PCT/IB2022/056635 2021-07-22 2022-07-19 Treatment of hematological malignancy WO2023002362A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202163224453P 2021-07-22 2021-07-22
US63/224,453 2021-07-22
US202163224915P 2021-07-23 2021-07-23
US63/224,915 2021-07-23
US202263351883P 2022-06-14 2022-06-14
US63/351,883 2022-06-14

Publications (1)

Publication Number Publication Date
WO2023002362A1 true WO2023002362A1 (en) 2023-01-26

Family

ID=82839283

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/056635 WO2023002362A1 (en) 2021-07-22 2022-07-19 Treatment of hematological malignancy

Country Status (1)

Country Link
WO (1) WO2023002362A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035298A1 (en) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing gum containing medicament active agents
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2008001575A1 (en) 2006-06-28 2008-01-03 Nikon Corporation Tracking device, automatic focusing device, and camera
WO2009004427A2 (en) 2007-06-29 2009-01-08 Pfizer Inc. Benzimidazole derivatives
WO2016170451A1 (en) 2015-04-24 2016-10-27 Pfizer Inc. Crystalline forms of 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6106864A (en) 1995-09-15 2000-08-22 Pfizer Inc. Pharmaceutical formulations containing darifenacin
WO2000035298A1 (en) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing gum containing medicament active agents
WO2008001575A1 (en) 2006-06-28 2008-01-03 Nikon Corporation Tracking device, automatic focusing device, and camera
WO2009004427A2 (en) 2007-06-29 2009-01-08 Pfizer Inc. Benzimidazole derivatives
US8148401B2 (en) 2007-06-29 2012-04-03 Pfizer Inc. Benzimidazole derivatives
US8431597B2 (en) 2007-06-29 2013-04-30 Pfizer Inc. Benzimidazole derivatives
WO2016170451A1 (en) 2015-04-24 2016-10-27 Pfizer Inc. Crystalline forms of 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate

Non-Patent Citations (47)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY
ARBER D.A. ET AL.: "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.", BLOOD, vol. 127, no. 20, 2016, pages 2391 - 405
BEWERSDORF JP ET AL.: "Risk-adapted, individualized treatment strategies of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML", CANCERS (BASEL), vol. 13, no. 7, 2021, pages 1610
BIXBY D. ET AL.: "Safety and efficacy of vismodegib in relapsed / refractory acute myeloid leukemia: results of a phase 1 b trials", BR J HAEMATOL., vol. 185, no. 3, 2019, pages 595 - 598
BLOOD., vol. 112, no. 1, 2008, pages 45 - 52
BOUSCARY D.: "Rational for targeting the hedgehog signaling pathway in acute myeloid leukemia with FLT3 mutation", ANN TRANSL MED, vol. 4, October 2016 (2016-10-01), pages S53
CAMPBELL ET AL., STEM CELL CLONING, vol. 8, 2015, pages 27 - 38
CHESON B.D. ET AL.: "Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia", BLOOD, vol. 108, no. 2, 2006, pages 419 - 25
CORTES ET AL.: "Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study Results", AM. J. HEMATOL., vol. 93, 2018, pages 1301 - 1310
CORTES J.E. ET AL.: "Determination of fitness and therapeutic options in older patients with acute myeloid leukemia", AM J HEMATOL., vol. 96, no. 4, 2021, pages 493 - 507
CORTES J.E. ET AL.: "Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome", LEUKEMIA, vol. 33, no. 2, 2019, pages 379 - 389, XP036856732, DOI: 10.1038/s41375-018-0312-9
DINARDO C. D. ET AL., BLOOD, vol. 133, 2019, pages 7 - 17
DINARDO C.D. ET AL.: "Azacitidine and venetoclax in previously untreated acute myeloid leukemia", N ENGL J MED., vol. 383, no. 7, 2020, pages 617 - 629
DOHNER H ET AL.: "Diagnosis and management of AML in aduults, 2017 ENL recommendation from an international expert panel", BLOOD, vol. 129, no. 4, 2017, pages 424 - 47
DOMBRET H. ET AL.: "International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts", BLOOD, vol. 126, no. 3, 2015, pages 291 - 299
FUKUSHIMA ET AL., CANCER SCI, vol. 107, 2016, pages 1422 - 1429
GREENBERG P.L. ET AL.: "Revised international prognostic scoring system for myelodysplastic syndromes.", BLOOD, vol. 120, no. 12, 2012, pages 2454 - 65, XP086693842, DOI: 10.1182/blood-2012-03-420489
H. LIEBERMANL. LACHMAN: "Pharmaceutical Dosage Forms: Tablets", vol. 1, 1980, MARCEL DEKKER
JAMIESON C ET AL.: "Hedgehog pathway inhibitors: a new therapeutic class for the treatment of acute myeloid leukemia", BLOOD CANCER DISCOVERY, vol. 1, no. 2, 2020, pages 134 - 145
JERBY-ARNON L ET AL.: "A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade", CELL, vol. 175, no. 4, 2018, pages 984 - 997, XP085522248, DOI: 10.1016/j.cell.2018.09.006
JIFENG YU ET AL: "Advances in targeted therapy for acute myeloid leukemia", BIOMARKER RESEARCH, BIOMED CENTRAL LTD, LONDON, UK, vol. 8, no. 1, 20 May 2020 (2020-05-20), pages 1 - 11, XP021277065, DOI: 10.1186/S40364-020-00196-2 *
KIYOI H. ET AL.: "FLT3 mutations in acute myeloid leukemia therapeutic paradigm beyond inhibitor development", CANCER SCI, vol. 111, no. 2, 2020, pages 312 - 322
KIYOI H.: "FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development", CANCER SCI., vol. 111, 2020, pages 312 - 322
L. THOMPSON ET AL: "Glasdegib: A Novel Hedgehog Pathway Inhibitor for Acute Myeloid Leukemia", JOURNAL OF THE ADVANCED PRACTITIONER IN ONCOLOGY, vol. 11, no. 2, 1 March 2020 (2020-03-01), XP055973354, ISSN: 2150-0878, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848813/pdf/jadpro-11-196.pdf> DOI: 10.6004/jadpro.2020.11.2.8 *
LI QING-ROU ET AL: "Novel-smoothened inhibitors for therapeutic targeting of naïve and drug-resistant hedgehog pathway-driven cancers", ACTA PHARMACOLOGICA SINICA, NATURE PUBLISHING GROUP, GB, vol. 40, no. 2, 18 May 2018 (2018-05-18), pages 257 - 267, XP036672667, ISSN: 1671-4083, [retrieved on 20180518], DOI: 10.1038/S41401-018-0019-5 *
LIANGCHEN, EXPERT OPINION IN THERAPEUTIC PATENTS, vol. 11, no. 6, 2001, pages 981 - 986
LIM Y ET AL.: "Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia", SCI. TRANSL MED., vol. 7, no. 291, 2015, pages 291
LIM Y ET AL.: "Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.", SCI TRANSL MED., vol. 7, no. 291, 2015, pages 291
MERCHANT A ET AL.: "Biomarkers Correlating with overall survival (OS) and response to glasdegib and intensive or non-intensive chemotherapy in patients with acute myeloid leukemia (AML", CANCER RESEARCH, 2019, pages 79
MERCHANT A. ET AL.: "Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or non-intensive chemotherapy in patients with acute myeloid leukemia (AML", CANCER RESEARCH, vol. 79, 2019
MUNCHHOF ET AL., MED. CHEM., LETT, vol. 3, 2012, pages 106 - 111
PALOMO L. ET AL.: "Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms", BLOOD, vol. 136, no. 16, 2020, pages 1851 - 1862
PENG ET AL., ORG. LETT., vol. 16, 2014, pages 860 - 863
ROLLINSON D.E. ET AL., EPIDEMIOLOGY OF MYELODYSPLASTIC SYNDROMES AND CHORINCI MYELOPROLIFERATIVE DISORDERS IN THE UNITED STATES, 2001
SABATTINI E ET AL.: "WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview", PATHOLOGICA, vol. 102, no. 3, 2010, pages 83 - 7
SABATTINI EBACCI FSAGRAMOSO CPILERI SA.: "WHO classification of tumors of haematopoietic and lymphoid tissues in 2008: an overview", PATHOLOGICA
SAVONA M.R. ET AL.: "Phase 1 b study of glasdegib, a hedgehog pathway inhibtior, in combination with standard chemotherapy in patients with AML or high risk MDS.", CLIN CANCER RES., vol. 24, no. 14, 2018, pages 2294 - 303
SEKERES M.A. ET AL.: "American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults", BLOOD ADV., vol. 4, no. 15, 2020, pages 3528 - 3549
SEKERES M.A. ET AL.: "Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia, North American Intergroup Study SWOG S1117.", J. CLIN ONCOL., vol. 35, no. 24, 2017, pages 2745 - 53
SEKERES M.A. ET AL.: "Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117.", J CLIN ONCOL., vol. 35, no. 24, 2017, pages 2745 - 2753
SEKERES MA ET AL.: "How we treat higher-risk myelodysplastic syndromes", BLOOD, vol. 123, no. 6, 2014, pages 829 - 836
THEIN M.S. ET AL.: "Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades", CANCER, vol. 119, no. 15, 2013, pages 2720 - 2727
TYNER J.W.: "Functional genomic landscape of acute myeloid leukemia", NATURE, vol. 562, no. 7728, 2018, pages 526 - 31
VERMA ET AL., PHARMACEUTICAL TECHNOLOGY ON-LINE, vol. 25, no. 2, 2001, pages 1 - 14
VILLANI A. ET AL.: "Sonidegib: safety and efficacy in reatment of advanced basal cell carcinoma", DERMATOLOG. THER (HEIDELB, vol. 10, no. 3, pages 401 - 412
WHO, DRUG INFORMATION, vol. 29, no. 1, 2015, pages 89
ZHONG LEI ET AL: "Small molecules in targeted cancer therapy: advances, challenges, and future perspectives", SIGNAL TRANSDUCTION AND TARGETED THERAPY, vol. 6, no. 1, 31 May 2021 (2021-05-31), pages 201, XP055952654, DOI: 10.1038/s41392-021-00572-w *

Similar Documents

Publication Publication Date Title
JP7458188B2 (en) How to treat tumors
JP2018521973A (en) Compositions and methods for treating patients with RTK mutant cells
US20170002425A1 (en) Method for predicting long-term efficacy of vegf inhibitor
US20190201386A1 (en) Dosage regimen of mdm2 inhibitor for treating cancers
US20230172935A1 (en) Methods of monitoring kras mutations
KR20220145891A (en) Systems and methods for protecting nucleic acid molecules
WO2015127172A1 (en) Therapeutically active compounds and their methods of use
JP2021520349A (en) RET Inhibitors for Use in the Treatment of Cancers with RET Changes
JP2019112416A (en) Methods for the treatment of cancer
EP3980563A2 (en) Ntrk fusion molecules and uses thereof
KR20210145161A (en) Compounds with antitumor activity against cancer cells with HER2 exon 21 insert
WO2012103060A1 (en) Method of administration and treatment
WO2015066432A1 (en) Method of treating post-myeloproliferative neoplasms (mpns) and post-mpn acute myeloid leukemia
WO2017165491A1 (en) Use of a pd-1 antagonist and a raf inhibitor in the treatment of cancer
CA3140146A1 (en) Bisfluoroalkyl-1,4-benzodiazepinone compounds for treating notch-activated breast cancer
WO2023002362A1 (en) Treatment of hematological malignancy
US20230167505A1 (en) Circulating tumor dna as a biomarker for leukemia treatment
JP2023553588A (en) Biomarkers for myelodysplastic syndrome (MDS) and their use
JP7334194B2 (en) Cancer therapeutics based on TP53 mutation status and hypermutation status
US20220305008A1 (en) Treatment of cancer having gnaq or gna11 genetic mutations with protein kinase c inhibitors
CN116437924A (en) Methods of treating HER 2-altering driven solid tumors with combinations of tocatinib and anti-HER 2 antibodies
US20200316067A1 (en) Combination of raf inhibitors and taxanes
CN115698338A (en) Methods of treating HER2 mutant cancers with tocatinib
US20240139196A1 (en) Combination treatments in difficult to treat patients with advanced and/or metastatic trop-2 overexpressing cancers
WO2017066664A1 (en) Combination therapy including a raf inhibitor for the treatment of colorectal cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22751453

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE