US20150335668A1 - Method for cancer therapy - Google Patents

Method for cancer therapy Download PDF

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US20150335668A1
US20150335668A1 US14/716,761 US201514716761A US2015335668A1 US 20150335668 A1 US20150335668 A1 US 20150335668A1 US 201514716761 A US201514716761 A US 201514716761A US 2015335668 A1 US2015335668 A1 US 2015335668A1
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Prior art keywords
dose
formula
ixazomib
therapy
compound
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US14/716,761
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Inventor
Ai-Min Hui
Richard Labotka
Neeraj Gupta
Karthik VENKATAKRISHNAN
Guohui Lui
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Takeda Pharmaceutical Co Ltd
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Millennium Pharmaceuticals Inc
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Priority to US14/716,761 priority Critical patent/US20150335668A1/en
Publication of US20150335668A1 publication Critical patent/US20150335668A1/en
Assigned to MILLENNIUM PHARMACEUTICALS, INC. reassignment MILLENNIUM PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HUI, Ai-Min, LIU, Guohui, VENKATAKRISHNAN, Karthik, LABOTKA, Richard, GUPTA, NEERAJ
Priority to US16/229,524 priority patent/US20190125773A1/en
Priority to US16/517,963 priority patent/US20190343851A1/en
Priority to US16/781,432 priority patent/US20200171061A1/en
Priority to US17/188,492 priority patent/US11241448B2/en
Assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED reassignment TAKEDA PHARMACEUTICAL COMPANY LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MILLENNIUM PHARMACEUTICALS, INC.
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    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • 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
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present disclosure relates to methods or dosing regimens comprising proteasome inhibitors of formula (I) for treating cancer, or preventing cancer recurrence or progression.
  • Cancer has a major impact on society in the United States and across the world. Cancer is the second most common cause of death in the US, exceeded only by heart disease, accounting for nearly 1 of every 4 deaths. The National Cancer Institute estimates that in 2015, approximately 1,658,370 new cases of cancer will be diagnosed in the United States and 589,430 people will die from the disease. Although medical advances have improved cancer survival rates, there is a continuing need for new and more effective treatment.
  • Multiple myeloma a B-cell tumor of malignant plasma cells within the bone marrow, remains incurable despite advances in novel therapies with proteasome inhibitors (PIs), immunomodulating drugs (IMiD), and stem cell transplant (SCT) therapy.
  • PIs proteasome inhibitors
  • IMD immunomodulating drugs
  • SCT stem cell transplant
  • Multiple myeloma is characterized by the accumulation of plasma cells in the bone marrow (and other organs) and can result in bone marrow failure, bone destruction, hypercalcemia, and renal failure. It constitutes approximately 1% of all reported neoplasms and approximately 13% of hematologic cancers worldwide. In the Americas, Canada, and Western European countries, approximately five to seven new cases of multiple myeloma are diagnosed per 100,000 people each year.
  • myeloma is sensitive to many cytotoxic drugs including alkylating agents, anthracyclines, and corticosteroids for both initial treatment and relapsed disease.
  • cytotoxic drugs including alkylating agents, anthracyclines, and corticosteroids for both initial treatment and relapsed disease.
  • novel therapies such as thalidomide, bortezomib, and lenalidomide.
  • PFS progression-free survival
  • TTP time-to-progression
  • HDT high-dose therapy
  • NDMM multiple myeloma
  • ASCT autologous stem cell transplant
  • the present disclosure provides methods or dosing regimens for treating cancer, or preventing cancer recurrence or progression.
  • the methods or the dosage regimens comprise administering to a patient, who has undergone a primary cancer therapy, a compound of formula (I), or a pharmaceutically acceptable salt thereof,
  • a dosing schedule comprising at least four 28-day treatment cycles, wherein the 28-day treatment cycle comprises four consecutive weeks in which the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered once a week for the first three weeks of the treatment cycle and the compound of formula (I), or pharmaceutically acceptable salt thereof, is not administered during the fourth week, wherein ring A is
  • Z 1 and Z 2 are each independently hydroxyl; or Z 1 and Z 2 together form a cyclic boronic ester having 2-20 carbon atoms, and optionally one or more heteroatoms selected from N, S, or O.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered orally.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered on days 1, 8, and 15 of each treatment cycle.
  • the dosing schedule comprises about twenty-six treatment cycles.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered at a first dose for at least four treatment cycles and a second dose for treatment cycles 5 through 26.
  • the first dose is from about 1.5 mg/week to about 3.0 mg/week
  • the second dose is from about 2.3 mg/week to about 4.0 mg/week for each of 3 weeks out of a 4 week treatment cycle.
  • the first dose of this disclosure is about 3.0 mg/week and the second dose is about 4.0 mg/week, or the first dose is about 3.0 mg/week and the second dose is about 3.0 mg/week, or the first dose is about 2.3 mg/week and the second dose is about 3.0 mg/week, or the first dose is about 2.3 mg/week and the second is about 2.3 mg/week, or the first dose is about 1.5 mg/week and the second is about 2.3 mg/week, or the first dose is about 1.5 mg/week and the second is about 1.5 mg/week for each of 3 weeks out of a 4 week treatment cycle. In certain aspects, the first dose is about 3.0 mg/week and the second dose is about 4.0 mg/week for each of 3 weeks out of a 4 week treatment cycle.
  • the first dose and the second dose are the same.
  • the dosing schedule comprises up to about twenty-six treatment cycles and the compound of formula (I), or pharmaceutically acceptable salt thereof, is administered at about 3.0 mg/week from the first treatment cycle up to the twenty-sixth treatment cycle.
  • the compound of formula (I) of this disclosure is a compound of formula (IV)
  • the compound of formula (I) of this disclosure is a compound of formula (IIIa)
  • the compound of formula (IV) is administered in the form of an ester.
  • the compound of formula (IV) is administered in the form of the compound of formula (IIIa).
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to treat cancer or prevent cancer recurrence or progression, wherein the cancer is a hematological malignancy.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to prevent progression of cancer in a cancer patient who has undergone a primary cancer, wherein the cancer is a hematological malignancy.
  • the present disclosure provides maintenance therapies to prevent relapse or recurrence of multiple myeloma in a cancer patient who has undergone a primary cancer therapy.
  • the present disclosure provides maintenance therapies to a cancer patient who has been diagnosed with multiple myeloma or refractory multiple myeloma.
  • the present disclosure provides maintenance therapies to prevent progression of multiple myeloma in a cancer patient who has undergone a primary cancer therapy.
  • the present disclosure provides maintenance therapies for treating a patient having, or at risk of developing or experiencing a recurrence of, a proteasome-mediated disorder.
  • the present disclosure provides maintenance therapies for treating a patient having, or at risk of developing, or experiencing a recurrence of, a cancer selected from multiple myeloma.
  • the present disclosure provides capsules comprising compound of formula (IIIa).
  • FIG. 1 illustrates the results of exposure-response analyses of safety and efficacy data from patients with relapsed, refractory multiple myeloma enrolled in a phase 1 study.
  • the numbers on the bar refer to the percentage of the patients.
  • Complete response (CR) or better was reached in 52 percent of patients.
  • Very good partial response (VGPR) or better was reached in 71 percent of patients. Forty-eight percent of patients improved their response during maintenance, including two VGPR to near-CR (nCR), five VGPR to CR, one VGPR to stringent complete response (sCR), and two CR to sCR.
  • the present disclosure provides various methods for treating cancer, or preventing cancer recurrence or progression.
  • the disclosure provides administering to a cancer patient a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a dosing schedule of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as a maintenance therapy to a patient who has undergone a primary cancer therapy and responded.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to improve and maintain response for patients who have undergone a primary cancer therapy.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to prevent patients from cancer recurrence or progression.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to prevent cancer recurrence or progression.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to treat cancer or prevent cancer recurrence or progression, wherein the cancer is a hematological malignancy.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to treat, or prevent recurrence or progression of relapsed multiple myeloma.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to treat, or prevent recurrence or progression of refractory multiple myeloma.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof, to treat or prevent recurrence or progression of newly diagnosed multiple myeloma.
  • the disclosure provides maintenance therapy comprising a proteasome inhibitor of formula (IIIa) to prevent progression of newly diagnosed multiple myeloma.
  • compositions containing a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof in another aspect, provides pharmaceutical compositions containing a proteasome inhibitor of formula (IIIa), or a pharmaceutically acceptable salt thereof.
  • the cancer is a hematological malignancy.
  • the hematological malignancy is multiple myeloma, mantle cell lymphoma, follicular cell lymphoma, T-cell lymphoma, peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's Macroglobulinemia.
  • the hematological malignancy is mantle cell lymphoma, follicular cell lymphoma, T-cell lymphoma, peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), or Waldenstrom's Macroglobulinemia.
  • the hematological malignancy is amyloidosis. In certain embodiments, the hematological malignancy is systemic light chain amylodosis.
  • the cancer is newly diagnosed.
  • the cancer is relapsed.
  • the cancer is refractory.
  • the cancer is relapsed, or refractory multiple myeloma.
  • the cancer is newly diagnosed multiple myeloma.
  • maintenance therapy refers to a therapeutic regimen that is designed to help a primary treatment succeed.
  • maintenance chemotherapy may be given to people who have a cancer in remission in an effort to prevent or delay a relapse, to reduce the likelihood of disease recurrence or progression.
  • Maintenance therapy can be provided for any length of time, including extended time periods up to the life-span of the subject. Maintenance therapy can be provided after initial therapy or in conjunction with initial or additional therapies. Dosages used for maintenance therapy can vary and can include low-intensity dosages as compared to dosages used for other types of therapies, for example, the primary therapy (i.e., the first line therapy, the induction therapy).
  • primary therapy refers to the initial treatment given to a patient based upon the diagnosis of the disease in the patient.
  • the diagnosis of the disease may be the first occurrence of that disease in the patient, i.e., a newly diagnosed patient, or a reoccurrence of the disease in a patient, i.e., a relapsed patient.
  • primary therapy include autologous stem cell transplant.
  • primary therapy is the one accepted as the best treatment. If it doesn't cure the disease or it causes severe side effects, other treatment may be added or used instead.
  • first-line therapy when referring to the initial treatment of a newly diagnosed patient, or induction therapy, initial therapy, or primary treatment, each of which can refer to the initial treatment of a newly diagnosed patient or the initial treatment of a relapsed patient.
  • induction therapy refers to the first phase of treatment for cancer.
  • the goal of induction therapy for multiple myeloma is to reduce the number of plasma cells in the bone marrow and the proteins that the plasma cells produce.
  • Induction therapy may comprise three-four weeks as one treatment cycle.
  • autologous stem cell transplant refers to stem cells that are collected from an individual and given back to that same individual.
  • a stem cell transplant is a procedure that is used in conjunction with high-dose chemotherapy, which is frequently more effective than conventional chemotherapy in destroying myeloma cells. Because high-dose chemotherapy also destroys normal blood-producing stem cells in the bone marrow, these cells must be replaced in order to restore blood cell production.
  • low-intensity dose refers to a reduced dose regimen in comparison with the dose regimen in the primary therapy.
  • the proteasome inhibitor of formula (I) is reduced to a dose that is less than, 20%, 30%, 40%, 50%, 60%, 70%, of the dosing regimens in the primary therapies, for example the 5.5 mg dosage.
  • the reduced dosage is from about 3.0 mg to about 1.5 mg.
  • the reduced dosage is 3.0 mg, 2.3 mg, or 1.5 mg.
  • survival refers to the patient remaining alive, and includes progression-free survival (PFS) and overall survival (OS). Survival can be estimated by the Kaplan-Meier method, and any differences in survival are computed using the stratified log-rank test.
  • PFS progression-free survival
  • OS overall survival
  • progression-free survival refers to the time from treatment (or randomization) to first disease progression or death. For example it is the time that the patient remains alive, without return of the cancer (e.g., for a defined period of time such as about one month, two months, three months, three and a half months, four months, five months, six months, seven months, eight months, nine months, about one year, about two years, about three years, about five years, about 10 years, about 15 years, about 20 years, about 25 years, etc.) from initiation of treatment or from initial diagnosis.
  • Progression-free survival can be assessed by Response Evaluation Criteria in Solid Tumors (RECIST).
  • all survival refers to the patient remaining alive for a defined period of time (such as about one year, about two years, about three years, about four years, about five years, about 10 years, about 15 years, about 20 years, about 25 years, etc.) from initiation of treatment or from initial diagnosis.
  • proteasome-mediated disorder refers to any disorder, disease or condition which is caused or characterized by an increase in proteasome expression or activity, or which requires proteasome activity to sustain the condition.
  • proteasome-mediated disorder also includes any disorder, disease or condition in which inhibition of proteasome activity is beneficial.
  • cancer refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites.
  • cancer includes, but is not limited to, solid tumors and bloodborne tumors (hematologic malignancy).
  • cancer encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels.
  • cancer further encompasses primary and metastatic cancers.
  • Non-limiting examples of hematologic malignancies include amyloidosis, acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML and CIVIL blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.
  • AML acute myeloid le
  • efficacy may be measured by assessing the duration of survival, duration of progression-free survival (PFS), the response rates (RR) to treatments, duration of response, and/or quality of life.
  • PFS duration of progression-free survival
  • RR response rates
  • immunomodulatory drugs are thalidomide analogues.
  • immunomodulating drugs include lenalidomide and pomalidomide.
  • Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Proteasome inhibitors are being studied in the treatment of cancer, especially multiple myeloma. Examples of proteasome inhibitors are bortezomib, carfilzomib, disulfiram, epigallocatechin-3-gallate, salinosporamid A, ONX0912, CEP-18770, and Epoxomicin.
  • proteasome inhibitors are bortezomib, ixazomib, carfilzomib, disulfiram, epigallocatechin-3-gallate, salinosporamid A, ONX0912, CEP-18770, and Epoxomicin.
  • the proteasome inhibitor is bortezomib.
  • the proteasome inhibitor is ixazomib or ixazomib citrate.
  • the proteasome inhibitor is carfilzomib.
  • pharmaceutically acceptable carrier is used herein to refer to a material that is compatible with a recipient subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
  • the toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the active agent.
  • compositions of this disclosure can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others.
  • Compositions may be produced in various forms, including granules, precipitates, particulates, or powders.
  • oral refers to administering a composition that is intended to be ingested.
  • oral forms include, but are not limited to, tablets, pills, capsules, powders, granules, solutions or suspensions, and drops. Such forms may be swallowed whole or may be in chewable form.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and gly
  • Solid compositions may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredients may be mixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents.
  • the active ingredients can also be in micro-encapsulated form with one or more excipients as noted above.
  • boronate ester and “boronic ester” are used interchangeably and refer to a chemical compound containing a —B(Z 1 )(Z 2 ) moiety, wherein Z 1 and Z 2 together form a cyclic boronic ester having 2-20 carbon atoms, and optionally one or more heteroatoms selected from N, S, or O.
  • the proteasome inhibitor of formula (I) refers to the following formula:
  • Z 1 and Z 2 are each independently hydroxyl; or Z 1 and Z 2 together form a cyclic boronic ester having 2-20 carbon atoms, and optionally one or more heteroatoms selected from N, S, or O.
  • the proteasome inhibitor of formula (I) is characterized by formula (Ia):
  • Z 1 and Z 2 are each independently hydroxyl; or Z 1 and Z 2 together form a cyclic boronic ester having 2-20 carbon atoms, and optionally one or more heteroatoms selected from N, S, or O.
  • the proteasome inhibitor of formula (I) is characterized by formula (II):
  • ring A is defined above; R 1 and R 2 independently is —(CH 2 ) p —CO 2 H; wherein one of carboxylic acids optionally forms a further bond with the boron atom; n is 0 or 1; and p is 0 or 1.
  • the proteasome inhibitor of formula (I) is characterized by formula (III):
  • the proteasome inhibitor of formula (I) is a compound of formula (IIIa):
  • the proteasome inhibitor of formula (IIIa) is in a substantially crystalline form.
  • proteasome inhibitor formula (I) is a compound of formula (IV):
  • the compound of formula (IV), also known as ixazomib, is a peptide boronic acid developed by Millennium Pharmaceuticals, Inc.
  • Ixazomib is the biologically active molecule that potently, reversibly, and selectively inhibits the proteasome.
  • the compound of formula (IIIa) is a citrate ester of ixazomib, referred to as ixazomib citrate herein. Ixazomib citrate rapidly hydrolyzes to ixazomib upon contact with either plasma or aqueous solutions.
  • ixazomib In contrast to the first-in-class, small molecule proteasome inhibitor bortezomib (VELCADE®), ixazomib demonstrates a faster dissociation rate from the proteasome, possibly resulting in enhanced tumor penetration, exhibits antitumor activity in a broader range of tumor xenografts, and has more prolonged tissue penetration.
  • Ixazomib preferentially binds the ⁇ 5 site of the 20S proteasome with a concentration producing 50% inhibition (IC 50 ) of 3.4 nM. At higher concentrations, it also inhibits the activity of the ⁇ 1 and ⁇ 2 sites. Ixazomib is selective for the proteasome when tested against a panel of proteases (IC 50 values between 20 and 100 ⁇ M), kinases (IC 50 values>10 ⁇ M), and receptors (IC 50 values>10 ⁇ M).
  • Ixazomib and bortezomib have different ⁇ 5 proteasome dissociation half-lives (t 1/2 ), reflecting differences in their on-off binding kinetics (the ⁇ 5 proteasome dissociation [t 1/2 ] for ixazomib citrate and bortezomib is 18 and 110 minutes, respectively).
  • Ixazomib has been evaluated in clinical studies that have included patients with advanced solid tumors, lymphoma, relapsed/refractory multiple myeloma (RRMM), and relapsed or refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. Data suggest a favorable toxicity profile with low rates of peripheral neuropathy (PN).
  • PN peripheral neuropathy
  • Applicant conducted exposure-response analyses of safety and efficacy data from patients with relapsed, refractory multiple myeloma enrolled in a phase 1 study of weekly single-agent ixazomib.
  • the analysis was designed to yield initial estimates of a biologically active exposure/dose range of ixazomib associated with disease control and acceptable tolerability, thereby ensuring adequate tolerability for long-term treatment while maintaining drug exposures in the biologically active range. The methods and results of these analyses are described below.
  • the non-hematologic adverse events data were categorized into grade ⁇ 2 vs. grade ⁇ 1 groups while hematologic adverse events data were grouped into grade ⁇ 3 vs. grade ⁇ 2.
  • the data were categorized in this way as maintenance treatment should have a tolerable adverse events profile and contribute to acceptable quality of life. Different cut-offs were used for hematologic and non-hematologic adverse events because grade 3 hematologic adverse events may have less impact on quality of life and be more manageable than grade 2 non-hematologic adverse events such as diarrhea.
  • SD stable disease
  • PD progressive disease
  • Clinical benefit rate including SD achieved in relapsed or refractory patients may be a meaningful predictor of expected response in a maintenance setting.
  • the logistic regression analyses were done using SPLUS software version 8.1.
  • AEs fatigue, rash, diarrhea, thrombocytopenia, neutropenia
  • ⁇ SD clinical benefit rate
  • the model predicts ⁇ 33% ⁇ SD, and incidence of grade ⁇ 2 non-H AEs (rash 16%, diarrhea 19% and fatigue 19%) and grade ⁇ 3 H AEs (neutropenia 10%, thrombocytopenia 22%).
  • the 3.0 mg dose is within the therapeutic range and represents one dose level below the starting dose used in ongoing phase 3 trials in relapsed, refractory and previously untreated multiple myeloma patients.
  • FIG. 1 illustrates the relationship of patients' exposure to response (clinical benefit and safety) of ixazomib dose.
  • FIG. 1 indicates that a favorable benefit versus risk may be achieved at weekly doses of 3.0 mg and 4.0 mg, below the maximum tolerated dose. Therefore, in the maintenance therapy, patients may initiate ixazomib at a once-weekly dose of 3.0 mg, increased to 4.0 mg if acceptable tolerability is determined after four cycles, to provide maximum clinical benefit.
  • Maintenance therapy is a long-duration therapy intended to prolong the duration of a patient's response to the primary treatment.
  • Long-term maintenance therapy improves survival outcomes, including progression-free survival and sometime overall survival, in both the transplant and non-transplant settings.
  • agents for continuous therapy need to be convenient and well tolerated.
  • the balance of benefit versus risk is paramount in the maintenance therapy.
  • Requirements for a successful maintenance therapy include good long-term tolerability and adherence (low discontinuation rates due to toxicity and convenience of administration), demonstration of clinical benefit either in prolonging survival or improving quality of life without shortening survival, and a favorable benefit to risk ratio.
  • the maintenance therapy of this disclosure comprises administering a compound of formula (IIIa) (ixazomib citrate) to patients with newly diagnosed multiple myeloma, wherein the patients have already undergone induction therapy and a single autologous stem cell transplant.
  • a compound of formula (IIIa) ixazomib citrate
  • the maintenance therapy of this disclosure comprises administering a compound of formula (IIIa) (ixazomib citrate) to patients with newly diagnosed multiple myeloma, wherein the patients have already undergone induction therapy and one or more autologous stem cell transplants.
  • the maintenance therapy of this disclosure comprises administering a compound of formula (IIIa) (ixazomib citrate) to patients with newly diagnosed multiple myeloma, wherein the patients have already undergone induction therapy according to regional standard of care, followed by a conditioning regimen containing high-dose therapy such as melphalan (200 mg/m 2 ) and a single autologous stem cell transplant.
  • Induction therapy must include proteasome inhibitor and/or immunomodulating drugs-based regimens.
  • the induction therapy includes a proteasome inhibitor, wherein the proteasome inhibitor is ixazomib or ixazomib citrate.
  • the maintenance therapy of this disclosure comprises administering a compound of formula (IIIa) (ixazomib citrate) to patients with newly diagnosed multiple myeloma wherein the patients have already undergone induction therapy and have not undergone autologous stem cell transplant.
  • patients who have achieved clinical and hematologic recovery following induction therapy, high-dose therapy, and autologous stem cell transplant will initiate screening for the maintenance therapy eligibility no earlier than 75 days after transplant, complete screening within 15 days, and be randomized no later than 115 days after transplant.
  • Eligible patients (those who have a documented complete response, very good partial response, or partial response to induction therapy during screening) may be treated with ixazomib maintenance therapy.
  • the stratification factors, induction regimen proteasome inhibitors without immunomodulating drugs, immunomodulating drugs without proteasome inhibitors, or proteasome inhibitors and immunomodulating drugs
  • pre-induction International Staging System (ISS) stage 1 vs. stage 2 or 3
  • response after transplantation defined as the response following induction therapy, high-dose therapy, and autologous stem cell transplant measured during screening (complete response, very good partial response, or partial response).
  • patients with newly diagnosed multiple myeloma who have had a response (complete response, very good partial response, or partial response) to induction therapy followed by high-dose therapy and autologous stem cell transplant may be treated with ixazomib maintenance therapy.
  • patients with newly diagnosed multiple myeloma who have had a response (complete response, very good partial response, or partial response) to induction therapy followed by autologous stem cell transplant may be treated with ixazomib maintenance therapy.
  • patients with newly diagnosed multiple myeloma who have had a response (complete response, very good partial response, or partial response) to induction therapy and who have not undergone stem-cell transplant may be treated with ixazomib maintenance therapy.
  • the maintenance therapy of this disclosure comprises administering a compound of formula (IIIa) (ixazomib citrate) to patients with a hematological malignancy wherein the patients have already undergone induction therapy.
  • the maintenance therapy of this disclosure comprises administering a compound of formula (IIIa) (ixazomib citrate) to patients with a hematological malignancy, wherein the patients have already undergone induction therapy and one or more autologous stem cell transplants
  • the maintenance therapy of this disclosure comprises administering a compound of formula (IIIa) (ixazomib citrate) to patients with a hematological malignancy, wherein the patients have already undergone induction therapy and have not undergone autologous stem cell transplant.
  • the induction therapy comprises a chemotherapeutic regimen.
  • chemotherapeutic regimen include but are not limited to, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-EPOCH (etoposide, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) with or without rituximab, or VAD (vincristine, doxorubicin, dexamethasone).
  • CHOP cyclophosphamide, doxorubicin, vincristine, and pred
  • the induction therapy comprises proteasome inhibitor and/or immunomodulating drugs-based regimens.
  • patients are administered with ixazomib citrate capsule orally once-a-week for three consecutive weeks followed by one week without the capsule.
  • This four-week (28-day) dosing regimen comprises one treatment cycle.
  • patients are administered ixazomib citrate capsules once on days 1, 8, and 15 in a 28-day cycle.
  • the proteasome inhibitor of formula (I), or a pharmaceutically acceptable salt thereof is administered at a first dose for at least four treatment cycles and a second dose in the treatment cycles 5 through 26.
  • the first dose strength of 3.0 mg/week of ixazomib in the form of ixazomib citrate capsule will be used for patients from the first treatment cycle through the fourth treatment cycle.
  • patients Upon evaluation of toxicities at the completion of the fourth treatment cycle, patients will receive a second dose strength of ixazomib at an increased dose strength of 4.0 mg/week beginning with the fifth treatment cycle through the twenty-sixth treatment cycle, and administered on the same schedule of the treatment cycles 1-4 for the duration of the maintenance therapy, to provide maximum possible clinical benefit for patients who tolerated the first four cycles of treatment.
  • the first dose strength of ixazomib in the form of ixazomib citrate capsule will be used for patients starting from the first treatment cycle. If the patient is tolerating the first dose strength, the patient may receive a second dose at an increased dose strength at any time upon evaluation of toxicities after the first dose.
  • the first dose strength of 3.0 mg/week of ixazomib in the form of ixazomib citrate capsule will be used for patients starting from the first treatment cycle. If the patient is tolerating the 3.0 mg/week of dose strength, the patient may receive a second dose at an increased dose strength of 4.0 mg/week at any time upon evaluation of toxicities after the first dose.
  • the first dose strength of 4.0 mg/week of ixazomib in the form of ixazomib citrate capsule will be used for patients starting from the first treatment cycle. If the patient is tolerating the 4.0 mg/week of dose strength, the patient may continue at the 4.0 mg/week dose strength.
  • the first dose of 3.0 mg of ixazomib in the form of ixazomib citrate capsule will be used for patients from the first treatment cycle through the fourth treatment cycle.
  • patients who would not tolerate the increased dose strength will remain at the starting dose strength of 3.0 mg/week for the fifth treatment cycle through the twenty-sixth treatment cycle, and administered on the same schedule of the treatment cycles 1-4 for the duration of the maintenance therapy.
  • patients experiencing adverse events during any treatment cycle may continue in the maintenance therapy, but may have ixazomib doses held or reduced by at least 1 dose level.
  • the reduced doses are from about 3.0 mg to about 1.5 mg. In certain embodiments, the reduced doses are 3.0 mg, 2.3 mg, and 2.5 mg.
  • the treatment period of the maintenance therapy is defined as any time a patient is receiving the proteasome inhibitor of formula (I) of this disclosure and will comprise 28-day treatment cycles.
  • patients will have treatment assessments performed at regular treatment cycle intervals while they are participating in the therapy: weekly (days 1, 8, and 15) for the first cycle, twice a treatment cycle during the second cycle (days 1 and 8), and then once a treatment cycle for the remainder of their participation in the treatment period, until they experience progressive disease or discontinue for alternate reasons.
  • patients will be assessed for disease response and progression, according to the International Myeloma Working Group criteria, every cycle during the treatment period and subsequently every four weeks during the progression-free survival on maintenance therapy or before the next line of therapy if discontinued before the progression follow-up period until progressive disease. Following progressive disease, patients will be followed in the overall survival follow-up period. Patients will initially be followed every four weeks until initiation of the next line of therapy by the treating physician. All patients will then be followed every 12 weeks until death or termination of the therapy. During the overall survival follow-up period, patients and their treating physician will be contacted for evaluation of the next line of therapy, Health-related quality of life (only until initiation of the next line of therapy), disease status, and survival.
  • Health-related quality of life will be evaluated through patient self-reported instruments, from randomization to the time of initiation of the next line of therapy. After progression and following initiation of the next line of therapy, determination of disease response and progression will be assessed by the treating physician according to International Myeloma Working Group criteria.
  • adverse events will be assessed, and laboratory values, vital signs, and electrocardiograms (ECGs) will be obtained to evaluate the safety and tolerability of ixazomib.
  • ECGs electrocardiograms
  • Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 Jun. 2010.
  • therapeutic efficacy will be measured.
  • a measured change in the patient between an earlier time point and a subsequent time point indicates that the maintenance therapy is therapeutically effective.
  • the first point may be, for example, prior to administration, after the first day of administration, after the fifth day of administration, at the beginning of a treatment cycle, at the end of a treatment cycle, etc. Regardless of when the first time point is, the second time point is subsequent to the first time point.
  • patient data may be collected and used to assess the efficacy of treatment.
  • the relevant data include pharmacokinetic(s) data.
  • patients will receive maintenance therapy for a maximum duration of approximately 24 months (26 cycles, to the nearest complete cycle), or until documented disease progression (on the basis of the International Myeloma Working Group criteria) or intolerable toxicities, whichever comes first.
  • patients will receive maintenance therapy for approximately 24 months. In certain embodiments, patients will receive maintenance therapy until documented disease progression (on the basis of the International Myeloma Working Group criteria) or intolerable toxicities. In certain embodiments, patients will receive maintenance therapy for as long as it is clinically indicated (beyond 26 cycles).
  • patients who complete 24 months of treatment cycles, clinical, laboratory, response, and Health-related quality of life with an emphasis on tolerability and symptom burden, as well as minimal residual disease assessments, will be made. Following documented disease progression, subsequent therapy will be determined by the treating physician.
  • adult patients age 18 years or older with a confirmed diagnosis of multiple myeloma who have had a response (complete response, very good partial response, or partial response) to primary multiple myeloma therapy consisting of standard of care induction, a conditioning regimen containing high-dose melphalan (200 mg/m 2 ), and single autologous stem cell transplant will be eligible for the maintenance therapy.
  • patients who meet the following criteria may receive the maintenance therapy:
  • patients who meet the following criteria may receive the maintenance therapy:
  • active ixazomib is provided to patients in strengths of 4.0 mg, 3.0 mg, 2.3 mg, and 1.5 mg.
  • ixazomib is administrated to the patients as ixazomib citrate in solid dose capsules.
  • ixazomib citrate capsules in the maintenance therapy contain various dose strengths, including 0.5 mg, 2.3 mg, 3.0 mg, or 4.0 mg of ixazomib.
  • the pharmaceutical compositions containing ixazomib citrate and pharmaceutically acceptable carriers of this disclosure can be manufactured by methods well known in the art, for example, described in International Patent Publication WO 2009/154737, which is hereby incorporated by reference specifically and in their entirety.
  • the ixazomib citrate capsules contain a mixture of ixazomib citrate, microcrystalline cellulose, talc, and magnesium stearate.
  • Tables 1A, 1B, 1C and 2 provide certain embodiments of ixazomib citrate capsules.
  • Dose strengths per capsule at the top of the Tables refer to the equivalent of ixazomib when it is hydrolyzed from ixazomib citrate upon contact with either plasma or aqueous solutions.
  • a 0.5 mg capsule refers to a capsule that contains the equivalent of 0.5 mg ixazomib per capsule.
  • a 2.0 mg capsule refers to a capsule that contains the equivalent of 2.0 mg ixazomib per capsule.
  • a 2.3 mg capsule refers to a capsule that contains the equivalent of 2.3 mg ixazomib per capsule.
  • a 3.0 mg capsule refers to a capsule that contains the equivalent of 3.0 mg ixazomib per capsule.
  • a 4.0 mg capsule refers to a capsule that contains the equivalent of 4.0 mg ixazomib per capsule.
  • a 5.0 mg capsule refers to a capsule that contains the equivalent of 5.0 mg ixazomib per capsule.
  • a single first dose of ixazomib is administrated orally to the patients weekly on days 1, 8, and 15 for three weeks, followed by one week without ixazomib in a 28-day cycle.
  • a second dose of ixazomib is administrated to the patients weekly on days 1, 8, and 15 for cycle 5 through cycle 26.
  • the first dose of ixazomib is 3.0 mg; the second dose of ixazomib is 4.0 mg.
  • the first dose of ixazomib is 3.0 mg; the second dose of ixazomib is 3.0 mg.
  • the first dose of ixazomib is 2.3 mg; the second dose of ixazomib is 3.0 mg.
  • the first dose of ixazomib is 2.3 mg; the second dose of ixazomib is 2.3 mg.
  • the first dose of ixazomib is 1.5 mg; the second dose of ixazomib is 2.3 mg.
  • the first dose of ixazomib is 1.5 mg; the second dose of ixazomib is 1.5 mg.
  • the maintenance therapy is initially given as a single, oral dose of 3.0 mg weekly on days 1, 8, and 15 for three weeks, followed by one week without ixazomib in a 28 day cycle. Following the first four cycles of therapy, the dose will be increased to 4.0 mg in cycle 5 through cycle 26 for patients tolerating the drug.
  • a single 3.0 mg dose of ixazomib is administrated orally to the patients weekly on days 1, 8, and 15 for 3 weeks, followed by one week without ixazomib in a 28-day cycle. Following the first four cycles of the 28-day cycle therapy, a second dose of 3.0 mg ixazomib is administrated to the patients weekly on days 1, 8, and 15 for cycle 5 through cycle 26.
  • a single 1.5 mg dose of ixazomib is administrated orally to the patients weekly on days 1, 8, and 15 for 3 weeks, followed by one week without ixazomib in a 28-day cycle.
  • a second dose of 2.3 mg ixazomib is administrated to the patients weekly on days 1, 8, and 15 for cycle 5 through cycle 26.
  • n 21 Median age, years (range) 68 (34-77) Age ⁇ 65 years, n (%) 12 (57) Age ⁇ 75 years, n (%) 2 (10) Male, n (%) 13 (62) White, n (%) 16 (76) ISS disease stage at diagnosis, n (%) I 14 (67) II 7 (33) III 0 MM subtype, n (%) IgG 16 (76) IgA 3 (14) IgD 0 Light chain 2 (10) Median creatinine clearance, ml/min 83.5
  • n 21 Patients with cytogenetic assessment, N* 19 Conventional/karyotype 3 (16) Molecular/FISH 6 (32) Both 10 (53) Unfavorable cytogenetics ⁇ , n (%) 3 (16) Type of cytogenetic abnormality, n (%) del 13 (by metaphase cytogenetics) 2 (11) del 17 1 (5) t(4; 14) 0 t(14; 16) 1 (5) 1q amplification 0
  • Unfavorable cytogentics includes del 17, t(4;14), t(14;16), and 1q amplification abnormalities detected by FISH or metaphase cytogenetics and del 13 detected by metaphase cytogenetics.
  • the patients received single agent ixazomib for a median of 19 treatment cycles (range 3-23), with a median treatment duration of 29.0 months (range 14.3-33.3).
  • Table 5 shows the treatment exposure.

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