US20220193071A1 - Methods for cancer therapy - Google Patents

Methods for cancer therapy Download PDF

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Publication number
US20220193071A1
US20220193071A1 US16/646,304 US201916646304A US2022193071A1 US 20220193071 A1 US20220193071 A1 US 20220193071A1 US 201916646304 A US201916646304 A US 201916646304A US 2022193071 A1 US2022193071 A1 US 2022193071A1
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bcr
abl
formula
compound
patients
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Inventor
Yifan Zhai
Zi Chen
Qian Jiang
Xiaojun Huang
Wei Liu
Dajun Yang
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Ascentage Pharma Suzhou Co Ltd
Ascentage Pharma Group Co Ltd
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Ascentage Pharma Suzhou Co Ltd
Ascentage Pharma Group Co Ltd
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the present invention relates to methods for treating patients with cancer, including patients with hematological malignancy.
  • Cancer has a major impact on society across the world. Cancer is the second most common cause after cardiovascular disease responsible for human death. 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.
  • Chronic myeloid leukemia is a type of cancer that starts in certain blood forming cells of the bone marrow.
  • CML cells contain an abnormal gene, BCR-ABL, that isn't found in normal cells. This gene makes a protein, BCR-ABL, which causes CML cells to grow and reproduce out of control.
  • BCR-ABL is a type of protein known as a tyrosine kinase.
  • Drugs known as tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the standard treatment for CML.
  • Imatinib (Gleevec®) is the first drug to specifically target the BCR-ABL tyrosine kinase protein for treating CML.
  • BCR-ABL tyrosine kinase protein tyrosine kinase protein
  • emerging acquired resistance to imatinib has become a major challenge for clinical management of CML.
  • More than 100 resistance-related BCR-ABL mutants have been identified in the clinic, among which the “gatekeeper” T315I is most common mutation, as it accounts for approximately 15-20% of all clinically acquired mutants. Ren et al., J. Med Chem. 2013, 56, 879-894.
  • BCR-ABL T315I induced drug resistance remains an unmet clinical challenge for CML treatment. Accordingly, there is a continuing need for new and more effective treatment.
  • the methods of the present invention present cancer patients with new options.
  • the present invention relates methods for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I):
  • R 1 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkyloxy, or phenyl; and R 2 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or halogen.
  • the cancer is hematological malignancy.
  • the hematological malignancy is leukemia, including chronic myelogenous leukemia.
  • the method is in the treatment of the patient with chronic myeloid leukemia resistant to current tyrosine kinase inhibitor therapies.
  • the patient with chronic myeloid leukemia resistant to the current tyrosine kinase inhibitor therapies is caused by BCR-ABL mutations.
  • BCR-ABL mutation is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL WT mutations.
  • BCR-ABL mutation is T315I mutation.
  • the compound of formula (I), or pharmaceutically acceptable salt thereof is administered orally to the patients in need such treatment.
  • the compound of formula (I), or pharmaceutically acceptable salt thereof is administered once every other day (QOD) during the 28-day treatment cycle.
  • the compound of formula (I) is a compound of formula (I-A):
  • the compound of formula (I) or formula (I-A) is administered once every other day in an amount of about 1 mg, about 2 mg, about 4 mg, or about 8 mg.
  • the compound of formula (I) or formula (I-A) is administered once every other day in an amount of about 12 mg or about 20 mg.
  • the compound of formula (I) or formula (I-A) is administered once every other day in an amount of about 30 mg, about 40 mg, or about 45 mg.
  • the compound of formula (I) or formula (I-A) is administered once every other day in an amount of about 50 mg or about 60 mg.
  • the present invention relates to a method of inhibiting BCR-ABL mutants, comprising contacting a compound of formula (I) or a salt thereof with BCR-ABL mutants, wherein the BCR-ABL mutants is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL WT .
  • the present invention relates to a method of inhibiting BCR-ABL mutants, comprising contacting a compound of formula (I) or a salt thereof with BCR-ABL mutants selected from T315I.
  • the present invention provides a medicament or pharmaceutical composition comprising the compound of formula (I) or formula (I-A) or pharmaceutically acceptable salt thereof for treat hematological malignancy, including chronic myelogenous leukemia.
  • the present invention relates to us of a compound of formula (I) or (I-A), or pharmaceutically acceptable salt thereof in the manufacture of medicament for the treatment of hematological malignancy, including chronic myelogenous leukemia.
  • FIGS. 1A and 1B illustrate efficacy (CHR n %) of the compound of formula (I-A) in a phase 1 study.
  • FIGS. 2A and 2B illustrate efficacy (MCyR n %) of the compound of formula (I-A) in a phase 1 study.
  • FIGS. 3A, 3B, and 3C illustrate efficacy (MCyR n %) by dose (CP) of the compound of formula (I-A) in a phase 1 study.
  • FIGS. 4A and 4B illustrate MMR (MCyR n %) of the compound of formula (I-A) in a phase 1 study.
  • FIGS. 5A and 5B illustrate plasma concentration-time profiles of the compound of formula (I-A) in a phase 1 study.
  • FIGS. 6A and 6B illustrate the efficacy of the compound of formula (I-A) in a phase 1 study.
  • FIG. 7A illustrates the response rate and the depth of response of the compound of formula (I-A) in CML-CP patients, Example 2.
  • FIG. 7B illustrates the progression free survival (PFS) rate of the compound of formula (I-A) in CML patients.
  • PFS progression free survival
  • FIG. 8 illustrates the effect of the compound of formula (I-A) on survival of Ba/F3 tumor bearing mice expressing the BCR-ABL T315I .
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, including but not limited to therapeutic benefit.
  • treatment is administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • Therapeutic benefit includes eradication and/or amelioration of the underlying disorder being treated such as cancer; it also includes the eradication and/or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • treatment includes one or more of the following: (a) inhibiting the disorder (for example, decreasing one or more symptoms resulting from the disorder, and/or diminishing the extent of the disorder); (b) slowing or arresting the development of one or more symptoms associated with the disorder (for example, stabilizing the disorder and/or delaying the worsening or progression of the disorder); and/or (c) relieving the disorder (for example, causing the regression of clinical symptoms, ameliorating the disorder, delaying the progression of the disorder, and/or increasing quality of life.)
  • administering or “administration” of the compound of formula (I) or formula (I-A) or a pharmaceutically acceptable salt thereof encompasses the delivery to a patient a compound or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, e.g., as described herein.
  • the term “therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disorder, is sufficient to effect such treatment of the disorder.
  • the effective amount will vary depending on the disorder, and its severity, and the age, weight, etc. of the subject to be treated.
  • the effective amount may be in one or more doses (for example, a single dose or multiple doses may be required to achieve the desired treatment endpoint).
  • An effective amount may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any co-administered compounds may optionally be lowered due to the combined action, additive or synergistic, of the compound.
  • Delaying development of a disorder mean to defer, hinder, slow, stabilize, and/or postpone development of the disorder. Delay can be of varying lengths of time, depending on the history of the disease and/or the individual being treated.
  • patient to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys).
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)
  • other primates e.g., cynomolgus monkeys, rhesus monkeys.
  • pharmaceutically acceptable or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Pharmaceutically acceptable salts of Compound 1 include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.
  • Alkyl groups can be substituted or unsubstituted.
  • cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.
  • alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy butoxy, isobutoxy, sec-butoxy, or tert-butoxy. Alkoxy groups can be substituted or unsubstituted.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • compound of formula (I) has the following structure:
  • R 1 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkyloxy, or phenyl; and R 2 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or halogen.
  • the chemical name for the compound of (I-A) is 3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-benzamide.
  • the compounds of formula (I) or (I-A) include any tautomer forms.
  • tautomerization may occur in the pyrazole and pyrimidine groups.
  • the compounds of formula (I) or (I-A) are novel, selective potent inhibitors against a broad spectrum of BCR-ABL mutations, including T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL WT .
  • the compounds of formula (I) or formula (I-A) or a pharmaceutically acceptable salt thereof are also potent inhibitors against other kinases including KIT, BRAF, DDR1, PDGFR, FGFR, FLT3, RET, SRC, TIE1, and TIE2.
  • compositions and dosage forms comprising compounds of formula (I) or formula (I-A) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Compositions and dosage forms provided herein may further comprise one or more additional active ingredients.
  • Compounds of formula (I) or formula (I-A) or a pharmaceutically acceptable salt thereof may be administered as part of a pharmaceutical composition as described.
  • a method for hematological malignancy in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I):
  • R 1 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkyloxy, or phenyl; and R 2 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or halogen.
  • the compound of formula (I) is a compound of formula (I-A):
  • the hematological malignancy is leukemia, including chronic myelogenous leukemia.
  • the method is in the treatment of the patient with chronic myeloid leukemia resistant to current tyrosine kinase inhibitor therapies, wherein resistant to the current tyrosine kinase inhibitor therapies is caused by BCR-ABL mutations.
  • Examples of the current tyrosine kinase inhibitors include, but not limit to, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, or bafetinib,
  • BCR-ABL mutation is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL WT mutations.
  • BCR-ABL mutation is T315I mutation.
  • the method of the invention relates to a method for treating a hematological malignancy resistant to Ponatinib.
  • Ponatinib is a third-generation inhibitor of BCR-ABL for the treatment of Chronic Myelogenous Leukemia (CML) carrying the T315I mutation, Ph+ALL (Philadelphia chromosome positive ALL), and CML and Ph+ALL that are not responsive to other Tyrosine Kinase Inhibitors (TKIs).
  • CML Chronic Myelogenous Leukemia
  • Ph+ALL Philadelphia chromosome positive ALL
  • TKIs Tyrosine Kinase Inhibitors
  • the compound mutation of BCR-ABL may be involved in clinical drug resistance of CML and Ph+ALL to Ponatinib.
  • Ph+ALL the E255V/T315I double mutation can produce 20-fold resistance compared to the T315I single mutation, and other compound mutations such as Q252H/T315I, T315I/M351I and T315I/F359V are also less sensitive to Ponatinib (see: Zabriskie M S, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014; 26(3):428-42).
  • the inhibitory effect of the compound of formula (I) and Ponatinib on BCR-ABL complex mutant cell proliferation is confirmed by constructing a stably transfected cell line with BCR-ABL complex mutation, and a potential therapeutic approach to overcome Ponatinib resistance is provided.
  • the invention proves that the compound of the formula (I-A) has better antiproliferative effect than Ponatinib on Ba/F3 cells with complex mutations of BCR-ABL E255V/T315I , BCR-ABL Y253H/E255V , BCR-ABL T315M , BCR-ABL Y253H/T315I , BCR-ABL Y253H/F359V and BCR-ABL T315I/F317L .
  • the results suggest that the compound of formula (I-A) is a potential candidate drug for overcoming the resistance of Ponatinib caused by BCR-ABL complex mutation.
  • the compound of formula (I), or pharmaceutically acceptable salt thereof is administered orally to the patients in need such treatment.
  • the compound of formula (I), or pharmaceutically acceptable salt thereof is administered once every one, two, or three days during the treatment cycle.
  • the said treatment cycle may be 20-40 days, preferably 25-35 days, more preferably 28-day treatment cycle.
  • the compound of formula (I) or formula (I-A) is administered every day, or once every other day (QOD), or once every three days, particularly once every other day.
  • the amount of administration is from 0.5 mg to 100 mg, preferably from 1 mg to 80 mg, more preferably from 1 mg to 60 mg. In the most preferable embodiments, it is in an amount of about 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 52 mg, 54 mg, 56 mg, 58 mg, or 60 mg.
  • the compound of formula (I) or formula (I-A) is administered once every other day in an amount of about 30 mg, about 40 mg, or about 45 mg.
  • the compound of formula (I) or formula (I-A) is administered once every other day in an amount of about 50 mg or about 60 mg.
  • the compound of formula (I) or formula (I-A) is formulated into a dosage unit to be administered every day, or once every other day (QOD), or once every three days, particularly once every other day.
  • the amount of the dosage unit is from 0.5 mg to 100 mg, preferably from 1 mg to 80 mg, more preferably from 1 mg to 60 mg.
  • the present invention relates to a method of inhibiting BCR-ABL mutants, comprising contacting a compound of formula (I) or a salt thereof with BCR-ABL mutants, wherein the BCR-ABL mutants is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL WT .
  • the present invention relates to a method of inhibiting BCR-ABL mutants, comprising contacting a compound of formula (I) or a salt thereof with BCR-ABL mutants selected from T315I.
  • the inhibition is in vitro or in vivo.
  • the inhibition is in a patient with chronic myeloid leukemia resistant to current tyrosine kinase inhibitor therapies.
  • the present invention provides a medicament or pharmaceutical composition comprising the compound of formula (I) or formula (I-A) or pharmaceutically acceptable salt thereof for treat hematological malignancy, including chronic myelogenous leukemia.
  • the present invention relates to the use of a compound of formula (I) or (I-A), or pharmaceutically acceptable salt thereof in the manufacture of medicament for the treatment of hematological malignancy, including chronic myelogenous leukemia.
  • the compound of formula (I) or (I-A) is in a solid dosage form.
  • the cancer is newly diagnosed.
  • the cancer is relapsed.
  • the cancer is refractory.
  • embodiments of the disclosure include treatment of various disorders, patient populations, administrations of dosage forms, at various dosages, minimization of various adverse events, and improvements in various efficacy measures, etc. Any combinations of various embodiments are within the scope of the disclosure.
  • 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.
  • 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.
  • Non-limiting examples of hematologic malignancies also include amyloidosis, acute myeloid leukemia (AML); chronic myelogenous leukemia (CML) including accelerated CML and CML 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), 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 leuk
  • 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
  • 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.
  • the compound of formula (I-A) was administered orally once every other day (QOD) in 28-days cycles at 11 dose cohorts ranging from 1 mg to 60 mg.
  • the eligible patients received treatments until disease progression or intolerable toxicities.
  • CHR hematological response
  • MyR major cytogenetic response
  • PCyR partial cytogenetic response
  • CyR complete cytogenetic response
  • BCR-ABL inhibition was evaluated using tyrosine phosphorylation of CRKL and STAT5 in peripheral blood mononuclear cell (PBMCs) collected from the patients before and 4, 8, 24 and 48 hours post the compound of formula (I-A) treatments on Day 1, 15 and 27 during cycle 1.
  • PBMCs peripheral blood mononuclear cell
  • patients who meet the following criteria may receive the treatments:
  • patients who has the following criteria may exclude from the treatments:
  • Dose Number On-treatment duration cohort of patients median range 1 mg 3 12.6 12.3-16.5 2 mg 3 9.6 2.0-15.3 4 mg 3 8.5 8.4-9.3 8 mg 3 10.4 7.3-13.3 12 mg 3 11.4 11.4-12.9 20 mg 4 10.9 8.4-14.0 30 mg 37 7.4 0.0-11.4 40 mg 37 3.7 1.2-7.0 45 mg 3 11.3 11.1-11.3 50 mg 24 5.2 0.7-7.2 60 mg 3 9.4 9.4-9.7
  • the anti-leukemic activities of the compound of formula (I-A) treatment were observed in this study. Sixty-five (93%) patients including 58 (100%) CP and 7 (58%) AP patients achieved CHR at the dose of 2 mg to 60 mg within 3 cycles. In 47 evaluable patients receiving the compound of formula (I-A)-treatment ⁇ 3 cycles, 24 (51%) achieved MCyR including 21 (54%) CP and 3 (38%) AP patients at the dose of 12 mg to 50 mg, and 14 (30%) patients achieved CCyR including 12 (31%) CP and 2 (25%) AP patients. Total 6 (15%) CP patients achieved MMR. More than 65% of the patients achieved MCyR or MMR at the end of cycle The compound of formula (I-A) was highly active in patients with or without T315I mutation at baseline (Table 2).
  • the peak concentration was reached at 2-8 hrs.
  • the elimination appeared to be linear with a mean terminal T 1/2 of 15.3-36.5 hrs on Day 1, 18.8-42.5 hours on Day 27, respectively (the window period of the observation time is 48 hrs).
  • the ratios for AUC0-t and Cmax of the compound of formula (I-A) treatment on Day 27 versus Day 1 ranged from 1.03 to 2.12 and from 0.78 to 1.93, respectively.
  • the compound of formula (I-A) exhibited an approximately dose proportional increase in Cmax and AUC0-t following single or multiple oral administration dose ranging from 1 to 60 mg.
  • PD study results demonstrated that reduction of CRKL phosphorylation was schedule and dose-dependent, ⁇ 50% reduction was observed at doses ranging 12 mg-60 mg.
  • FIGS. 1A and 1B illustrate the efficacy (CHR n %) of the compound of formula (I-A) in a phase 1 study.
  • FIGS. 2A and 2B illustrate the efficacy (MCyR n %) of the compound of formula (I-A) in a phase 1 study.
  • FIGS. 3A, 3B and 3C illustrate the efficacy (MCyR n %) of the compound of formula (I-A) with specific doses (CP) in a phase 1 study.
  • FIGS. 4A and 4B illustrate MMR (MCyR n %) of the compound of formula (I-A) in a phase 1 study.
  • FIGS. 5A and 5B illustrate the plasma concentration-time profiles of the compound of formula (I-A) in a phase 1 study.
  • the preliminary results of the phase 1 clinical study showed that the compound of formula (I-A), a novel 3 rd -generation TKI, is safe and highly active in treatment of the TKI-resistant patients with CML-CP and CML-AP, with or without T315I mutation.
  • the compound of formula (I-A) is designed for treatment of patients with chronic myeloid leukemia (CML) resistant to current TKI-therapies including those with T315I mutation. This experiment is focus on the efficacy and safety assessment of the compound of formula (I-A) in a relatively long term.
  • CML chronic myeloid leukemia
  • the compound of formula (I-A) was administered once every other day (QOD) in 28-day cycles at 11 dose cohorts ranging from 1 mg to 60 mg.
  • the eligible patients received continuous treatment until disease progression or unacceptable toxicity, consent withdrawal, or death.
  • the primary efficacy endpoints were major cytogenetic response (MCyR) for CP and complete hematological response (CHR) for AP.
  • MyR includes partial cytogenetic response (PCyR) and complete cytogenetic response (CCyR).
  • PCyR partial cytogenetic response
  • CyR complete cytogenetic response
  • the compound of formula (I-A) was well-tolerated in all dose cohorts with an exception of 60 mg cohort. In all patients, 101 (100%) patients experienced ⁇ 1 treatment related adverse events (TRAEs), the most frequent TRAEs were reported as grade 1 or grade 2. The most common grade 3/4 TRAEs were hematological AEs, including thrombocytopenia (49.5%). The incidences of AEs tended to be dose-dependent. No death and no CTCAE grade 5 events have occurred on study. The incidence of common TRAEs ( ⁇ 10%) are shown in Table 3.
  • TRAEs treatment related adverse events
  • the compound of formula (I-A) showed the potent anti-leukemic activities at doses ⁇ 12 mg QOD. In sixty-eight (67%) evaluable patients, the compound of formula (I-A) showed potent anti-leukemic activities in CML patients. In the 68 evaluable patients with non-CHR at baseline, 63 (92.6%) achieved CHR including 52 out of 55 (94.5%) CP patients and 11 out of 13 (84.6%) AP patients, respectively. In the 95 evaluable patients with non-CCyR at baseline, 56 out of 81 (69.1%) CP patients achieved MCyR including 49 (60.5%) CCyR; and 6 out of 14 (42.9%) AP patients, achieved MCyR including 5 (35.7%) CCyR, respectively.
  • the peak concentration of the compound of formula (I-A) was reached between 1-12 h on Day 1, with median Tmax ranging from 4-8 h.
  • the elimination appeared to be linear with a mean terminal T 1/2 of 17.5 to 36.5 h on Day 1. Peak concentration of the compound of formula (I-A) were observed at 1 ⁇ 12 h on Day 27, With median Tmax ranging from 4-6 h.
  • the mean terminal T 1/2 ranged from 19.8 to 42.5 h on Day 27 (both of the watching time window is 48 hrs).
  • the compound of formula (I-A) exhibits significant and durable antitumor activity, it is well tolerated in the patients with TKI-resistant CML, including those patients with T315I mutation.
  • the progression free survival (PFS) rate at 18-month was 94% in the CP patients and 61% in the AP patients.
  • compound of the formula (I-A) induced complete regression of subcutaneous tumors in a human CML xenograft model and an isogenic model derived from murine Ba/F3 cells expressing BCR-ABL WT or BCR-ABL T315I mutants, and significantly improved the survival rate of isogenic leukemia mice carrying Ba/F3 cells having BCR-ABL WT or BCR-ABL T315I .
  • BCR-ABL complex mutation cells were used to determine the inhibitory effect of the compound of the formula (I-A) and Ponatinib on the proliferation of BCR-ABL complex mutation cells.
  • the experiment proved that the compound of the formula (I-A) was a potential effective medicament capable of overcoming the drug resistance of the Ponatinib.
  • Ba/F3 cells stably expressing BCR-ABL (F359V, H396R, E255K, Y253H, T315I, F317L) mutations were provided by the Institute of Life and Health, Guangzhou Academy of Sciences.
  • the mutated Ba/F3 cell line stably expressing BCR-ABL (E255V, T315M, Y253H/E255V, Y253H/T315I, Y253H/F359V, T315I/F317L, F317L/F359V) mutation was constructed by electro-transformation method
  • the Ba/F3 cell line stably expressing the BCR-ABL (E255V/T315I, T315I/F359V) mutation was constructed by lentivirus infection method.
  • the solution of the sample (the compound of the formula (I-A) or Ponatinib) to be tested with a 9-dose concentration obtained by serial dilution was added proportionally at 100 ⁇ l/well in a 96-well culture plate.
  • the dilution was used as a cell blank control (excluding the sample to be tested, which was added to the cells).
  • a negative control (excluding the sample to be tested and cells) was prepared.
  • 100 ⁇ l of complete medium cell suspension was added to each well.
  • the dilution was added to the negative control wells at 100 ⁇ l/well. 3 repeated wells were set in the experiment. Cells were incubated for 72 hours at 37° C. in a CO 2 incubator.
  • CCK-8 detection solution (Shanghai Life iLab Biotech Co., LTD, Cat #D3100L4057) was added to each well, incubating at 37° C. for 2 hours in a CO 2 incubator. The OD value was measured at A 450 nm by a microplate reader.
  • the percentage of cell viability was calculated using the following formula:
  • the IC 50 was calculated using a non-linear regression data analysis method of Graphpad Prism 6.0 software (Golden software, Golden, Colo., USA).
  • the compound of the formula (I-A) has better anti-proliferation effect on Ba/F3 cells with complex mutations of BCR-ABL E255V/T315I , BCR-ABL Y253H/E255V , BCR-ABL T315M , BCR-ABL Y253H/T315I , BCR-ABL Y253H/F359V , BCR-ABL T315I/F317L than Ponatinib, the IC 50 value of the compound of the formula (I-A) was 2-9 folds lower than the IC 50 value of Ponatinib (Table 5). The results suggest that the compound of the formula (I-A) is a potential candidate drug for overcoming the drug resistance of Ponatinib caused by BCR-ABL complex mutation.
  • BCR-ABL the compound of Mutation Region mutation Imatinib Nilotinib Dasatinib Ponatinib the formula (I-A) Wild Type Wild Type 565 ⁇ 656 31 ⁇ 4 10 ⁇ 3 11 6 ⁇ 3 Substrate F359V 9626 ⁇ 481 4643 ⁇ 2260 2161 ⁇ 1090 2173 ⁇ 1481 281 ⁇ 187 Binding Region A-Ring H396R 9179 ⁇ 1303 4665 ⁇ 799 1641 ⁇ 1180 2035 ⁇ 1024 274 ⁇ 82 P-Ring E255K 8222 ⁇ 484 648 ⁇ 395 14 ⁇ 1 49 ⁇ 4 22 ⁇ 13 Y253H 8936 ⁇ 1.774 497 ⁇ 122 11 ⁇

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