Treatment of acute myeloid leukemia with ortasidenib, venetoclax, and hypomethylating agents

Abstract

A method is provided for treating a subject having a hematological malignancy or premalignancy, comprising administering an effective dose of ortasidenib, venetoclax, and a hypomethylating agent. In some cases, the patient has an IDH1 mutation.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 525,639, filed July 7, 2023, which is incorporated herein by reference in its entirety.

[0002] preface Mutant IDH1 is a genetically validated target in hematological malignancies, including AML. Mutations in IDH1 present in certain cancer cells can impart a new ability to catalyze the NADPH-dependent reduction of α-ketoglutarate to 2-hydroxyglutarate (2HG) (usually the enantiomer (R)-2-hydroxyglutarate (R-2HG)). 2HG is not formed by wild-type IDH. A mutation at codon 132 of IDH1 imparts neomorphic activity to the enzyme, leading to the production of 2HG, a "cancer metabolite" that plays a multifaceted role in tumorigenesis. Excessive production of 2HG has been shown to inhibit α-KG-dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling, thereby hindering the normal differentiation of progenitor cells and subsequently leading to 2HG neomorphic activity, specifically IDH1 cancer mutations associated with R-2HG neomorphic activity, such as mutations at residues 97, 100, and 132, e.g., G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. IDH mutation-specific inhibitors have been shown to reduce abnormally elevated levels of the tumor metabolite 2HG, resulting in antitumor effects in preclinical models. [Overview of the Initiative]

[0003] A method is provided for treating a subject having a hematological malignancy or premalignancy, comprising administering an effective amount of ortasidenib, venetoclax, and a hypomethylating agent. For example, the hypomethylating agent may be azacitidine or decitabine. In some cases, the malignancy or premalignancy has an IDH1 mutation. In certain embodiments, the hematological malignancy includes acute myeloid leukemia (AML). [Brief explanation of the drawing]

[0004] [Figure 1] This shows the design of a clinical trial. [Modes for carrying out the invention]

[0005] Before describing the present invention in more detail, it should be understood that the present invention is not limited to the specific embodiments described and is therefore subject to change. It should also be understood that the terminology used herein is merely for the purpose of describing specific embodiments and is not intended to limit the scope of the present invention, as it is limited only by the appended claims.

[0006] Where a range of values ​​is provided, understand that unless the context explicitly indicates otherwise, each intermediate value between the upper and lower limits of that range, up to one-tenth of the lower limit unit, is also specifically disclosed. Each smaller range between any of the stated values ​​or intermediate values ​​within the stated range and any other stated value or intermediate values ​​within the stated range is included in the present invention. The upper and lower limits of these smaller ranges may or may not be included independently within this range, and each range that includes either of these limits, does not include any limits, or includes both of these limits is included in the present invention, subject to any specifically excluded limitations within this stated range. Where a stated range includes one or both limits, a range that excludes one or both of the limits that they include is also included in the present invention.

[0007] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the present invention, but some potential and exemplary methods and materials may be described below. All publications referenced herein are incorporated herein by reference to disclose and explain the methods and / or materials cited in those publications. To the extent of any conflict, understand that this disclosure takes precedence over any disclosure in any publication that invokes it.

[0008] It should be noted that the singular forms “a,” “an,” and “the” used herein and in the appended claims include plural nouns unless the context otherwise explicitly indicates otherwise. Thus, for example, a reference to “droplets” includes multiple such droplets, a reference to “distinct entities” includes one or more distinct entities, and so on. It should be further noted that the claims may be constructed to exclude any element, e.g., any element of any choice. Therefore, this statement is intended to serve as a precedent for the use of exclusive technical terms such as “simply,” “only,” or “negative” restrictions with respect to the enumeration of elements in the claims.

[0009] The publications discussed herein are provided only for disclosures made prior to the filing date of this application. Furthermore, the dates of the publications provided may differ from the actual publication dates and may need to be verified separately. To the extent to which there is a discrepancy between the definition or use of any term herein and the definition or use of a term in an application or reference incorporated herein by reference, this application shall prevail.

[0010] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated from or combined with any of the features of some other embodiments without departing from the scope or spirit of the invention. Any of the recited methods can be performed in the order of the recited events or in any other order that is logically possible.

[0011] Definitions Oltiprazide has a Chemical Abstract Service (CAS) number of 1887014-12-1 and the following structure:

Chem.

[0012] Venetoclax has a CAS number of 1257044-40-8 and the following structure:

Chem.

[0013] Azacitidine has a CAS number of 320-67-2 and the following structure:

Chem.

[0014] Decitabine has a CAS number of 2353-33-5 and the following structure:

Chem.

[0015] Sedazurin has a CAS number of 1141397-80-9 and the following structure:

Chem.

[0016] The term “standard treatment” or “SOC” refers to a treatment that is acceptable to those skilled in the art as appropriate treatment for a particular type of disease, such as a treatment that is widely used by medical professionals. In certain embodiments, National Comprehensive Cancer Network (NCCN) guidelines may serve as a source of standard treatment for AML, MDS, and other hematological malignancies and pre-malignancies.

[0017] The terms activator, active pharmaceutical ingredient, pharmacologically active agent, and drug are used interchangeably herein and refer to chemical substances or compounds that, when administered to a living organism (human or animal), induce a desired pharmacological and / or physiological effect by local and / or systemic action.

[0018] The terms "QD" and "BID" refer to once a day and twice a day, respectively.

[0019] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein and are not limited to humans and non-human primates, including monkeys, and animals, including humans, rodents, rats, and mice, cattle, horses, sheep, cats, dogs, etc. “Mammal” means singular or plural members of any mammalian species, including, for example, dogs, cats, horses, cattle, sheep, rodents, etc., and primates, e.g., non-human primates, as well as humans. Non-human animal models, e.g., mammals, e.g., non-human primates, mice, lagomorphs, etc., may be used for experimental studies.

[0020] As used herein, the term “remission” includes complete remission (”CR”), complete remission with partial hematological recovery (”CRh”), complete remission with incomplete recovery (”CRi”), morphological leukemia-free state (”MLFS”), partial remission (”PR”), and stable state (”SD”). CR includes complete remission, complete cytogenetic remission (”CRc”), and complete molecular remission (CRm). Remission status is determined by the investigator's assessment using the modified response criteria of the International Working Group on AML (Cheson et al., J Clin Oncol. 2003;21:4642-4649). CRh is defined as myeloblast count <5% and absolute neutrophil count >0.5 × 10⁻⁶. 9 / L, and platelet count > 50 × 10 9 Defined as / L

[0021] As used herein, terms such as “treatment” and “to treat” refer to obtaining pharmacological and / or physiological effects, such as a reduction in viral titer. Such effects may be prophylactic in that they completely or partially prevent the disease or symptoms thereof, and / or therapeutic in that they result in the partial or complete cure of the disease and / or side effects caused by the disease. As used herein, “treatment” encompasses any treatment of a disease in mammals, in particular humans, and includes (a) preventing the onset of the disease or symptoms thereof in subjects susceptible to the disease but not yet diagnosed with it (e.g., including diseases associated with or that can be caused by an underlying disease (e.g., hepatic fibrosis that may occur in association with chronic HCV infection)), (b) inhibiting the disease, i.e., preventing its manifestation, and (c) mitigating the disease, i.e., causing its regression (e.g., a reduction in viral titer).

[0022] A “therapeutic effective dose,” “effective dose,” “therapeutic effective dosage,” or “therapeutic dosage” is an amount sufficient to produce a desired clinical outcome (i.e., to achieve a therapeutic effect, to achieve a desired therapeutic response, etc.). A therapeutic effective dose may be administered in one or more doses. For the purposes of this disclosure, a therapeutic effective dose of a composition is an amount sufficient, when administered to an individual, to alleviate, improve, stabilize, reverse, prevent, slow or delay the progression of a disease condition (e.g., cancer) present in the subject.

[0023] As used herein, the terms “determine,” “measure,” “evaluate,” and “assay” are used interchangeably and include both quantitative and qualitative determinations.

[0024] As used herein, the term “unit dose form” refers to physically distinct units suitable as unit doses for human and animal subjects, each unit containing a predetermined amount of a compound (e.g., an aminopyrimidine compound as described herein) calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or medium. The specifications for unit dose forms depend on the specific compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0025] "Pharmacologically acceptable excipients," "pharmaceutically acceptable diluents," "pharmaceutically acceptable carriers," and "pharmaceutically acceptable adjuvants" mean excipients, diluents, carriers, and adjuvants that are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients, diluents, carriers, and adjuvants that are acceptable for veterinary use as well as for human pharmaceutical use. As used herein and in the claims, "pharmaceutically acceptable excipients, diluents, carriers, and adjuvants" encompasses one or more such excipients, diluents, carriers, and adjuvants.

[0026] As used herein, “pharmaceutical composition” means a composition suitable for administration to subjects such as mammals, particularly humans. Generally, “pharmaceutical composition” is sterile and preferably free from contaminants that could induce undesirable reactions in the subject (e.g., the compounds in the pharmaceutical composition are pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients requiring them via multiple different routes of administration, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, and similar.

[0027] The terms “simultaneous administration” and “in combination with” include administering two or more therapeutic agents simultaneously or consecutively, or consecutively, within a treatment plan such as a treatment cycle. Typically, a treatment cycle is a period of administration of a drug or combination of drugs followed by a rest period. In the methods of the present invention, rest periods between cycles are optional. Therefore, simultaneous administration in the present method, such as simultaneous administration of ortasidenib, venetoclax, and a hypomethylating agent, refers to the administration of three components within a treatment plan. A treatment cycle (or dosing cycle) follows a dosing schedule. As used herein, a dosing schedule represents the frequency at which a drug is administered in a particular dose. In one embodiment, simultaneous administration means administering three components within 28 days of each other, for example, on the same or different days within a 28-day treatment cycle. In one embodiment, the drugs are simultaneously present in cells or within the body of the subject, or exert their biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agent is in another composition or unit dosage form. In certain embodiments, the first agent may be administered before (e.g., 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) or simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, or 4 weeks after) the administration of one or more additional therapeutic agents.

[0028] The term "ineligible" refers to an assessment of whether a patient is ineligible to receive chemotherapy, and is made by practitioners such as clinical hematologists or hematologist-oncologists. For example, Ferrara et al. discuss a consensus-based definition of ineligibility for intensive and non-intensive chemotherapy in AML (Leukemia, 2013, 27, 997, doi: 10.1038 / leu.2012.303). Eligibility is also described by Samra et al. (Frontier in Oncology, 2020, 10, 562558, doi: 10.3389 / fonc.2020.562558). In some cases, a patient may be ineligible because they are over 65 years of age, have organ dysfunction (e.g., heart, lung, kidney, liver), or a combination thereof. In some cases, the determination of ineligibility includes an assessment that chemotherapy is more likely to cause harm or death than leaving the cancer untreated.

[0029] The term "IDH1-mediated disease or disorder" includes diseases associated with or implying IDH1 activity, such as hyperactivity of IDH1, and conditions associated with such diseases. Hyperactivity of IDH-1 is known to be involved in the pathogenesis of several diseases, including inflammatory and autoimmune diseases, proliferative disorders, neoplastic disorders, and cancer, as described herein.

[0030] The term “proliferative disorder or disease” refers to the undesirable cell proliferation of one or more subsets of cells in a multicellular organism that causes harm to the multicellular organism (i.e., discomfort or reduced lifespan). Proliferative disorders or diseases can occur in different types of animals and in humans. For example, as used herein, “proliferative disorder or disease” includes neoplastic disorders and other proliferative disorders.

[0031] The terms “neoplastic disorder or disease” or “cancer” refer to tumors resulting from abnormal or uncontrolled cell growth. Examples of neoplastic disorders include, but are not limited to, hematopoietic disorders, such as myeloproliferative disorders, thrombocythemia, essential thrombocytosis (ET), angiogenic myelometaplasia, myelofibrosis (MF), myelofibrosis with myelometaplasia (MMM), chronic idiopathic myelofibrosis (IMF), polycythemia vera (PV), cytopenia, and premalignant myelodysplastic syndromes; cancers, such as gliomas, lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, colon cancer, pancreatic cancer, ovarian cancer, and hematological malignancies.

[0032] The term "hematological malignancies" refers to cancers of the blood-forming and immune systems—the bone marrow and lymphoid tissues—in the body. Examples of hematological malignancies include myelodysplasia, lymphoma, leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also called Hodgkin lymphoma), and myeloma, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with tricytic myelodysplasia (AML / TMDS), mixed-plasmody leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), and multiple myeloma (MM).

[0033] As used herein, the term “premalignant” refers to somatic mutations that can cause or increase the risk of developing hematological malignancies. Certain hematopoietic mutations confer favorable adaptive advantages to their disproportionate expansion. Examples of premalignant tumors that can be treated as described herein include, but are not limited to, clonal hematopoiesis with undetermined potential (CHIP), cytopenia of unspecified significance (CCUS), and premalignant or low-risk MDS. Other premalignant conditions are characterized by specific mutations and are known to those skilled in the art.

[0034] The term "leukemia" refers to malignant tumors of hematopoietic tissue, including but not limited to chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia.

[0035] method As described above, this invention relates to a method for treating subjects with hematological malignancies such as acute myeloid leukemia (AML) or MDS. In one embodiment, the hematological malignancies include MDS, AML, or both. Accordingly, this specification provides a method for treating MDS. Similarly, a method for treating AML is also provided. Such a method comprises administering ortasidenib, venetoclax, and a hypomethylating agent. Such a method may result in beneficial remission of AML and improvement of the patient's symptoms.

[0036] In some embodiments, MDS is characterized by mutations in isocitrate dehydrogenase 1 (IDH1). In one embodiment, the IDH1 mutation is detected in the patient's blood, bone marrow, or both.

[0037] In some embodiments, AML is characterized by mutations in isocitrate dehydrogenase 1 (IDH1). Cancer patients may be diagnosed with AML, characterized by the detection of IDH1 mutations in the blood, bone marrow, or both. AML patients without IDH1 mutations at diagnosis may be retested at the time of relapse, as IDH1 mutations may surface during treatment and at the time of relapse. In some cases, administration can inhibit IDH1 mutations, for example, leading to increased levels of 2HG in leukemia cells. The most common of such mutations are R132H and R132C substitutions. Therefore, in some cases, patients have IDH1 mutations, e.g., R132H mutations, R132C mutations, or combinations thereof.

[0038] In some cases, administration of ortasidenib, venetoclax, and hypomethylating agents may be repeated for multiple days, for example, for 10 days or more, 50 days or more, 100 days or more, 200 days or more, or 400 days or more. In some cases, administration is repeated to slow cancer growth or reduce the amount of cancer. Therefore, administration may be repeated over a long period.

[0039] DiNardo et al. described the use of decitabine or azacitidine in combination with venetoclax in a phase 1b dose-escalation and expansion study in elderly patients with untreated AML (DiNardo et al. Blood. 2015-12-03 00:00:00 2015;126(23):327-327). In this study, venetoclax was administered at a dose of 20 mg / m² on days 1-5. 2 Decitabine, or 75 mg / m² on days 1-7. 2 Venetoclax was administered daily in 28-day cycles, along with azacitidine. Venetoclax was administered at 400, 800, or 1200 mg during the escalation phase and at 400 or 800 mg during the expansion phase.

[0040] In some cases, the amount of ortasidenib administered per day is approximately 300 mg. Ortasidenib may be administered as a single dose, for example, 300 mg, or as multiple doses, for example, 150 mg twice daily, giving a total daily dose of approximately 300 mg. In some cases, the “approximately 300 mg” of ortasidenib administration is in the range of 200 mg to 400 mg, for example, 250 mg to 350 mg or 275 mg to 325 mg. In some cases, the administration is 300 mg of ortasidenib. In one embodiment, ortasidenib is administered in doses of 150 mg twice daily.

[0041] In some cases, the daily dose of venetoclax is in the range of approximately 400 mg to 800 mg. For example, the daily dose of venetoclax may be in the range of 300 mg to 900 mg, e.g., 400 mg to 800 mg, 500 mg to 700 mg, or 550 mg to 650 mg. Venetoclax may be administered as a single dose or as multiple doses throughout the day. In certain embodiments, the dose of venetoclax is reduced throughout the course of treatment. For example, the dose of venetoclax on day 1 may be 800 mg, and the dose on the following day may be lower, e.g., approximately 400 mg to 700 mg, e.g., 400 mg, 500 mg, or 600 mg. Venetoclax is usually introduced to the patient during the initial “dose escalation” phase. The dose escalation regimen varies depending on the type of malignancy being treated, but for example, the treatment of AML with venetoclax includes an initial dose escalation depending on the combination regimen used. In a particular embodiment, the dose escalation period of venetoclax consists of 100 mg, 200 mg, and 400 mg administered on days 1, 2, and 3, respectively, with the dose of venetoclax from day 4 onward being 400 mg / day when administered in combination with azacitidine or decitabine, and 600 mg / day when administered in combination with low-dose cytarabine. The 3-day dose escalation is shown in Table 1. [Table 1]

[0042] In certain embodiments, dose escalation of venetoclax is for the purpose of managing the risk of tumor lysis syndrome (TLS). In certain embodiments, the patient is assessed for patient-specific factors regarding the risk level of TLS, for example, as described in Veneclexta® USPI, and prophylactic hydration and uric acid-lowering medications are provided to the patient before the initial dose of venetoclax to reduce the risk of TLS. Venetoclax is administered over 5 weeks according to a weekly dose escalation schedule, up to the recommended daily dose of 400 mg, as shown in Table 2. The 5-week dose escalation schedule is designed to gradually reduce tumor volume (debulk) and decrease the risk of TLS. The patient is instructed to take the venetoclax tablets with food and water at approximately the same time each day, and to swallow them whole, without chewing, crushing, or breaking them before swallowing. The dosing schedule for the 5-week dose escalation period is shown in Table 2. [Table 2]

[0043] In certain embodiments, venetoclax is administered at a dose of 200 mg once daily after a daily dose escalation of 100 mg once daily. In yet another embodiment, venetoclax is administered at a dose of 200 mg once daily without a dose escalation period. In one aspect of this embodiment, venetoclax is administered at a dose of 400 mg per day after dose escalation. In yet another embodiment, venetoclax is administered at a dose of 600 mg per day after dose escalation. In yet another embodiment, venetoclax is administered at a dose of 800 mg per day after dose escalation. In one embodiment of this specification, dose escalation of venetoclax is optional, as will be understood by those skilled in the art who treat hematological malignancies such as AML. In such embodiments, the patient is administered at a dose of 400 mg or 600 mg once daily for each 28-day cycle. In another embodiment, the patient is administered at a dose of 400 mg or 800 mg once daily for each 28-day cycle. Furthermore, in certain other embodiments, venetoclax is administered at 400 mg once daily or 600 mg once daily without a dose escalation period.

[0044] In certain embodiments, both venetoclax and azacitidine are administered in a dosing cycle. In even more specific embodiments, venetoclax and azacitidine are administered in a 28-day cycle, with venetoclax administered at 400 mg PO QD on days 1–28 and azacitidine at 75 mg / m² on days 1–7. 2 It is administered IV / SC. Furthermore, in a specific embodiment, during cycle 1, the dose of venetoclax is 100 mg PO QD on day 1, 200 mg PO QD on day 2, 400 mg PO QD on day 3, and maintained at 400 mg PO QD until day 28, with azacitidine at 75 mg / m² on days 1-7. 2 It is administered IV / SC. In cycle 2 and subsequent 28-day cycles, the dose of venetoclax is 400 mg PO QD, and azacitidine is 75 mg / m² on days 1-7. 2 It is administered IV / SC.

[0045] In certain embodiments, venetoclax and decitabine are administered in a dosing cycle. In a particular embodiment of a 28-day cycle, decitabine is administered on days 1–5 of the cycle, and venetoclax is administered on days 1–28 of the cycle, or a subset of days 1–28, for example, days 1–7, 1–10, 1–14, or 1–21. In one embodiment, decitabine is administered at 20 mg / m² on days 1–5 of a 28-day cycle. 2 Venetoclax is administered intravenously at doses of 300–800 mg daily, for example, 400 mg daily, 600 mg daily, or 800 mg daily. In such embodiments, ortasidenib is administered on days 1–28 of a 28-day cycle, or a subset of days, for example, days 1–7, 8–21, or 8–28. Ortasidenib is administered once or twice daily, totaling 300 mg / day, for example, 150 mg twice daily. Embodiments of dosing schedules for the simultaneous administration of decitabine, venetoclax, and ortasidenib are shown in Table 3 below.

[0046] [Table 3]

[0047] The terms "optimal dose" and "sub-optimal dose" are also used herein. The meaning of these terms can be understood by considering a hypothetical example where ivosidenib is the only agent being used to treat a patient with AML, i.e., the patient is not receiving any other agents for AML. In such an example, a medical professional can determine the dose of ivosidenib to administer to the patient. The "optimal dose of ivosidenib" is the amount of ivosidenib that results in the greatest improvement in AML when ivosidenib is the only agent being administered for AML. Thus, if the actual dose of ivosidenib is below the optimal level, that dose is considered "sub-optimal" and the medical improvement in the patient will be less than the medical improvement with the optimal dose.

[0048] In some embodiments of the methods described herein, a patient is administered a sub-optimal dose of ivosidenib. Since the methods also include the administration of venetoclax and a hypomethylating agent (e.g., azacitidine or decitabine), and since venetoclax and hypomethylating agents also promote improvement in AML, lower doses of ivosidenib can be used.

[0049] Similarly, in some cases, venetoclax is administered at a sub-optimal dose where there is no contribution from combination therapy with ivosidenib. When venetoclax is administered under standard treatment conditions for AML, the optimal dose of venetoclax can result in the best medical outcome. However, in one embodiment, combination therapy with ivosidenib also allows for a reduction in the dose of venetoclax without reducing the benefit to the patient. Considering the toxicity associated with SOC treatment with venetoclax, a reduction in the dose, frequency, or duration of venetoclax is desirable.

[0050] In some cases, the hypomethylating agent is azacitidine. For example, the amount of azacitidine is about 75 mg / m 2 e.g., 60 mg / m 2~90mg / m 2 , or 70 mg / m² 2 ~80mg / m 2 This is possible. Azacitidine can be administered in single or multiple doses throughout the day.

[0051] In some embodiments, the low-methylating agent is decitabine, which may be administered in amounts such as approximately 35 mg per day, or for example, 20 mg to 50 mg or 30 mg to 40 mg per day. Decitabine may be administered in single or multiple doses throughout the day.

[0052] The compounds can be administered over several days according to a dosing schedule. Therefore, the amount of each compound administered per day can be planned before the start of the dosing schedule. In certain embodiments, the combination therapy is administered over a set period according to the dosing schedule. In certain embodiments, the combination therapy is administered over a 28-day dosing schedule. For example, ortasidenib may be administered from day 1 to day 28 of the dosing schedule. In other words, ortasidenib may be administered on any day within the range of day 1 to day 28. Furthermore, venetoclax may be administered daily from day 1 to day 14 of the dosing schedule. In some cases, the hypomethylating agent is azacitidine, which is administered daily from day 1 to day 7 of the dosing schedule. In some embodiments, the hypomethylating agent is decitabine, which is administered from day 1 to day 5 of the dosing schedule. In certain embodiments, the combination therapy is administered over the course of one or more 28-day medication schedules, with an optional non-treatment period between two 28-day medication schedules.

[0053] In some embodiments, the method further includes administering sedazuridine to the subject. In one such embodiment, the hypomethylating agent includes a combination of decitabine and sedazuridine, such as that marketed under the trademark name INQOVI®. In one such embodiment, the hypomethylating agent includes a dose of 35 mg of decitabine and 100 mg of sedazuridine. The combination of decitabine and sedazuridine is usually administered orally in the form of tablets. In certain embodiments, venetoclax, as well as the combination of decitabine and sedazuridine, are administered in a dosing cycle. In a certain embodiment of a 28-day cycle, decitabine and sedazuridine are administered on days 1–5 of the cycle, and venetoclax is administered on days 1–28 of the cycle, or a subset of days 1–28, for example, days 1–7, 1–10, 1–14, or 1–21. In one embodiment, decitabine and sedazuridine are administered orally in a single tablet. In one such embodiment, 35 mg of decitabine and 100 mg of sedazulidine are administered on days 1–5 of a 28-day cycle, and venetoclax is administered at doses of 200–800 mg once daily, for example, 200 mg once daily, 400 mg once daily, 600 mg once daily, or 800 mg once daily. In one such embodiment, 35 mg of decitabine and 100 mg of sedazulidine are administered on days 1–5 of a 28-day cycle, and venetoclax is administered at doses of 300–800 mg daily, for example, 400 mg daily, 600 mg daily, or 800 mg daily. In one such embodiment, ortasidenib is administered on days 1–28 of a 28-day cycle, or on a subset of days, for example, days 1–7, 8–21, or 8–28. Ortasidenib is administered once or twice daily, for a total of 300 mg / day, for example, 150 mg twice daily. Examples of dosing schedules for the concurrent administration of 35 mg of decitabine and 100 mg of sedazulidine, venetoclax, and ortasidenib are shown in Table 4 below. [Table 4]

[0054] With regard to the above-described embodiment of drug administration, the dosage can be changed in the event of adverse events or dose-related toxicity, as is well known to those skilled in the art.

[0055] In one embodiment, the dose of the hypomethylating agent is reduced. For example, the first ("-1") dose reduction for patients experiencing decitabine-related adverse events is 15 mg / m² on days 1-5. 2 The second dose reduction ("-2") is 15 mg / m² on days 1-4. 2 This is the IV, and the third dose reduction ("-3") is 15 mg / m² on days 1-3. 2 It is IV.

[0056] In another embodiment where the hypomethylating agent is decitabine / sedazulidine, the first dose reduction for patients experiencing decitabine / sedazulidine-related adverse events such as bone marrow suppression is one tablet (35 mg decitabine and 100 mg sedazulidine) on days 1-4, the second dose reduction is one tablet (35 mg decitabine and 100 mg sedazulidine) on days 1-3, and the third dose reduction is one tablet (35 mg decitabine and 100 mg sedazulidine) on days 1, 3, and 5.

[0057] If a venetoclax-related adverse event occurs, the first dose reduction for patients starting with 400 mg of venetoclax is 400 mg over 10 days, and the second dose reduction is 400 mg of venetoclax over 7 days. Similarly, for patients starting with 600 mg of venetoclax, the first dose reduction is 600 mg over 10 days, and the second dose reduction is 600 mg of venetoclax over 7 days.

[0058] In one embodiment in which ortasidenib-related adverse events are observed, the first dose reduction is from 150 mg twice daily to 150 mg once daily.

[0059] In some embodiments, the hypomethylating agent is administered orally. In some embodiments, decitabine, azacitidine, sedazuridine, or a combination thereof may be administered orally. For example, decitabine, sedazuridine, or both may be administered orally.

[0060] In some cases, this method includes diagnosing subjects with AML. Cancer patients may be diagnosed with AML characterized by the detection of IDH1 mutations in the blood or bone marrow. Therefore, the diagnosis may include taking a bone marrow sample from the patient and examining the bone marrow sample. AML patients without IDH1 mutations at diagnosis may be retested at the time of relapse, as IDH1 mutations may surface during treatment and at the time of relapse. Methods for diagnosing AML are described in U.S. Patent Application Publications 2008 / 028077 and US2007 / 0287163. Methods for characterizing AML by IDH1 mutation status are described in Mardis et al. N.Engl.J.Med.2009,361,1058-1066.

[0061] In some cases, the medication schedule includes an initial “dose escalation” phase followed by a “maintenance” phase. During the initial dose escalation phase, the administered dose is increased from zero to one or more intermediate values. For example, the dose of ortasidenib might be 100 mg on day 1, followed by 200 mg on day 2. Subsequently, a “maintenance dose” is administered each day of the maintenance phase. For example, 300 mg of ortasidenib might be administered on days 3, 4, 5, and daily thereafter. Thus, in some cases, the administration includes an initial dose during the initial phase and maintenance doses during the maintenance phase, where the initial dose is one or more increasing intermediate values, and the maintenance phase involves the administration of a single maintenance dose.

[0062] The term “dose escalation period” is used interchangeably with the terms “initial” and “escalation period.” In some cases, the escalation period can range in length from 1 day to 10 weeks, for example, 4 to 6 weeks or 1 to 3 days. In some cases, the maintenance period can range in length from 1 day to 500 days, for example, 2 to 250 days or 14 to 28 days.

[0063] Furthermore, a method for treating acute myeloid leukemia (AML) is also provided, comprising treating a subject with AML with venetoclax until the subject achieves remission, and then treating the subject with ortasidenib while in remission. Thus, the initial treatment includes administration of venetoclax but does not include administration of ortasidenib. Similarly, the second-line treatment when the subject is in remission includes administration of ortasidenib but does not include administration of venetoclax. Such a method may be called “switch maintenance” therapy. The above-described embodiments (e.g., dosages of venetoclax and ortasidenib) can also be used in switch maintenance therapy.

[0064] Specific Embodiments This disclosure intends, in particular, to cover the following numbered embodiments: 1. A method for treating a subject having a hematological malignancy or premalignant tumor, comprising administering an effective amount of ortasidenib in combination with venetoclax and a hypomethylating agent.

[0065] 2. The method according to Embodiment 1, wherein the hematological malignancy is acute myeloid leukemia (AML).

[0066] 3. The method according to Embodiment 1, wherein the hematological malignancy or pre-malignancy is characterized by an IDH1 mutation.

[0067] 4. The method according to any one of Embodiments 1 to 2, wherein the administration is repeated daily for 10 days or more.

[0068] 5. The method according to any one of Embodiments 1 to 4, wherein the amount of ortasidenib administered per day is approximately 300 mg.

[0069] 6. The method according to any one of Embodiments 1 to 5, wherein the amount of venetoclax administered per day is in the range of approximately 400 mg to approximately 800 mg.

[0070] 7. The method according to any one of Embodiments 1 to 6, wherein the low-methylating agent comprises azacitidine.

[0071] 8. The method according to Embodiment 7, wherein the amount of azacitidine administered per day is approximately 75 mg / m2.

[0072] 9. The method according to any one of Embodiments 1 to 6, wherein the low-methylating agent comprises decitabine.

[0073] The method according to Embodiment 9, wherein the amount of decitabine administered per 10.1 days is approximately 35 mg.

[0074] 11. The method according to any one of Embodiments 1 to 10, wherein ortasidenib is administered daily on days 1 to 28 of the medication schedule.

[0075] 12. The method according to any one of Embodiments 1 to 11, wherein the venetoclax is administered daily on days 1 to 14 of the medication schedule.

[0076] 13. The method according to any one of Embodiments 1 to 11, wherein the venetoclax is administered daily on days 1 to 28 of the medication schedule.

[0077] 14. The method according to any one of Embodiments 1 to 13, wherein the low-methylating agent is azacitidine, and the azacitidine is administered daily on days 1 to 7 of the drug administration schedule.

[0078] 15. The method according to any one of Embodiments 1 to 14, wherein the low-methylating agent is decitabine, and the decitabine is administered on days 1 to 5 of the drug administration schedule.

[0079] 16. The method according to any one of Embodiments 1 to 15, wherein ortasidenib, venetoclax, or both are administered in a suboptimal dose.

[0080] 17. The method according to any one of Embodiments 1 to 16, further comprising administering sedazuridine to the subject.

[0081] 18. The method according to any one of Embodiments 1 to 17, further comprising diagnosing the subject as AML.

[0082] 19. A method for treating acute myeloid leukemia (AML), comprising: treating a subject having AML with venetoclax until the subject is in remission; and treating the subject in remission with ortasidenib.

[0083] 20. The method according to Embodiment 19, wherein the AML is characterized by an IDH1 mutation.

[0084] The method according to any one of Embodiments 19 to 20, wherein the amount of ortasidenib administered per day is approximately 300 mg.

[0085] The method according to any one of Embodiments 19 to 21, wherein the amount of venetoclax administered per day is in the range of approximately 400 mg to approximately 800 mg.

[0086] 23. The method according to any one of Embodiments 19 to 22, wherein the amount of venetoclax administered is 400 mg per day.

[0087] 24. The method according to any one of Embodiments 19 to 22, wherein the amount of venetoclax administered is 800 mg per day.

[0088] 25. The method according to any one of embodiments 19 to 24, further comprising diagnosing the subject with AML.

[0089] 26. The method according to any one of embodiments 19 to 25, further comprising treating the subject with a low-methylating agent.

[0090] 27. The method according to Embodiment 24, wherein the low-methylating agent comprises azacitidine or decitabine.

[0091] 28. A method for treating a subject having a hematological malignancy or premalignant tumor, comprising administering to the subject an effective amount of venetoclax and a hypomethylating agent in one or more 28-day dosing schedules, followed by administering ortasidenib in combination with the hypomethylating agent in one or more 28-day dosing schedules.

[0092] 29. The method according to Embodiment 28, wherein the low-methylating agent is azacitidine.

[0093] 30. The method according to Embodiment 28 or 29, wherein the venetoclax is administered once daily at a dose of 400 mg.

[0094] 31. The azacitidine is administered once daily at a dose of 75 mg / m². 2 The method according to embodiment 29 or 30, administered via IV / SQ.

[0095] 32. The method according to Embodiments 28-31, wherein ortasidenib is administered at a dose of 300 mg daily.

[0096] 33. The method according to Embodiments 28-32, wherein ortasidenib is administered at a dose of 150 mg twice daily.

[0097] This disclosure further intends, in particular, to envision the following additional embodiments: 1. A method for treating a subject having a hematological malignancy or premalignant tumor, comprising administering an effective amount of ortasidenib in combination with venetoclax and a hypomethylating agent.

[0098] 2. The method according to Embodiment 1, wherein the hematological malignancy is acute myeloid leukemia (AML).

[0099] 3. The method according to Embodiment 1, wherein the hematological malignancy or pre-malignancy is characterized by an IDH1 mutation.

[0100] 4. The method according to any one of Embodiments 1 to 3, wherein the administration is repeated daily for 10 days or more.

[0101] 5. The method according to any one of Embodiments 1 to 4, wherein the amount of ortasidenib administered per day is approximately 300 mg.

[0102] 6. The method according to any one of Embodiments 1 to 5, wherein the amount of venetoclax administered per day is in the range of approximately 400 mg to approximately 800 mg.

[0103] 7. The method according to any one of Embodiments 1 to 6, wherein the low-methylating agent comprises azacitidine.

[0104] 8. The method according to Embodiment 7, wherein the amount of azacitidine administered per day is approximately 75 mg / m2.

[0105] 9. The method according to any one of Embodiments 1 to 6, wherein the low-methylating agent comprises decitabine.

[0106] The method according to Embodiment 9, wherein the amount of decitabine administered per 10.1 days is approximately 35 mg.

[0107] 11. The method according to any one of embodiments 1 to 6, 9 and 10, wherein the low-methylating agent comprises sedazulidine.

[0108] 12. The method according to any one of Embodiments 1 to 11, wherein ortasidenib is administered daily on days 1 to 28 of the medication schedule.

[0109] 13. The method according to any one of Embodiments 1 to 12, wherein the venetoclax is administered daily on days 1 to 7 of the medication schedule.

[0110] 14. The method according to any one of Embodiments 1 to 12, wherein the venetoclax is administered daily on days 1 to 10 of the medication schedule.

[0111] 15. The method according to any one of Embodiments 1 to 12, wherein the venetoclax is administered daily on days 1 to 14 of the medication schedule.

[0112] 16. The method according to any one of Embodiments 1 to 12, wherein the venetoclax is administered daily on days 1 to 28 of the medication schedule.

[0113] 17. The method according to any one of Embodiments 13 to 16, wherein the venetoclax administered daily is approximately 600 mg.

[0114] 18. The method according to any one of Embodiments 1 to 17, wherein the low-methylating agent is azacitidine, and the azacitidine is administered daily on days 1 to 7 of the drug administration schedule.

[0115] 19. The method according to any one of Embodiments 1 to 17, wherein the low-methylating agent comprises decitabine, and the decitabine is administered on days 1 to 5 of the drug administration schedule.

[0116] 20. The method according to any one of Embodiments 1 to 17, wherein the hypomethylating agent comprises decitabine and sedazulidine, and the hypomethylating agent is administered on days 1 to 5 of the drug administration schedule.

[0117] 21. The method according to any one of Embodiments 1 to 20, wherein ortasidenib, venetoclax, or both are administered in a suboptimal dose.

[0118] 22. The method according to any one of Embodiments 1 to 10, further comprising administering sedazuridine to the subject.

[0119] 23. The method according to any one of Embodiments 1 to 22, further comprising diagnosing the subject as AML.

[0120] 24. A method for treating acute myeloid leukemia (AML), comprising: treating a subject having AML with venetoclax until the subject is in remission; and treating the subject in remission with ortasidenib.

[0121] 25. The method according to Embodiment 24, wherein the AML is characterized by an IDH1 mutation.

[0122] The method according to any one of Embodiments 24 to 25, wherein the amount of ortasidenib administered per day is approximately 300 mg.

[0123] 27. The method according to any one of Embodiments 24 to 26, wherein the amount of venetoclax administered per day is in the range of approximately 400 mg to approximately 800 mg.

[0124] 28. The method according to any one of Embodiments 24 to 27, wherein the amount of venetoclax administered is 400 mg per day.

[0125] 29. The method according to any one of Embodiments 24 to 27, wherein the amount of venetoclax administered is 800 mg per day.

[0126] 30. The method according to any one of embodiments 24 to 29, further comprising diagnosing the subject as AML.

[0127] 31. The method according to any one of embodiments 24 to 30, further comprising treating the subject with a low-methylating agent.

[0128] 32. The method according to Embodiment 31, wherein the low-methylating agent comprises azacitidine or decitabine.

[0129] 33. The method according to Embodiment 31, wherein the low-methylating agent comprises decitabine and sedazulidine.

[0130] 34. A method for treating AML, comprising co-administering an effective amount of ortasidenib, venetoclax, and a hypomethylating agent to a subject having IDH1 mutation AML.

[0131] 35. The method according to Embodiment 34, wherein the concurrent administration includes administering ortasidenib, venetoclax, and the hypomethylating agent in a 28-day treatment cycle.

[0132] 36. The method according to Embodiment 35, wherein ortasidenib is administered daily on days 1 to 28 of the treatment cycle.

[0133] 37. The method according to Embodiment 35, wherein the venetoclax is administered daily on days 1 to 7 of the treatment cycle.

[0134] 38. The method according to Embodiment 35, wherein the venetoclax is administered daily on days 1 to 10 of the treatment cycle.

[0135] 37. The method according to Embodiment 35, wherein the venetoclax is administered daily on days 1 to 14 of the treatment cycle.

[0136] 39. The method according to any one of Embodiments 34 to 37, wherein the venetoclax administered daily is approximately 400 mg to approximately 800 mg.

[0137] 40. The method according to any one of Embodiments 34 to 39, wherein the venetoclax administered daily is approximately 600 mg.

[0138] 41. The method according to any one of Embodiments 35 to 40, wherein the hypomethylating agent comprises decitabine, and the decitabine is administered on days 1 to 5 of the treatment cycle.

[0139] 42. The low methylating agent comprises decitabine and sedazulidine, and the low methylating agent is The method according to any one of embodiments 34 to 40, administered on days 1 to 5 of the aforementioned treatment cycle.

[0140] 43. The method according to any one of Embodiments 34 to 42, wherein the ortasidenib administered daily is approximately 150 mg.

[0141] 44. The method according to any one of Embodiments 34 to 42, wherein ortasidenib is administered in a dose of approximately 150 mg twice daily.

[0142] 45. The method according to any one of Embodiments 34 to 44, wherein ortasidenib, venetoclax, or both are administered in a suboptimal dose. [Examples]

[0143] The following examples are provided to those skilled in the art to provide a complete disclosure and explanation of the manufacturing method and use of the present invention, and are not intended to limit the scope of the invention as envisioned by the inventors, nor are they intended to represent that the following experiments are all or only those conducted. While efforts have been made to ensure accuracy with respect to the figures used (e.g., quantities, temperatures, etc.), some experimental error and deviation should be taken into consideration.

[0144] Clinical trials to determine the efficacy of ortasidenib, venetoclax, and hypomethylating agents are described herein.

[0145] Example 1: Phase 1b / 2 Clinical Trial Phase 1b / 2 will evaluate the safety and PK / PD of ortasidenib, venetoclax, and azacitidine or decitabine in IDH1m+ (IDH1 mutation-positive) AML and MDS.

[0146] The objectives of Phase 1b / 2 are as follows:

[0147] Optimization of venetoclax dosage in triple therapy.

[0148] Safety and tolerability,

[0149] Determining the recommended dosage,

[0150] PK and PD evaluation, and

[0151] Evaluation of activity signals.

[0152] Inclusion selection criteria: IDH1 m+ AML / MDS

[0153] Cohort A will receive venetoclax DL1 + INQOVI® + ortasidenib, followed by venetoclax DL2 + INQOVI® + ortasidenib.

[0154] Cohort B will be administered venetoclax DL1 + azacitidine + ortasidenib, followed by venetoclax DL2 + azacitidine + ortasidenib.

[0155] Treatment A: Venetoclax 400 mg (dose level 1 or DL1) or 800 mg (dose level 2 or DL2) PO QD (after a 3-day dose escalation in cycle 1) days 1-14 + INQOVI® 1 tablet (35 mg decitabine / 100 mg sedazulidine) PO QD days 1-5 + Ortasidenib 150 mg PO BID days 1-28

[0156] Treatment B: Venetoclax 400 mg (DL1) or 800 mg (DL2) PO QD (after a 3-day dose escalation in Cycle 1) days 1-14 + azacitidine 75 mg / m² 2 IV / SC QD days 1-7 + Ortasidenib 150mg PO BID days 1-28.

[0157] Treatment continues until the disease progresses, intolerance occurs, or withdrawal occurs.

[0158] Phase 1b is open-label and single-arm.

[0159] 3+3 dose escalation design

[0160] N=maximum 36 people

[0161] The trial period was 36 months, with 12 months of follow-up for individual patients.

[0162] Primary endpoints: Safety and PK / PD, and identification of RP2D.

[0163] Secondary evaluation criteria: • Response rates including CR, CRi, CRh, MLFS, and PR • Time to response, DOR (Duration of Response), EFS (Event-Free Survival), and OS (Overall Survival).

[0164] Exploratory: • Evaluation of MRD (measurable residual disease) and VAF (variant allele frequency) • 2HG level rating.

[0165] Example 2: Phase 3 Phase 3 is a randomized, open-label evaluation of ortasidenib + venetoclax + decitabine versus ortasidenib + venetoclax + azacitidine in ineligible, treatment-naïve patients with IDH1m+ AML and MDS.

[0166] The evaluation criteria for Phase 3 include the following:

[0167] Major metric: mEFS (median event-free survival)

[0168] Primary secondary: ·CR, compound CR (CR, CRi, CRh), • Time to response, duration of response, mOS (median overall survival), and • Incidence and severity of adverse events, dose interruption or discontinuation.

[0169] Exploratory: Incidence of MRD negativity, disappearance of IDH1m clones.

[0170] Primary inclusion criteria: Unqualified IDH1 m+ AML patients who have not received prior treatment.

[0171] N=200, students will be randomly assigned to cohorts A and B in a 1:1 ratio.

[0172] Cohort A: SOC venetoclax + azacitidine. Venetoclax 400mg PO QD days 1-28 + azacitidine 75mg / m² 2 IV / SQ WD Days 1-7

[0173] Cohort B: Venetoclax 400mg PO QD days 1-28* + Azacitidine 75mg / m² 2 IV / SC QD days 1-7 + Ortasidenib 150mg PO BID days 1-28

[0174] Dosage escalation of venetoclax on days 1-3 of cycle 1

[0175] Continue until disease progression, intolerance, or withdrawal.

[0176] Phase 3, open-label, randomized. N=200 (100 per arm), up to 55 sites in the US.

[0177] The trial period was approximately 4 years (from the first patient to the last patient being evaluated).

[0178] The trial period for each individual subject was 24 months.

[0179] Primary endpoint: EFS

[0180] Secondary evaluation criteria: • Response rates including CR, Cri, CRh, MLFS, and PR • Time to effect, DOR, and OS • Incidence and severity of AEs and SAEs

[0181] Example 3: Phase 3 clinical trial comparing maintenance with venetoclax versus maintenance with ortasidenib This study is a randomized, open-label phase 3 trial comparing venetoclax plus azacitidine versus ortasidenib plus azacitidine in patients who have experienced remission after treatment with venetoclax.

[0182] Newly diagnosed IDH1-mutated AML patients receive two cycles of venetoclax plus azacitidine.

[0183] After two cycles, subjects in remission (240) will be randomized into two maintenance phase cohorts:

[0184] Cohort 1 (120 subjects) will be treated with ortasidenib + azacitidine.

[0185] Cohort 2 (120 subjects) will be treated with venetoclax + azacitidine.

[0186] The maintenance phase is 28 days per cycle.

[0187] Cohort 1 will receive ortasidenib 150 mg BID for days 1-28 and azacitidine 75 mg / m2 IV / SC QD for days 1-7.

[0188] Cohort 2 will receive venetoclax 400 mg PO QD days 1-28 and azacitidine 75 mg / m2 IV / SC QD days 1-7.

[0189] Primary endpoint: regression free survival (RFS)

[0190] Secondary evaluation items: Time to response, DOR, and OS

[0191] Response rates including CR, CRi, CRh, MLFS, and PR

[0192] Incidence and severity of AEs and SAEs

[0193] Example 3: Phase 1b / 2 study of decitabine and venetoclax in combination with the targeted mutation IDH1 inhibitor ortasidenib Olutasidenib has demonstrated efficacy in the treatment of relapsed or refractory AML and was approved for the treatment of this disorder in 2022 (de Botton S, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv. 2023;7(13):3117-3127 (de Botton)). However, there is insufficient evidence of its efficacy in combination therapy.

[0194] The clinical trial will be conducted in adults with AML or MDS who have IDH1 mutations. A summary of the trial design is shown in Figure 1. This trial will be a single-center, open-label, non-randomized phase 1b / 2 clinical trial with dual primary objectives to evaluate the safety and efficacy of IV or oral decitabine / sedazulidine in combination with the BCL2 inhibitor venetoclax (VEN) and the mutation-targeted IDH1 inhibitor ortasidenib for IDH1-mutant AML.

[0195] The maximum number of patients treated in this clinical trial will be 78.

[0196] Patients will continue the experimental treatment until it is discontinued due to relapse, unacceptable toxicity, withdrawal of consent, or progression of the disease.

[0197] This study will be the first to evaluate the efficacy of a triple regimen of the IDH1 inhibitor ortasidenib in combination with hypomethylation + venetoclax therapy.

[0198] The purpose of this examination is as follows:

[0199] Phase 1b: Safety and tolerability of decitabine (either IV or oral decitabine / sedazulidine (ASTX727, INQOVI®)) and venetoclax in combination with ortasidenib, and determination of the recommended Phase 2 dose (RP2D).

[0200] Phase 2: Determination of composite remission rates (CR, CRh, and CRi) of decitabine (either IV or oral decitabine / sedazulidine (ASTX727, INQOVI®)) and venetoclax in combination with ortasidenib in newly diagnosed patients (Arm A) or relapsed / refractory patients (Arm B) with IDH1 mutations in myeloid malignancies.

[0201] Determination of duration of response (DOR), event-free survival (EFS), and overall survival (OS).

[0202] Evaluation of the occurrence of minimal residual disease (MRD) negative status using multi-parameter flow cytometry and molecular evaluation.

[0203] Determination of overall response rate (CR, CRh, CRi, MLFS, and PR).

[0204] Characterization of the pharmacokinetic (PK) profiles of venetoclax and ortasidenib in plasma samples (Phase 1b only).

[0205] Exploration of predictors of antitumor activity and / or resistance to treatment through the investigation of global gene expression profiles, DNA methylation profiles, BH3 profiling, and other potential prognostic markers.

[0206] The selection criteria must meet all of the following conditions: 1. Age 18 or older, 2. Subjects must have a documented IDH1 gene mutation. 3. Patients diagnosed with relapsed or refractory AML (including biphenotypic or bisystemic leukemia with myeloid components, or isolated extramedullary AML), high-risk MDS according to IPSS-R (International Prognostic Scoring System-Revised, developed by the International Working Group for Prognosis in MDS (IWG-PM)) or IPSS-M (Internal Prognostic Scoring System-Molecular, a clinical molecular prognosis model - see Bernard et al. 2022 NEJM Evid 2022;1(7)), or 4. Newly diagnosed AML patients who are not eligible or appropriate for intensive chemotherapy are also eligible (Phase 2 portion only). 5. To be considered ineligible for intensive chemotherapy, participants must be defined as: aged 75 years or older, or aged 18-74 years with at least one of the following comorbidities: a) Severe cardiac impairment (e.g., congestive heart failure requiring treatment, ejection fraction of 50% or less, or chronic stable angina). b) Severe lung impairment (e.g., DLCO ≤ 65% or forced expiratory volume in one second [FEV1] ≤ 65%). c) Creatinine clearance is 30 mL / min or more but less than 45 mL / min. d) Moderate liver impairment with total bilirubin levels greater than 1.5 times but less than or equal to 3.0 times the upper limit of normal (ULN). e) ECOG performance status is 2 or 3 f) Any other comorbidity that, in the opinion of the principal investigator, makes the patient unsuitable for intensive chemotherapy. 6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (excluding newly diagnosed AML patients aged 18-74 years who are not eligible for intensive chemotherapy according to "e" above). 7. Adequate renal function, including creatinine < 1.5, except for those aged 18-74 years with newly diagnosed AML that is disease-related or not eligible for intensive chemotherapy according to "c)" above. 8. Adequate liver function (direct bilirubin <2 times the upper limit of normal (ULN), except when the increase is due to Gilbert's disease or leukemia; AST and / or ALT <3 times the ULN, except when 18-74 year olds with newly diagnosed AML who are considered eligible if direct bilirubin or AST and / or ALT <5 times is considered eligible, or who are not eligible for intensive chemotherapy according to "d)" above). 9. In the absence of rapidly proliferative disorders, the interval from prior treatment to the start of treatment should be at least 14 days for cytotoxic or non-cytotoxic immunotherapeutic agents (multiple agents), or 5 half-lives of the prior treatment. Oral hydroxyurea and / or cytarabine (up to 2 g / m2) for patients with rapidly proliferative disorders is permissible before the start of the study therapy, if necessary, for the clinical benefit as judged by those skilled in the art. Concurrent intrathecal therapy for central nervous system (CNS) prophylaxis or continuation of treatment for controlled CNS disease is permitted. 10. Women of childbearing age (WOCBP) and sexually active, non-vasectomy-treated male subjects must be willing to use barrier contraception and refrain from providing semen from the first study drug dose until 90 days after the final dose of the study drug.

[0207] Exclusion criteria: Patients must not have any of the following: t(15;17) karyotype abnormalities or acute promyelocytic leukemia (France, USA, UK [FAB] M3-AML). 1. Patients with t(15;17) karyotype abnormalities or acute promyelocytic leukemia (France, USA, UK [FAB] M3-AML). 2. Patients with any concurrent, uncontrolled, clinically significant medical condition, including life-threatening severe infections or mental illnesses, that could expose the patient to an unacceptable risk of the investigational treatment. 3. Patients with uncontrolled CNS activity and involvement of leukemia. 4. Patients with active graft-versus-host disease (GVHD) after stem cell transplantation (patients who do not have active GVHD due to chronic suppressive immunosuppression and / or phototherapy for chronic cutaneous GVHD are permitted). 5. Patients with any severe gastrointestinal or metabolic condition that may interfere with the absorption of the oral test drug. 6. Known active hepatitis B (HBV) or hepatitis C (HCV) infection, or known HIV infection. 7. The subject's white blood cell count is >25 × 10⁻⁶ 9 / L. (Note: Hydroxyurea and cytarabine are permitted to meet this standard.) 8. Breastfeeding women, pregnant women who have tested positive for pregnancy (WOCBP), or pregnant women who do not intend to maintain appropriate contraception.

[0208] Treatment plan (Phase 1b): Only patients with relapsed / refractory disease will be enrolled in three cohorts, starting at dose level 1. The starting dose will evaluate the approved doses of decitabine (or oral decitabine / sedazulidine), venetoclax, and ortasideb.

[0209] Dose level 2 evaluates venetoclax at 600 mg per day due to potential drug interactions of ortasidenib with reduced venetoclax exposure, in relation to in vitro evidence that ortasidenib acts as a CYP3A inducer and is therefore expected to significantly reduce the AUC of venetoclax.

[0210] Cycle 1: Dose escalation of venetoclax.

[0211] For patients with a target venetoclax dose of 400 mg per day, venetoclax should be administered at a dose of 100 mg (or equivalent) on day 1 of the first cycle, 200 mg (or equivalent) on day 2, and 400 mg (or equivalent) on days 3 through 14.

[0212] For patients with a target venetoclax dose of 600 mg per day, venetoclax should be administered at a dose of 100 mg (or equivalent) on day 1 of the first cycle, 200 mg (or equivalent) on day 2, 400 mg (or equivalent) on day 3, and 600 mg (or equivalent) on days 4-14.

[0213] During dose escalation of venetoclax in cycle 1, TLS monitoring (K+, uric acid, phosphorus, calcium, and creatinine) should be performed before administration, 6–8 hours after administration, and 24 hours after administration.

[0214] The combination RP2D will be selected at the end of the Phase 1b portion based on safety and efficacy analysis. Once the RP2D is identified, the trial will proceed to the Phase 2 portion.

[0215] Phase 2 treatment plan: Only patients with relapsed / refractory disease will be enrolled in three cohorts, starting at dose level 1 as shown in Table 1. The starting dose will evaluate the approved doses of decitabine (or oral decitabine / sedazulidine), venetoclax, and ortasideb.

[0216] Dose level 2 evaluates venetoclax at 600 mg per day due to potential drug interactions of ortasidenib with reduced venetoclax exposure, in relation to in vitro evidence that ortasidenib acts as a CYP3A inducer and is therefore expected to significantly reduce the AUC of venetoclax.

[0217] The combination RP2D will be selected at the end of the Phase 1b portion based on safety and efficacy analysis. Once the RP2D is identified, the trial will proceed to the Phase 2 portion.

[0218] Administration of triple therapy:

[0219] Phase 1b will begin with the triple therapy dosing schedule shown in Table 1:

[0220] [Table 5]

[0221] Dose adjustment

[0222] CYP3 inducers and inhibitors

[0223] While CYP3A inhibitors are not recommended, they are permissible at all trial time points with appropriate dose reductions of venetoclax, according to US prescribing information, including an 82.5% dose reduction for posaconazole (i.e., 70 mg QD of venetoclax instead of 400 mg) and a 75% dose reduction for other potent CYP3A inhibitors (i.e., 100 mg QD of venetoclax instead of 400 mg when used in combination with voriconazole).

[0224] If a moderate CYP3A inhibitor is prescribed in the trial, a 50% dose reduction of venetoclax will be necessary (i.e., 200 mg instead of 400 mg, 300 mg instead of 600 mg, etc.).

[0225] Differentiation syndrome (DS) and / or leukocytosis

[0226] Subjects treated with ortasidenib may develop signs and symptoms of differentiation-like syndrome and / or leukocytosis. Differentiation-like syndrome (DS) may include any of the following: fever of unknown origin, skin rash, leukocytosis, thrombocytosis, hypoxia, dyspnea, interstitial pulmonary infiltration, pleural effusion and / or pericardial exudation, weight gain, or clinical exacerbation. No single sign or symptom should be considered a diagnosis of DS in itself. The prophylactic and therapeutic measures described below are recommended to be initiated at the earliest symptom suggestive of differentiation-like syndrome: Prompt initiation of hydroxyurea. Gradually reduce hydroxyurea only after leukocytosis has improved or disappeared. If DS is suspected or diagnosed, discontinue ortasidenib until signs and symptoms improve. Systemic corticosteroids should be administered immediately for at least 3 days until symptoms and signs disappear. Start furosemide if clinically necessary. If clinically necessary, prompt initiation of leukocytapheresis or administration of cytarabine. After the differentiation syndrome resolves, ortasidenib will be restarted at 150 mg BID. If a relapse of DS is suspected, discontinue ortasidenib and initiate treatment according to the guidance above. After symptom resolution, ortasidenib may be restarted at a reduced dose of 150 mg QD for at least 7 days, and then increased to 150 mg BID. Once signs and symptoms have resolved and the subject's clinical condition has improved, ortasidenib (if previously withheld) may be restarted as outlined above.

[0227] Ortasidenib-induced hepatotoxicity

[0228] Subjects treated with ortasidenib may develop hepatotoxicity. Hematologic chemistry, including liver function tests, should be assessed during screening at least once a week for the first two cycles, every two weeks in cycle 3, and at least once per cycle thereafter.

[0229] If grade 3 hepatotoxicity occurs, including elevated liver function tests, withhold ortasidenib and monitor LFT twice weekly until values ​​return to baseline or grade 1 toxicity. Restart ortasidenib at a dose of 150 mg once daily and continue monitoring. If hepatotoxicity does not resolve to baseline for at least 28 days, ortasidenib may be increased again to 150 mg twice daily. If grade 3 hepatotoxicity recurs at 150 mg once daily, ortasidenib should be discontinued.

[0230] If grade 4 hepatotoxicity occurs without a clear alternative explanation, or if AST or ALT >3 times the ULN, total bilirubin >2 times the ULN, and alkaline phosphatase <2 times the ULN, ortasidenib should be permanently discontinued.

[0231] Recommended dose adjustments for other grade 3 or higher toxicities thought to be associated with ortasidenib treatment.

[0232] Discontinue ortasidenib until toxicity resolves to grade 2 or lower. Restart ortasidenib at 150 mg once daily (dose level -1). If toxicity resolves to grade 1 or lower for at least one week, the dose may be increased to 150 mg twice daily (dose level 1 / starting dose). If grade 3 or higher toxicity recurs at 150 mg once daily, discontinue ortasidenib.

[0233] Patients whose dose has been reduced should have their dose increased again, provided they do not experience any toxicity requiring dose adjustment for one month. Dose increases should be made in increments of only one dose level, and not more frequently than monthly.

[0234] Any other treatment interruptions and dose adjustments may be considered after consultation with the PI and proper documentation of the rationale. If the toxicity is most likely to be related to one of the drugs as determined by the principal investigator, dose adjustment / postponement of only one of the drugs may be permitted.

[0235] Management of bone marrow suppression

[0236] Myelosuppression and related adverse events (thrombocytopenia, anemia, neutropenia, febrile neutropenia) are common in both treated and untreated patients with AML. Furthermore, based on clinical experience with BCL-2 inhibitors, patients treated with venetoclax may experience an increased incidence of neutropenia.

[0237] Unless the patient achieves a clinical response, including CR, CRh, or MLFS, during the study and the ANC does not recover to >500 / uL within 14 days of discontinuing venetoclax, administration of venetoclax may be further discontinued until the ANC recovers to >500 / uL, unless the patient achieves a clinical response, including CR, CRh, or MLFS, and the ANC is not attributed to the underlying disease. Furthermore, GCSF may be administered if it is in the greatest benefit to the patient.

[0238] The recommended dose reductions for ASTX727 / INQOV for myelosuppression are: a first dose reduction of one oral tablet during the dose reduction period on days 1-4 of a given cycle; a second dose reduction of one oral tablet during the dose reduction period on days 1-3; and a third dose reduction of one oral tablet on days 1, 3, and 5.

[0239] The recommended dose adjustment for decitabine-related adverse events is 15 mg / m² on days 1-5. 2 The first dose reduction of decitabine administered intravenously is 15 mg / m² on days 1-4. 2 Second dose reduction of decitabine administered intravenously, and 15 mg / m² on days 1-3. 2 This includes a third dose reduction of decitabine administered intravenously.

[0240] Recommended dose adjustments for venetoclax-related adverse events include a first dose reduction (DL-1) of 400 mg for 10 days and a second dose reduction (DL-2) of 400 mg for 7 days in a given cycle for patients starting with venetoclax 400 mg.

[0241] Recommended dose adjustments for venetoclax-related adverse events include a first dose reduction (DL-1) of 600 mg for 10 days and a second dose reduction (DL-2) of 600 mg for 7 days in patients starting with venetoclax 600 mg.

[0242] If the toxicity is deemed by the treating physician to be severe and life-threatening, and / or if it is in the patient's best interest, a dose reduction of two levels at a time may be considered.

[0243] Following consultation between the principal investigator and the PI, additional or alternative dose adjustments may be permitted if, with appropriate documentation, they are deemed to be in the patient's best interest.

[0244] General guidelines for concomitant medications and treatment support

[0245] Supportive therapies, including blood products, prophylactic agents for infection, and growth factors, should be administered according to the guidelines of the institution and department.

[0246] Intrathecal chemotherapy may be permitted for the treatment or prevention of extramedullary disease.

[0247] Investigational drugs or supportive therapy trials not designed for the treatment of leukemia itself (even under an IND) are permitted.

[0248] Because of the potential for interactions between venetoclax and other co-administered drugs, case reports must document the co-administration of all other medications, over-the-counter drugs, or alternative therapies. The principal investigator of the trial must warn patients if they are taking any agent known to affect or have the potential to affect drug interactions. The trial team must check frequently updated medical references for a list of drugs that should be avoided or minimized in use.

[0249] Treatment period

[0250] All subjects must complete screening visits, visits on day one of each new cycle, visit on day 15 of cycle 1, and visit at the end of treatment.

[0251] Treatment continues until recurrence, unacceptable toxicity, withdrawal of consent, or discontinuation due to disease progression. Reasons for discontinuation of investigational treatment include: Clinically significant progressive disease at any point, or The possibility of receiving an allogeneic stem cell transplant Concurrent disease that precludes further administration of treatment, or Unacceptable adverse event(s), or The patient's decision to withdraw from the trial, or General or specific changes in the patient's condition that, in the judgment of the principal investigator of the trial, render the patient unacceptable for further treatment

[0252] ​Patients can continue the trial as long as they continue to demonstrate clinical benefit and there is no excessive toxicity (i.e., no clinically significant grade > 3 toxicity related to the investigational drug).

[0253] For the clinical benefit of the patient, dose adjustments and interruptions are permitted as necessary. If the side effects or toxicity are related to only one investigational drug, in the assessment of the principal investigator of the clinical trial, if the patient continues to demonstrate clinical benefit and all the criteria defined in the clinical trial implementation plan for continuing the trial treatment are met, the patient can proceed with dose adjustment and / or discontinuation of that drug and continue treatment with the remaining investigational drugs. All dose adjustments need to be discussed with the PI and clearly documented in the medical record. Treatment may be withheld as clinically necessary after discussion with the PI until resolution.

[0254] For patients with clinically significant toxicity related to the investigational drug, the following dose adjustment rules apply:

[0255] For grade 0 - 2 non - hematological toxicity, dose reduction is not necessary. For persistent and / or intolerable grade 2 toxicity (e.g., stomatitis), the patient can either interrupt treatment or reduce the dose to the next lower dose level.

[0256] For grade 3 - 4 clinically significant non - hematological toxicity, withhold until recovery to grade 0 - 1 or, if grade 2 at trial enrollment, until recovery to baseline. If applicable, the dose needs to be reduced by one dose level.

[0257] Continuously evaluate the survival of all patients who discontinue trial treatment for any reason other than withdrawal of consent for treatment and follow - up. Reasons for trial discontinuation include: Disease progression Concurrent disease interfering with further administration of treatment [[ID=*]] Intolerable adverse event(s) Patient's decision to withdraw from the trial General or specific changes in the patient's condition that, in the judgment of the principal investigator, make the patient unacceptable for further treatment. clinical progression Patient non-compliance Pregnancy (All women of childbearing age must be instructed to immediately contact the principal investigator at any time during the trial if they suspect they may be pregnant (e.g., missed or delayed menstruation).) The trial was terminated by the clinical trial sponsor. Pharmaceutical manufacturers will be unable to supply test drugs.

[0258] The reasons for discontinuation of protocol therapy (multiple reasons are permitted), reasons for exclusion from the trial (multiple reasons are permitted), and the corresponding dates must be documented in the case report form (CRF).

[0259] Follow-up period

[0260] Patients will be tracked for survival information (i.e., date and cause of death) and collected via telephone and / or clinical visits at 3-month intervals for 3 years from the date the last subject enrolled in the study.

[0261] Patients excluded from the study due to unacceptable adverse events (multiple events) will be followed up until the adverse events resolve or stabilize.

[0262]

[0263] Test evaluation and procedures

[0264] screening

[0265] The following activities—a complete medical history, physical examination, performance status, documentation of measurable diseases, fractionated CBC, creatinine, total bilirubin, ALT and / or AST measurements, pregnancy test, bone marrow aspiration and / or biopsy, and correlations to the bone marrow—will be performed within 14 days prior to administration of the study drug, and during screening, staging, and further examinations.

[0266] On the first day (±7 days) of each cycle, perform a complete physical examination and document concomitant medications.

[0267] CBC with differential, creatinine, total bilirubin, ALT or AST are performed at least once a week (±4 days) during the first 2 cycles, then every 2 weeks in cycle 3, and every 2 - 4 weeks in subsequent cycles.

[0268] Pregnant women need to have a pregnancy test either on urine or plasma 72 hours before the start of protocol therapy.

[0269] Bone marrow aspiration and / or biopsy must be performed within 28 days (±7 days) from the start of treatment. Then, after cycle 3, after cycle 5, and then every 3 cycles thereafter, and also at the end of the study. Cytogenetics and molecular annotation may be used from a previous bone marrow analysis if these are not reported on screening bone marrow. See section 8.3 for tests completed on bone marrow specimens.

[0270] Correlation tests are collected from peripheral blood on day 1 (pre - dosing), on days 21 - 28 of cycle 1, and at the end of cycles 3 and 5. Thereafter, if possible, peripheral blood is collected at progression. All these tests can be ±5 days.

[0271] Collect correlation tests from bone marrow at baseline (pre - dosing), on day 28 (±7 days), at the end of cycles 3 and 5, and at progression.

[0272] At EOS visit (30 days after the last dose), a physical examination, CBC with differential and platelets, and a limited chemical profile (total bilirubin, serum creatinine, AST or ALT) are included. If a non - responsive or progressive disease cannot be clearly diagnosed from peripheral blood, a bone marrow aspiration may be performed.

[0273] In subsequent cycles, bone marrow (aspiration and / or biopsy) is performed every three cycles at the discretion of the treating physician. For tests that are completed with bone marrow specimens, see Section 8.3.

[0274] TLS monitoring (potassium, uric acid, phosphorus, calcium, and creatinine) should be performed during dose escalation in cycle 1, before administration, 6-8 hours after administration, and 24 hours after administration (in hospitalized patients, AM testing may be used instead of the 24-hour post-administration test).

[0275] Phase 1b portion only: Blood samples were taken on day 7 of cycle 1, day 15 of cycle 1, day 7 of cycle 2, and day 15 of cycle 2 to assess plasma concentrations of venetoclax and ortasidenib. See Section 6.3.

[0276] The same screening procedure will be performed in both Phase 1b and Phase 2.

[0277]

[0278] Cycle 1, Day 1

[0279] To mitigate the risk of TLS, subjects must receive tumor lysis prophylaxis, including hydration (oral and / or intravenous) and treatment with uric acid-reducing agents (allopurinol, rasburicase), in accordance with institutional guidelines, before and during the venetoclax dose escalation period of Cycle 1.

[0280]

[0281] Cycle 1: Dose escalation of venetoclax.

[0282] Venetoclax is administered at a dose of 100 mg (or equivalent) on day 1 of the first cycle, 200 mg (or equivalent) on day 2, and 400 mg (or equivalent) on days 3 through 14. For patients scheduled to receive 600 mg of venetoclax daily, venetoclax is administered at a dose of 100 mg (or equivalent) on day 1 of the first cycle, 200 mg (or equivalent) on day 2, 400 mg (or equivalent) on day 3, and 600 mg (or equivalent) on days 4 through 14.

[0283] During dose escalation of venetoclax in cycle 1, TLS monitoring (K+, uric acid, phosphorus, calcium, and creatinine) should be performed before administration, 6-8 hours after administration, and 24 hours after administration (in hospitalized patients, AM testing may be used instead of the 24-hour post-administration test).

[0284] Treatment schedule

[0285] All subjects must complete a screening visit, a visit on day 1 of cycle 1, a visit on day 1 of each new cycle, and a visit at the end of treatment.

[0286] Bone marrow aspiration and / or biopsy on day 28 (±7 days). If there is no morphological evidence of leukemia, or if the count does not recover, bone marrow aspiration should be repeated every two weeks (±7 days). Bone marrow aspiration and / or biopsy should also be performed after cycles 3 and 5. Subsequent bone marrow aspiration and / or biopsy should be performed every three cycles or as clinically indicated. If non-responsive or progressive disease can be clearly diagnosed from peripheral blood tests, bone marrow aspiration during the trial is not necessary.

[0287] Cytogenetic testing should be performed each time a bone marrow examination is conducted if abnormalities were found prior to treatment. Molecular testing, including IDH1 analysis, should be performed depending on positive pre-treatment tests (specific mutations, whole-genome sequencing) and should be performed each time a bone marrow examination is conducted.

[0288] Multi-parameter flow cytometry for the presence of leukemia-associated immunophenotypes (minimal residual disease) should be performed each time a remission bone marrow examination is conducted.

[0289] Ortasidenib is a medication administered twice daily. If there is no toxicity, or if the cycle length extends beyond 28 days, treatment with ortasidenib should be continued.

[0290] After completing 12 cycles of treatment, the patient must visit MDACC at least once every three months. In between, a virtual monthly visit by an MDACC physician may be conducted, and the test supply will be delivered directly to the patient after each virtual visit.

[0291]

[0292] PK sample collection

[0293] Phase 1b portion only: To evaluate the plasma concentrations of venetoclax and ortasidenib, blood samples were taken at the following time points in relation to venetoclax dose administration: before administration (0 hours or within 90 minutes prior to administration), 2 hours (±5 minutes), 4 hours (±5 minutes), 6 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±30 minutes), and on the following days: day 7 of C1D7 / cycle 1 (before initiation of ortasidenib), day 15 of C1D15 / cycle 1, day 7 of C2 / D7 / cycle 2, and day 15 of C2D15 / cycle 2. Actual study dates may be shifted as long as the following criteria are met:

[0294] a. C1D7 PK serial sampling is intended to be performed on the day before initiating ortasidenib and after maintaining the venetoclax dose at the same dose level for at least 3 consecutive days (i.e., after the dose escalation period).

[0295] b. Pre-administration samples for C1D15 and C2D15 are intended to be collected 24 hours after the last venetoclax dose in each cycle.

[0296] c.C2D7 PK serial sampling is intended to be performed after at least 7 consecutive days of administration of ortasidenib and venetoclax.

[0297] Key safety analysis:

[0298] Overall incidence and severity of all adverse events using Common Toxicity Criteria v5.0.

[0299] Adverse events are any undesirable medical occurrences that may occur during treatment with a drug, but which are not necessarily causally related to the treatment.

[0300] Adverse drug reactions are responses to drugs that are harmful or unintended and occur in humans at doses normally used for the prevention, diagnosis, or treatment of disease, or for the modification of physiological function.

[0301] Biomarker analysis for diagnostic purposes:

[0302] Peripheral blood and bone marrow aspiration samples are obtained at the specified time points in the study. Biomarker assays may include, but are not limited to, the following:

[0303] 1. Leukemia Mutation Panel: As standard treatment, all AML patients at MDACC are evaluated for karyotype and molecular mutation profiles using a CLIA-certified next-generation gene sequencing platform. The effects of combination therapy are compared at the molecular and cellular levels by correlating them with karyotype and molecular mutation profiles, as well as with historical outcomes in the matched patient group. The leukemia mutation panel is performed on screening BM aspirates and advanced / recurrent BM aspirates. Aliquots of DNA are stored for additional analysis of DNA mutations in responding patients. 2. Minimal residual disease (MRD) by flow cytometry: As a standard treatment, aspirates from all remitted BMs are evaluated for MRD using validated 17-color multi-parameter flow cytometry. 3. Gene expression signature by RNA sequencing and / or RT-PCR: This is performed on the BM aspirate on the screening BM sample. 4. Pharmacokinetics: Plasma concentrations and PK parameters of ortasidenib and venetoclax are presented in tables for each subject, visit, and dose level, and summary statistics are calculated for each sampling time and parameter. Pharmacokinetic parameters are estimated using the non-compartmental method.

[0304] Primary efficacy analysis: Clinical activity will be assessed based on the revised IWG response criteria for AML. The primary endpoint is the composite remission rate (CRc), which is defined as the proportion of adult patients with AML who achieve complete remission (CR), complete remission with incomplete hematological recovery (CRh), and / or complete remission with incomplete numerical recovery (CRi) within 5 cycles of treatment initiation.

[0305] CR: Absolute neutrophil count > 10 3 / μL, platelets ≥10 5 / μL, transfusion-independent, no extramedullary disease, and bone marrow blasts <5%.

[0306] CRi: Bone marrow blasts <5%, peripheral neutrophils <1000 / μL, or platelets ≤100,000 / μL.

[0307] CRh: Bone marrow blasts <5%, peripheral neutrophils ≥500 / μL, and platelets ≥50,000 / μL.

[0308] PR: All hematological values ​​for CR, however, the percentage of blast cells in bone marrow aspirate is reduced by at least 50%, from 5% to 25%.

[0309] Improvement in hematological parameters that do not meet the HR:PR criteria (i.e., transfusion-independent and / or reduced incidence of febrile neutropenia and associated hospitalizations).

[0310] MLFS: Bone marrow blasts <5%, no extramedullary disease, no need for hematological recovery.

[0311] For registered subjects, analysis of CR+CRh+CRi+PR+MLFS, as well as overall response rate (ORR) defined as CR rate, CR / CRi rate, and CR / CRh rate, will be performed, and the effectiveness of the test will be evaluated ±10 days after bone marrow evaluation. The depth of remission will also be assessed using exploratory analysis of MRD-negative results by flow cytometry and / or concurrent molecular analysis.

[0312] For each subject, response to treatment, duration of response, event-free survival, and overall survival are calculated. Duration of response is defined as the number of days from the date of the first response to the earlier of the first documented disease progression / recurrence or death. Event-free survival is defined as the number of days from the treatment initiation date (i.e., C1D1) to the earlier of the earlier of any documented treatment failure, recurrence, or death due to any cause, and is calculated for all patients. These endpoints are terminated on the final day of tumor evaluation if disease progression or death is not documented before the end of the study, cessation of analysis, or initiation of confounding anticancer therapy.

[0313] Although the above invention has been described in some detail with examples and embodiments for the purpose of clarifying its understanding, it will be readily apparent to those skilled in the art, in view of the teachings of the present invention, that modifications can be made to them without departing from the spirit or scope of the appended claims.

[0314] Therefore, the above is merely illustrative of the principles of the present invention. Those skilled in the art will understand that various configurations embodying the principles of the present invention and falling within its spirit and scope, although not explicitly described or illustrated herein, can be devised. Furthermore, all examples and conditional language listed herein are intended primarily to assist the reader's understanding of the principles of the present invention and the concepts to which the inventors contribute to advance the art, and should be interpreted as not being limited to such specifically listed examples and conditions. Moreover, all descriptions herein listing the principles, aspects, and embodiments of the present invention and specific examples thereof are intended to encompass both their structural and functional equivalents. Furthermore, such equivalents are intended to include both currently known equivalents and equivalents to be developed in the future, i.e., any elements developed to perform the same function regardless of their structure. Furthermore, nothing disclosed herein is intended to be exclusive to publication, regardless of whether such disclosure is explicitly stated in the claims.

[0315] Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention are embodied in the appended claims. The claims explicitly define that 112(f) of the U.S. Patent Act is invoked only if the exact phrase “means for” or “steps for” is placed at the beginning of such limitation in the claim. If such exact phrase is not used in the limitation in the claim, 112(f) of the U.S. Patent Act is not invoked.

Claims

1. A method for treating a subject having a hematological malignancy or premalignant tumor, comprising administering an effective amount of ortasidenib in combination with venetoclax and a hypomethylating agent.

2. The method according to claim 1, wherein the hematological malignancy is acute myeloid leukemia (AML).

3. The method according to claim 1, wherein the hematological malignancy or pre-malignancy is characterized by an IDH1 mutation.

4. The method according to any one of claims 1 to 3, wherein the administration is repeated daily for 10 days or more.

5. The method according to any one of claims 1 to 4, wherein the amount of ortasidenib administered per day is approximately 300 mg.

6. The method according to claim 5, wherein the ortasidenib is administered at a dose of 150 mg twice daily.

7. The method according to any one of claims 1 to 6, wherein the amount of venetoclax administered per day is in the range of about 200 mg to about 800 mg.

8. The method according to claim 7, wherein the amount of venetoclax administered per day is approximately 200 mg.

9. The method according to claim 7, wherein the amount of venetoclax administered per day is approximately 400 mg.

10. The method according to claim 7, wherein the amount of venetoclax administered per day is approximately 600 mg.

11. The method according to claim 7, wherein the amount of venetoclax administered per day is approximately 800 mg.

12. The method according to any one of claims 7 to 11, wherein the venetoclax is administered once daily.

13. The method according to any one of claims 1 to 12, wherein the low-methylating agent comprises azacitidine.

14. The azacitidine administered per day is approximately 75 mg / m². ２ The method according to claim 13.

15. The method according to claim 14, wherein the azacitidine is administered once daily.

16. The method according to any one of claims 1 to 12, wherein the low-methylating agent comprises decitabine.

17. The method according to claim 16, wherein the amount of decitabine administered per day is approximately 35 mg.

18. The method according to claim 17, wherein the decitabine is administered once daily.

19. The method according to any one of claims 16 to 18, wherein the low-methylating agent comprises sedazulidine.

20. The method according to claim 19, wherein the sedazulidine is administered once daily at a dose of 100 mg.

21. The method according to any one of claims 1 to 20, wherein the ortasidenib is administered daily on days 1 to 28 of the medication schedule.

22. The method according to any one of claims 1 to 20, wherein the ortasidenib is administered daily on days 8 to 28 of the medication schedule.

23. The method according to any one of claims 1 to 22, wherein the venetoclax is administered once daily on days 1 to 7 of the medication schedule.

24. The method according to any one of claims 1 to 22, wherein the venetoclax is administered once daily on days 1 to 10 of the medication schedule.

25. The method according to any one of claims 1 to 22, wherein the venetoclax is administered once daily on days 1 to 14 of the medication schedule.

26. The method according to any one of claims 1 to 22, wherein the venetoclax is administered once daily on days 1 to 28 of the medication schedule.

27. The method according to any one of claims 1 to 26, wherein the low-methylating agent is azacitidine, and the azacitidine is administered daily on days 1 to 7 of the drug administration schedule.

28. The method according to any one of claims 1 to 26, wherein the low-methylating agent comprises decitabine, and the decitabine is administered on days 1 to 5 of the drug administration schedule.

29. The method according to any one of claims 1 to 26, wherein the hypomethylating agent comprises decitabine and sedazulidine, and the hypomethylating agent is administered on days 1 to 5 of the drug administration schedule.

30. The method according to any one of claims 1 to 29, wherein ortasidenib, venetoclax, or both are administered in a suboptimal dose.

31. The method according to any one of claims 1 to 28, further comprising administering sedazuridine to the subject.

32. The method according to any one of claims 1 to 31, further comprising diagnosing the subject as the AML.

33. A method for treating acute myeloid leukemia (AML), comprising: treating a subject having AML with venetoclax until the subject is in remission; and treating the subject in remission with ortasidenib.

34. The method according to claim 33, wherein the AML is characterized by an IDH1 mutation.

35. The method according to any one of claims 33 to 34, wherein the amount of ortasidenib administered per day is approximately 300 mg.

36. The method according to claim 35, wherein the ortasidenib is administered at a dose of approximately 150 mg twice daily.

37. The method according to any one of claims 33 to 36, wherein the amount of venetoclax administered per day is in the range of about 200 mg to about 800 mg.

38. The method according to any one of claims 33 to 37, wherein the amount of venetoclax administered is 200 mg per day.

39. The method according to any one of claims 33 to 37, wherein the amount of venetoclax administered is 400 mg per day.

40. The method according to any one of claims 33 to 37, wherein the amount of venetoclax administered is 600 mg per day.

41. The method according to any one of claims 33 to 37, wherein the amount of venetoclax administered is 800 mg per day.

42. The method according to any one of claims 33 to 41, wherein the venetoclax is administered once daily.

43. The method according to any one of claims 33 to 42, further comprising diagnosing the subject as the AML.

44. The method according to any one of claims 33 to 43, further comprising treating the subject with a low-methylating agent.

45. The method according to claim 44, wherein the low-methylating agent comprises azacitidine or decitabine.

46. The method according to claim 45, wherein the low-methylating agent comprises decitabine and sedazulidine.

47. A method for treating hematological malignancies, comprising simultaneously administering an effective amount of ortasidenib, venetoclax, and a hypomethylating agent to a subject having IDH1 mutation AML.

48. The method according to claim 47, wherein the co-administration comprises administering the ortasidenib, venetoclax, and the hypomethylating agent in a 28-day treatment cycle.

49. The method according to claim 48, wherein ortasidenib is administered daily on days 1 to 28 of the treatment cycle.

50. The method according to claim 48 or 49, wherein the venetoclax is administered daily on days 1 to 7 of the treatment cycle.

51. The method according to claim 48 or 49, wherein the venetoclax is administered daily on days 1 to 10 of the treatment cycle.

52. The method according to claim 48 or 49, wherein the venetoclax is administered daily on days 1 to 14 of the treatment cycle.

53. The method according to any one of claims 47 to 53, wherein the venetoclax administered daily is approximately 200 mg to approximately 800 mg.

54. The method according to any one of claims 47 to 53, wherein the venetoclax administered daily is approximately 200 mg.

55. The method according to any one of claims 47 to 53, wherein the venetoclax administered daily is approximately 400 mg.

56. The method according to any one of claims 47 to 53, wherein the venetoclax administered daily is approximately 600 mg.

57. The method according to any one of claims 47 to 53, wherein the venetoclax administered daily is approximately 800 mg.

58. The method according to any one of claims 53 to 57, wherein the venetoclax is administered once daily.

59. The method according to any one of claims 47 to 58, wherein the low-methylating agent comprises decitabine, and the decitabine is administered on days 1 to 5 of the treatment cycle.

60. The low methylating agent comprises decitabine and sedazulidine, and the low methylating agent is The method according to any one of claims 47 to 59, administered on days 1 to 5 of the aforementioned treatment cycle.

61. The method according to any one of claims 47 to 60, wherein the ortasidenib administered daily is approximately 150 mg.

62. The method according to any one of claims 47 to 60, wherein the ortasidenib is administered in a dose of approximately 150 mg twice daily.

63. The method according to any one of claims 47 to 62, wherein ortasidenib, venetoclax, or both are administered in a suboptimal dose.

64. The method according to any one of claims 47 to 63, wherein the hematological malignancy includes AML.

65. The method according to any one of claims 1 and 3 to 63, wherein the hematological malignancy includes MDS.

66. The method according to claim 64, wherein the AML is relapsed or refractory AML that is not eligible for chemotherapy or newly diagnosed AML.

67. The method according to claim 65, wherein the hematological malignancy is a high-risk MDS.

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