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EP-4739313-A1 - TREATMENT OF ACUTE MYELOID LEUKEMIA WITH OLUTASIDENIB, VENETOCLAX AND A HYPOMETHYLATING AGENT

EP4739313A1EP 4739313 A1EP4739313 A1EP 4739313A1EP-4739313-A1

Abstract

Provided are methods of treating a subject having a hematologic malignancy or pre-malignancy that involve administering an effective amount of olutasidenib, venetoclax, and a hypomethylating agent. In some cases, the patient has an IDH1 mutation.

Inventors

  • CHAO, Mwe Mwe
  • DINARDO, Courtney

Assignees

  • Rigel Pharmaceuticals, Inc.

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. 1. A method of treating a subject having a hematologic malignancy or premalignancy, comprising administering an effective amount of olutasidenib in combination with venetoclax and a hypomethylating agent.
  2. 2. The method of claim 1 , wherein the hematologic malignancy is acute myeloid leukemia (AML).
  3. 3. The method of claim 1, wherein the hematologic malignancy or pre-malignancy is characterized by an IDH1 mutation.
  4. 4. The method of any one of claims 1 - 3, wherein the administration is repeated each day for 10 days or more.
  5. 5. The method of any one of claims 1 - 4, wherein the amount of olutasidenib administered per day is about 300 mg.
  6. 6. The method of claim 5, wherein the olutasidenib is administered at 150 mg twice daily.
  7. 7. The method of any one of claims 1 - 6 wherein the amount of venetoclax administered per day ranges from about 200 mg to about 800 mg.
  8. 8. The method of claim 7, wherein the amount of ventoclax administered per day is about 200 mg.
  9. 9. The method of claim 7, wherein the amount of ventoclax administered per day is about 400 mg.
  10. 10. The method of claim 7, wherein the amount of ventoclax administered per day is about 600 mg.
  11. 11. The method of claim 7, wherein the amount of ventoclax administered per day is about 800 mg.
  12. 12. The method of any one of claims 7 - 11, wherein the venetoclax is administered once daily.
  13. 13. The method of any one of claims 1 - 12, wherein the hypomethylating agent comprises azacitidine.
  14. 14. The method of claim 13, wherein the azacitidine is administered per day is about 75 mg/m 2 .
  15. 15. The method of claim 14, wherein the azacitidine is administered once daily.
  16. 16. The method of any one of claims 1 - 12, wherein the hypomethylating agent comprises decitabine.
  17. 17. The method of claim 16, wherein the decitabine administered per day is about 35 mg.
  18. 18. The method of claim 17, wherein the decitabine is administered once daily.
  19. 19. The method of any one of claims 16 - 18, wherein the hypomethylating agent comprises cedazuridine.
  20. 20. The method of claim 19 wherein the cedazuridine is administered at 100 mg once daily.

Description

TREATMENT OF ACUTE MYELOID LEUKEMIA WITH OLUTASIDENIB, VENETOCLAX AND A HYPOMETHYLATING AGENT CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/525,639, filed on July 7, 2023, which is incorporated herein by reference in its entirety. INTRODUCTION [0002] Mutant IDH1 is a genetically validated target in hematologic cancers, including AML. Mutations of IDH1 present in certain cancer cells can result in a new ability of this enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to 2-hydroxyglutarate (2HG), usually the enantiomer (R)-2-hydroxyglutarate (R-2HG). 2HG is not formed by wild-type IDH. The presence of mutations at codon 132 in IDH1 imparts a neomorphic activity to the enzyme, resulting in the production of the “oncometabolite” 2HG, which has pleotropic roles in tumorigenesis. Excess production of 2HG has been shown to inhibit a-KG-dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling, thereby leading to a block in normal differentiation of progenitor cells and the subsequent development of cancer mutations in IDH1 associated with 2HG neomorphic activity, specifically R-2HG neomorphic activity, including 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 aberrantly elevated levels of the oncometabolite 2HG, resulting in antitumor efficacy in preclinical models. SUMMARY [0003] Provided are methods of treating a subject having a hematologic malignancy or premalignancy that involve administering an effective amount of olutasidenib, venetoclax, and a hypomethylating agent. For instance, the hypomethylating agent can be azacytidine or decitabine. In some cases, the malignancy or pre-malignancy has an IDH1 mutation. In certain embodiments the hematologic malignancy comprises acute myeloid leukemia (AML). BRIEF DESCRIPTION OF THE FIGURES [0004] FIG. 1 illustrates the design of a clinical trial. DETAILED DESCRIPTION [0005] Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. [0006] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. [0007] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and exemplary methods and materials may now be described. Any and all publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction. [0008] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a droplet" includes a plurality of such droplets and reference to "the discrete entity" includes reference to one or more discrete entities, and so forth. It is further noted that the claims may be drafted to exclude any element, e.g., any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation. [0009] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of public