A Phase 2 Study Evaluating Olutasidenib in Combination With Hypomethylating Agents in Patients With IDH1-mutated Higher-risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Advanced Myeloproliferative Neoplasm

To learn if olutasidenib, when combined with a drug called a hypomethylating agent (HMA) can help to control MDS, CMML, and/or MPN. The safety of the drug combination will also be studied.

Study Overview

• Status: Withdrawn
• Conditions: Chronic Myelomonocytic Leukemia; Advanced Myeloproliferative Neoplasms; IDH1-mutated Higher-Risk Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Olutasidenib

Detailed Description

Primary Objectives To determine the overall response rate of olutasidenib in combination with investigator's choice of HMA in patients with IDH1-mutated higher-risk MDS/CMML or advanced MPN Secondary Objectives

The secondary objectives of this study are:

• To evaluate the rates of complete remission (CR) and median duration of CR
• To ascertain the safety and tolerability of olutasidenib with HMA in this participant population
• To determine survival including overall survival (OS), progression-free survival (PFS), and duration of response (DOR) To analyze reduction in IDH1 clone size Exploratory Objectives
• To examine overall response rate of patients previously exposed to venetoclax
• To investigate global gene expression profiles, DNA methylation profiles, and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Pathologically proven higher-risk MDS/CMML or advanced MPN

   1. MDS participants must have International Prognostic Scoring System (IPSS) intermediate-2- or high-risk disease or Revised IPSS (IPSS-R) score >= 3.5 or Molecular IPSS (IPSS-M) moderate high-, high-, or very high-risk disease or bone marrow blast percentage.
   2. CMML patients must have CPSS-Mol int-1, int-2, or high-ris disease (Elena C et al, Blood 2016)
   3. Advanced MPN is defined as bone marrow blast percentage >=/=10%.
   4. Participants on the treatment-naive arm must not have received a prior HMA. Agents such as growth factors (e.g. erythropoietin stimulating agents, luspatercept, eltrombopag, granulocyte colony stimulating factors), cyclosporine, and/or hydroxyurea are allowed.
   5. Patients on the previously-treated arm must have received a prior HMA and/or ivosidenib. Prior stem cell transplantation in allowed>
2. Participants must have a documented IDH1 mutation
3. Patients with previously-treated MDS must be ineligible to receive treatment with ivosidenib or have progressed on treatment with ivosidenib.
4. Participants >=/= 18 years old
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Appendix A)

6. Acceptable liver function

   1. Bilirubin </= 2 times upper limit of normal (ULN) or <;/= 3 times ULN in participants with Gilbert Syndrome
   2. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase </= 3 times ULN
7. Acceptable renal function calculated creatinine clearance >/= 50 mL/min (as assessed by Cockcroft-Gault, MDRD, or CKD-Epi validated measures)
8. Negative serum or urine pregnancy test if female of childbearing potential c. For fertile men and women, agreement to use highly effective contraceptive methods for the duration of study participation and 90 days after the last dose of study medication d. Agreement for male participants not to donate sperm and for female participants of childbearing potential not to donate ova during the study and for 90 days after the final dose of study drug
9. Ability and willingness to sign informed consent prior to beginning study and undergoing procedures

Exclusion Criteria:

1. Participants unable to swallow oral medications, or participants with gastrointestinal conditions (e.g., malabsorption, resection, etc.) deemed by the Investigator to jeopardize intestinal absorption
2. Participants with any concurrent uncontrolled clinically significant medical condition, including life-threatening severe infection or psychiatric illness, which could place the participant at unacceptable risk of study treatment
3. Patients must have discontinued prior chemotherapy at least 1 week prior to the start of study treatment. Patients with MPN must be off JAK inhibitors at the start of study treatment
4. Patients with active graft-versus-host-disease (GVHD) status post stem cell transplantation, including active chronic GVHD requiring topical therapy. Patients must have discontinued calcineurin inhibitors at least 4 weeks prior to the start of study treatment
5. Known active hepatitis B (HBV) or hepatitis C (HCV) or HIV infection
6. Pregnant or nursing women or women of childbearing potential not using highly effective contraception; male participants not using highly effective contraception
7. Participants with white blood cell count > 25 x109/L Note: hydroxyurea use is permitted to meet this criterion
8. Unwillingness or inability to comply with procedures either required in this protocol or considered standard of care

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Olutasidenib+Azacitidine-IV or SubQ; Participants will take capsules of olutasidenib 2 times each day while you are on study. Each dose should be taken about 12 hours apart at least 1 hour before or 2 hours after a meal. Azacitidine IV or Sub Q for 7 days every 28 days.	Drug: Olutasidenib; Given by PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and adverse events (AEs)	Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0	Through study completion; an average of 1 year.

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: Rigel Pharmaceuticals
• Investigators: Principal Investigator: Kelly Chien, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2025
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: September 12, 2024
• First Submitted That Met QC Criteria: September 12, 2024
• First Posted (Actual): September 19, 2024

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Myelomonocytic, Chronic; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; olutasidenib
• Other Study ID Numbers: 2024-0515; NCI-2024-07758 (Other Identifier: Clinical Trials Reporting Program (CTRP))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No