Phase 1b/2 Study of Decitabine and Venetoclax in Combination With the Targeted Mutant IDH1 Inhibitor Olutasidenib

To find a recommended combination dose of decitabine and venetoclax that can be given in combination with olutasidenib to participants with AML.

Study Overview

• Status: Recruiting
• Conditions: Mutant IDH1 Inhibitor Olutasidenib
• Intervention / Treatment: Drug: Venetoclax; Drug: Decitabine; Drug: Olutasidenib; Drug: Decitabine/cedazuridine

Detailed Description

Primary Objectives

• Phase 1b: To determine the safety and tolerability and recommended phase 2 dose (RP2D) of decitabine (either IV or oral decitabine/cedazuridine (ASTX727, Inqovi)) and venetoclax in combination with olutasidenib.
• Phase 2: To determine the composite remission rate (CR, CRh and CRi) of decitabine (IV or oral decitabine/cedazuridine (ASTX727, Inqovi)) and venetoclax in combination with olutasidenib for newly diagnosed (Arm A) or relapsed/refractory (Arm B) participants with IDH1-mutated myeloid malignancy.

Secondary Objectives

• To determine duration of response (DOR), event-free survival (EFS), and overall survival (OS)
• To evaluate occurrence of minimal residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation.
• To determine the overall response rate (CR, CRh, CRi, MLFS, and PR)
• To characterize the pharmacokinetic (PK) profiles of venetoclax and olutasidenib in plasma samples (Phase 1b only).

Exploratory Objectives

- To investigate global gene expression profiles, DNA methylation profiles, BH3 profiling and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Courtney DiNardo, MD; Phone Number: (713) 794-1141; Email: cdinardo@mdanderson.org

Study Locations

• United States
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Recruiting
      • The University of Kansas Medical Center
      • Contact: Yacoub Abdulraheem, MD; Email: ayacoub@kumc.edu
      • Principal Investigator: Yacoub Abdulraheem, MD
  • New York
    • Buffalo, New York, United States, 14263
      • Recruiting
      • Roswell Park
      • Principal Investigator: Eunice Wang, MD
      • Contact: Eunice Wang, MD; Email: eunice.wang@roswellpark.org
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Contact: Courtney DiNardo, MD; Phone Number: 713-794-1141; Email: cdinardo@mdanderson.org
      • Principal Investigator: Courtney DiNardo, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age > 18 years
2. Participants must have a documented IDH1 gene mutation
3. Participants with a diagnosis of relapsed or refractory AML (including biphenotypic or bilineage leukemia including a myeloid component or isolated extramedullary AML), high-risk MDS by IPSS-R or IPSS-M; OR
4. Participants with newly diagnosed AML not eligible or appropriate for intensive chemotherapy are also eligible. (Phase 2 portion only)

5. To be considered not eligible for intensive chemotherapy, participants must be defined by the following: Age 75 years or older, or Age 18 to 74 years with at least one of the following comorbidities:

   1. Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
   2. Severe pulmonary disorder (eg, DLCO ≤65% or forced expiratory volume in 1 second [FEV1] ≤65%).
   3. Creatinine clearance ≥30 mL/min to <45 mL/min.
   4. Moderate hepatic impairment with total bilirubin >1.5 to .3.0 x upper limit of normal (ULN)
   5. ECOG performance status of 2 or 3
   6. Any other comorbidity that per the investigator renders a patient inappropriate for intensive chemotherapy
6. Eastern Cooperative Oncology Group (ECOG) Performance Status </=2 (unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy as per 5e above)
7. Adequate renal function including creatinine < 1.5, unless related to the disease or unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy as per 5c above.
8. Adequate hepatic function (direct bilirubin < 2x upper limit of normal (ULN) unless increase is due to Gilbert fs disease or leukemic involvement, and AST and/or ALT < 3x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT < 5x ULN will be considered eligible, or unless age 18 to 74 years of age with newly diagnosed AML not eligible for intensive chemotherapy as per 5d above)
9. In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half-lives of the prior therapy. Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the PI. Concurrent intrathecal therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.
10. Male participants who are sexually active with a women of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception and refrain from sperm donation from initial study drug until 90 days after last dose of study drug.
11. Willing and able to provide informed consent.

Exclusion Criteria:

1. Participants with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML).
2. Participants with any concurrent uncontrolled clinically significant medical condition including life-threatening severe infection, or psychiatric illness, which could place the participants at unacceptable risk of study treatment.
3. Participants with active, uncontrolled leukemia involvement of the CNS
4. Participants with active graft-versus-host-disease (GVHD) status post stem cell transplant including active cGVHD requiring topic therapy. Patients must have discontinued calcineurin inhibitors at least 4 weeks prior to start of study treatment.
5. Participants with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
6. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.
7. Participant has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea and cytarabine is permitted to meet this criterion.)
8. Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception.

A) Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, IUD, and double barrier methods (for example a condom in combination with a spermicide).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1; Participants enrolled in Part 1, the dose of venetoclax/decitabine you receive will depend on when you join this study. Up to 3 dose levels will be tested. Up to 6 participants will be enrolled at each dose level. - All participants will receive the same dose level of olutasidenib.	Drug: Venetoclax; Given by PO; Other Names: ABT-199; GDC-0199; Drug: Decitabine; Given by IV; Other Names: Dacogen; Drug: Olutasidenib; Given by PO; Drug: Decitabine/cedazuridine; Given by PO; Other Names: INQOVI; ASTX727
Experimental: Part 2; Participants enrolled in Part 2, you will receive venetoclax/decitabine at the recommended dose that was found in Part 1. - All participants will receive the same dose level of olutasidenib.	Drug: Venetoclax; Given by PO; Other Names: ABT-199; GDC-0199; Drug: Decitabine; Given by IV; Other Names: Dacogen; Drug: Olutasidenib; Given by PO; Drug: Decitabine/cedazuridine; Given by PO; Other Names: INQOVI; ASTX727

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,Inc.
• Investigators: Principal Investigator: Courtney DiNardo, 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): August 29, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: May 31, 2024
• First Submitted That Met QC Criteria: May 31, 2024
• First Posted (Actual): June 6, 2024

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; Decitabine; venetoclax; decitabine and cedazuridine drug combination; olutasidenib
• Other Study ID Numbers: 2024-0180; NCI-2024-04807 (Other Identifier: NCI-CTRP Clinical Registry)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No