Phase 1/1b Trial Of Olutasidenib And Ziftomenib For NPM1 And IDH1 Co-Mutated Acute Myeloid Leukemia

The goal of Phase 1 is to find the recommended dose of ziftomenib and olutasidenib in patients with relapsed/refractory AML that has a mutation in the NPM1 and IDH1 genes.

The goal of Phase 1b is to learn if the recommended dose of ziftomenib and olutasidenib found in Phase 1 can help to control the disease.

The safety and effects of this combination will also be studied in both parts.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Olutasidenib; Drug: Ziftomenib

Detailed Description

Primary Objectives:

• Phase 1: To determine the safety and tolerability and recommended phase 2 dose (RP2D)) of ziftomenib and olutasidenib in adult patients with R/R NPM1 and IDH1 co-mutated AML
• Phase 1b: To determine the preliminary efficacy of combination treatment as reflected by the composite remission rate (CRc=CR+ CRi +CRh) of ziftomenib and olutasidenib in adult patients with R/R NPM1 and IDH1 co-mutated AML

Secondary Objectives:

• To determine the overall response rate (ORR) including composite remission rate (CRc), partial remission (PR), and morphologic leukemia free state (MLFS) following therapy
• To determine the duration of response (DOR), event-free survival (EFS), relapse-free survival (RFS), time to CRc, and overall survival (OS) following therapy
• To determine the occurrence of minimal residual disease (MRD) negative response (CR/CRi) as assessed by multiparameter flow cytometry and NPM1m qPCR following therapy
• To determine the time to achieve CR/CRi following initiation of therapy
• To determine the rate of transfusion independence (TI) achieved by patients on therapy
• To determine the proportion of patients that undergo allogeneic stem cell transplantation (alloSCT) following study therapy
• To monitor longitudinal changes in IDH1m VAF in patients following treatment

Exploratory Objective:

• To perform detailed bulk and single cell multi-omics (DNA sequencing, RNA sequencing, global gene expression profiles, DNA methylation profiles), and other potential prognostic marker assays on longitudinally collected samples over the course of therapy to explore potential predictors of anti-tumor activity and/or resistance to treatment

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

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

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas M. D. 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. Diagnosis of relapsed or refractory AML (including biphenotypic or bilineage leukemia) as defined by ≥ 5% marrow blasts; patients with isolated extramedullary AML without marrow involvement are not eligible
3. AML disease must be characterized by IDH1 and NPM1 co-mutations as determined by local molecular testing (next generation sequencing, PCR)
4. Eastern Cooperative Oncology Group (ECOG) Performance Status </=2
5. Adequate renal function with CrCl ≥30 ml/min to be calculated using Cockroft Gault formula
6. Adequate hepatic function (total bilirubin < 3.0x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement, and AST and/or ALT < 3x ULN unless considered due to leukemic involvement, in which case total bilirubin < 5x ULN or AST and/or ALT < 5x ULN will be considered eligible
7. Baseline QTcF ≤ 480 msec
8. In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation of study therapy will be 14 days from last cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half- lives of the prior therapy whichever is shorter. Cytarabine (up to 2 gm/m2), leukapheresis, and oral hydroxyurea are permitted in patients with rapidly proliferative disease before the start of study therapy for clinical benefit as needed. Hydroxyurea can also be administered during cycles 1-2 of study therapy for cytoreduction as deemed necessary by the treating physician 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.
9. Female patients of childbearing potential must agree to use a highly effective method of contraception as well as a double-barrier method (e.g., condom with spermicide) and refrain from egg donation from screening visit until 180 days following the last dose of study intervention. Male patients capable of having intercourse with females of childbearing potential and who have not had vasectomies must agree to abstain from heterosexual intercourse or use a double-barrier method of contraception and have their partner use a highly effective method of contraception from the screening visit until 90 days following the last dose of study intervention. They must also refrain from sperm donation from the screening visit until 90 days following the last dose of study intervention. Please refer to NIH Contraception Guidance (https://rsc.niaid.nih.gov/sites/default/files/trpguidancereproriskfinal.pdf) for additional recommendations.
10. Willing and able to provide informed consent

Exclusion Criteria:

1. Patients with t (15;17) karyotypic abnormality or acute promyelocytic leukemia (French American- British [FAB] class M3-AML).
2. Patients with any concurrent uncontrolled clinically significant medical condition including life- threatening severe infection, or psychiatric illness, which could place the patient at unacceptable risk of study treatment or be unable to consent or comply with protocol therapy. Patients with controlled infections are allowed. Other prior or concurrent malignancies will be considered after discussion with the PI.
3. Patients with active, uncontrolled, leukemia involvement of the CNS
4. Patients with grade II-IV active or extensive chronic graft-versus-host disease (cGHVD) status post stem cell transplant requiring topical therapy. Patients must have discontinued calcineurin inhibitors at least 2 weeks prior to the start of the study therapy.
5. Patients 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. Subject has a white blood cell count > 20 x 10⁹/L. (Note: Hydroxyurea, leukapheresis, and cytarabine is permitted to meet this criterion- see above Inclusion criteria #8.)
8. Prior treatment with ziftomenib or olutasidenib
9. 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. 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).
10. Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drugs including medical, psychological, familial, social or geographical consideration
11. Receiving treatment with moderate or strong CYP3A inducer within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug (see Appendix A for examples).

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: Phase 1 Escalation and Phase 1b Expansion: Treatment with Ziftomenib + Olutasidenib; Adult participants with relapsed/refractory NPM1m/ IDH1m AML will be enrolled. Treatment will consist of 28-day cycles of ziftomenib and olutasidenib given concomitantly. All participants will receive olutasidenib 150 mg orally twice daily (total 300 mg dose per day).	Drug: Olutasidenib; Given by mouth; Other Names: Rezlidhia; Drug: Ziftomenib; Given by mouth; Other Names: Komzifti

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
• Investigators: Principal Investigator: Courtney DiNardo, MD, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): August 31, 2026
• Primary Completion (Estimated): January 14, 2027
• Study Completion (Estimated): January 14, 2029

Study Registration Dates

• First Submitted: February 11, 2026
• First Submitted That Met QC Criteria: February 11, 2026
• First Posted (Actual): February 17, 2026

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; olutasidenib
• Other Study ID Numbers: 2025-1468; NCI-2026-01058 (Other Identifier: NCI-CTRP Clinical Trials 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
• product manufactured in and exported from the U.S.: No