Ziftomenib plus quizartinib dose-finding for relapsed/refractory AML with NPM1, KMT2A, or NUP98 alterations

Phase 1 Dose Escalation and Expansion of Ziftomenib in Combination With Quizartinib in Acute Myeloid Leukemia

This trial tests an all-oral combination of ziftomenib and quizartinib in adults with relapsed or refractory AML that has NPM1 mutations, KMT2A rearrangements, or NUP98 rearrangements.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 44 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: M.D. Anderson Cancer Center (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, quizartinib
• Locations: 1 site (Houston, Texas)
• Trial ID: NCT06769490 on ClinicalTrials.gov

What this trial studies

This Phase 1 dose-escalation and expansion study gives oral ziftomenib together with oral quizartinib to determine the recommended Phase 2 dose and maximum tolerated dose while monitoring safety. Adults with relapsed or refractory AML or mixed-phenotype acute leukemia who carry NPM1mt, KMT2Ar, or NUP98r are eligible following screening and baseline organ-function requirements. Secondary endpoints include preliminary efficacy stratified by FLT3 mutation status, survival outcomes (OS, RFS, EFS), duration of response, pharmacokinetics of both drugs, and minimal residual disease measured by flow cytometry. The trial is conducted at a single tertiary cancer center with careful dose and toxicity monitoring during escalation and then expands cohorts at the selected dose.

Who should consider this trial

Good fit: Ideal candidates are adults (≥18 years) with relapsed or refractory AML or MPAL harboring NPM1 mutation, KMT2A rearrangement, or NUP98 rearrangement, with ECOG <2, WBC <25,000/µL (or cytoreduced), and adequate cardiac, hepatic, and renal function who can swallow pills and consent.

Not a fit: Patients without the specified molecular alterations, with poor performance status (ECOG ≥2), significant cardiac/hepatic/renal dysfunction, or uncontrolled high leukocyte counts are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, the combination could offer a safe, effective all-oral targeted option for a substantial subset (~40–45%) of AML patients with these molecular alterations.

How similar studies have performed: Early-phase results from other menin inhibitors and from FLT3 inhibitors have shown promising single-agent activity in related AML subtypes, but this specific ziftomenib plus quizartinib combination is novel and not yet proven.

Eligibility criteria

Inclusion Criteria:

1. Age . 18 years.
2. ECOG performance status of \< 2.
3. Relapsed or refractory AML or myeloid mixed-phenotype acute leukemia (MPAL) with NPM1mt, or KMT2Ar, or NUP98r.
4. WBC must be below 25,000/ ƒÊL at time of enrollment. Patients may receive cytoreduction prior to enrollment.
5. Baseline ejection fraction must be \> 40%.
6. Adequate hepatic function (total bilirubin \< 2x upper limit of normal (ULN) unless increase is due leukemic involvement (\<2.5 ULN), unless due to ongoing hemolysis or Gilbert's syndrome 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).
7. Adequate renal function with an estimated glomerular filtration rate . 50 mL/min (using Cockcroft-Gault) unless related to disease.
8. Able to swallow pills.
9. Patient or parent/guardian is willing and able to provide informed consent.
10. 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, whichever is longer. Oral hydroxyurea and/or cytarabine (up to 1 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 therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.
11. Women of childbearing potential must agree to adequate methods of contraception during the study and at least 7 months for females and 4 months for males after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study and at least 4 months after the last treatment.

Exclusion Criteria:

1. Prior treatment with a menin inhibitor.
2. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea for patients with rapidly proliferative disease or for control of counts during differentiation syndrome. (3) use of steroids for treatment of differentiation syndrome.
3. Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
4. Patients with a concurrent active malignancy under treatment.
5. Known active hepatitis B (HBV) or Hepatitis C (HCV) or HIV infection.
6. Female subjects who are pregnant or breast-feeding.
7. Patient has an active uncontrolled infection.
8. Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class .II), life-threatening, uncontrolled arrhythmia including ventricular arrythmias or torsades de pointes, cerebrovascular accident, or transient ischemic attack.
9. History of sustained bradycardia of less than 50 beats per minute unless the subject has a pacemaker.
10. Diagnosis of or suspicion of congenital long QT syndrome (including family history of congenital long QT syndrome).
11. Uncontrolled hypertension with a systolic blood pressure .180 mmHg or diastolic blood pressure .110 mmHg, sustained despite optimal medical management.
12. QTc \>450 msec using the Fridericia Formula.
13. History of or any concurrent condition, therapy, or laboratory abnormality that in the Investigator's opinion might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate. Patients under legal protection measure (guardianship, trusteeship or safeguard of justice) and/or uncontrolled psychiatric comorbidities, ongoing illicit substance abuse, inability, any impairment or unwillingness to comply with the treatments, follow-up, requirements and procedures of this clinical trial.
14. Clinically active central nervous system (CNS) leukemia.
15. Patients with Grade \> 2 active acute GVHD, moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.

Where this trial is running

Houston, Texas

• The University of Texas M. D. Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Ghayas Issa, MD — M.D. Anderson Cancer Center
• Study coordinator: Ghayas Issa, MD

Conditions Acute Myeloid Leukemia