First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia

Phase 1

Recruiting

• Conditions: Acute Myeloid Leukemia; Mixed Lineage Leukemia; Mixed Lineage Acute Leukemia; Acute Leukemia of Ambiguous Lineage; Advanced Malignant Neoplasm; Mixed Phenotype Acute Leukemia
• Interventions: Drug: Ziftomenib

• Registration Number: NCT04067336
• Lead Sponsor: Kura Oncology, Inc.

Brief Summary

This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML) as part of Phase 1. In Phase 2, assessment of ziftomenib will continue in patients with NPM1-m AML.

Detailed Description

This Phase 1/2, first-in-human (FIH), open-label, dose-escalation and dose-validation/expansion study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML).

The dose-escalation part of the study (Phase 1a) will determine the maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D).

The dose-validation/expansion part of the study (Phase 1b) will determine the safety, tolerability, and minimal biologically effective dose of ziftomenib in dosing cohorts which have demonstrated early biological activity and have been determined to be safe in the dose-escalation phase.

The Phase 2 portion of the study will determine the safety, tolerability, and anti-leukemia activity of ziftomenib in patients with NPM1-m AML.

Study Timeline

• Study First Submitted: 2019-06-25
• Study First Submitted QC: 2019-08-22
• Study First Posted: 2019-08-26
• Study Start: 2019-09-12
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-15
• Last Update Posted: 2025-04-18
• Primary Completion: 2028-10-16
• Study Completion: 2028-10-16

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 199

Inclusion Criteria

Patients with refractory or relapsed AML defined as the reappearance of ≥ 5% blasts in the bone marrow and who have also failed or are ineligible for any approved standard of care therapies, including HSCT.

1. Phase 1b:

   1. Patients with a documented lysine[K]-specific methyltransferase 2-rearrangement (KMT2A-r), or
   2. Patients with a documented nucleophosmin 1 mutation (NPM1-m)

2. Phase 2:

   a. Patients with a documented nucleophosmin 1 mutation (NPM1-m)

3. ≥ 18 years of age.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 2 months.

5. Adequate liver and kidney function according to protocol requirements.

6. Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receive hydroxyurea to control and maintain white blood cell count prior to enrollment.

7. Women of childbearing potential must be willing to use a highly effective method of contraception throughout the study and for at least 180 days after the last dose of study treatment.

8. Males with female partners of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 90 days after the last dose of study treatment.

Key

Exclusion Criteria

1. Diagnosis of acute promyelocytic leukemia.
2. Diagnosis of chronic myelogenous leukemia in blast crisis.
3. Donor lymphocyte infusion < 30 days prior to study entry.
4. Clinically active central nervous system (CNS) leukemia.
5. Undergone HSCT and have not had adequate hematologic recovery.
6. Receiving immunosuppressive therapy post HSCT within 2 weeks of Cycle 1 Day 1.
7. Grade ≥ 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.
8. Received chemotherapy immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation) < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug.
9. Not recovered to < Grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) from all acute toxicities or deemed back to a stable baseline.
10. Treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome P450-isozyme 3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient.
11. Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection. Patients with controlled disease will not be excluded from study enrollment.
12. Pre-existing disorder predisposing the patient to a serious or life-threatening infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias not related to AML).
13. Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection.
14. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, history of cerebrovascular accident including transient ischemic attack within the past 6 months, congestive heart failure (NYHA Class III or IV) related to primary cardiac disease, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the first dose of study treatment.
15. Mean QTcF >480 ms on triplicate ECG.
16. Major surgery within 4 weeks prior to the first dose of study treatment.
17. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative serum pregnancy test within 72 hours prior to starting treatment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1a - Dose Escalation	Ziftomenib	-
Phase 1b - Dose-Validation Expansion	Ziftomenib	Cohort 1: KMT2A-r / NPM1-m patients will receive a dose previously studied in Phase 1a Cohort 2: KMT2A-r / NPM1-m patients will receive a dose previously studied in Phase 1a
Phase 2	Ziftomenib	NPM1-m patients will receive the recommended phase 2 dose determined in Phase 1

Primary Outcome Measures

Name	Time	Method
Phase 1a: Maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D)	Dose Limiting Toxicities (DLTs) will be evaluated during the first 28 days (1 cycle)	MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients.
Phase 1b: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs).	During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.	Assessed by NCI-CTCAE v5.0
Phase 1b: Minimal biologically effective dose	Up to 12 months following end of treatment	Minimal biologically effective dose in dosing cohorts which have demonstrated biological activity and have been determined to be safe as a part of Part 1a
Phase 2: Evidence of anti-leukemia activity	12 months following end of treatment	Anti-leukemia activity is assessed by the CR (CR+CRh) rate

Secondary Outcome Measures

Name	Time	Method
Phases 1a, 1b, and 2: Transfusion independence (TI)	Up to 12 months following discontinuation of treatment	To assess transfusion independence
Phase 1a: Tmax	Cycle 1 and Cycle 2. Each cycle is 28 days.	Time to observed maximum plasma concentration of ziftomenib and/or its metabolites
Phase 1a: AUC(0-last)	Cycle 1 and Cycle 2. Each cycle is 28 days.	Area under the plasma concentration-time curve from time 0 to time of last measurable concentration of ziftomenib and/or its metabolites
Phases 1a, 1b, and 2: Complete response (CR) with and without minimal residual disease (MRD)	Up to 12 months following discontinuation of treatment	To assess the CR rate with and without MRD
Phases 1a, 1b, and 2: Duration of remission (DOR)	Up to 12 months following discontinuation of treatment	To assess the DOR
Phase 1a: Cmax	Cycle 1 and Cycle 2. Each cycle is 28 days.	Maximum plasma concentration of ziftomenib and/or its metabolites
Phases 1a, 1b, and 2: Composite definition of complete remission (CR) and complete remission with partial hematologic recovery (CRh)	Up to 12 months following discontinuation of treatment	To assess the CR (CR+CRh) rate
Phases 1a, 1b, and 2: Event-free survival (EFS)	Up to 12 months following discontinuation of treatment	To assess event-free survival
Phase 1a: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs).	During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.	Assessed by NCI-CTCAE v5.0
Phases 1a, 1b, and 2: Overall survival	Up to 12 months following discontinuation of treatment	To assess overall survival

Trial Locations

Locations (49)

UCLA Bowyer Oncology Center; 🇺🇸 Los Angeles, California, United States

University of Maryland Greenebaum Comprehensive Cancer Center; 🇺🇸 Baltimore, Maryland, United States

University of Southern California; 🇺🇸 Los Angeles, California, United States

Universitat de Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitari i Politecnic La Fe; 🇪🇸 Valencia, Spain

St. George's Hospital; 🇬🇧 London, United Kingdom

Institution Fondazione Policlinico Tor Vergata; 🇮🇹 Roma, Italy

Hospital Universitario Central de Asturias; 🇪🇸 Oviedo, Spain

Hospital Universitario HM Sanchinarro; 🇪🇸 Madrid, Spain

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

UPMC Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

UZ Brussel; 🇧🇪 Jette, Belgium

IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"; 🇮🇹 Meldola, Italy

Beatson West of Scotland Cancer Centre; 🇬🇧 Glasgow, United Kingdom

MD Anderson Cancer Center; 🇪🇸 Madrid, Spain

Hospital Universitario Virgen del Rocio; 🇪🇸 Sevilla, Spain

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Banner MD Anderson Cancer Center; 🇺🇸 Gilbert, Arizona, United States

Indiana University Melvin and Bren Simon Comprehensive Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

University of Michigan Hospitals; 🇺🇸 Ann Arbor, Michigan, United States

Weill Cornell Medical College - NY Presbyterian Hospital; 🇺🇸 New York, New York, United States

Hackensack University Medical Center - John Theurer Cancer Center; 🇺🇸 Hackensack, New Jersey, United States

The Mount Sinai Hospital; 🇺🇸 New York, New York, United States

Duke Cancer Institute; 🇺🇸 Durham, North Carolina, United States

Oklahoma University Health - Stephenson Cancer Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

Vanderbilt-Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

AZ Delta - Campus Rumbeke; 🇧🇪 Roeselare, Belgium

Hopital Maisonneuve-Rosemont; 🇨🇦 Montréal, Quebec, Canada

Hopital de l'Enfant-Jesus - Centre Integre en Cancerologie du CHU de Quebec - Universite Laval; 🇨🇦 Québec, Quebec, Canada

CHU de Quebec - Universite Laval, Hopital de l'Enfant - Jesus; 🇨🇦 Québec, Quebec, Canada

CHU de Lille; 🇫🇷 Lille, France

CHU de Nantes; 🇫🇷 Nantes, France

Hopital Saint Louis; 🇫🇷 Paris, France

Institut Gustave Roussy; 🇫🇷 Villejuif, France

Magendie Hopital Haut-Leveque; 🇫🇷 Pessac, France

Centre Hospitalier Lyon Sud; 🇫🇷 Pierre-Bénite, France

University Medicine Greifswald; 🇩🇪 Greifswald, Germany

Medizinische Hochsschule Hannover; 🇩🇪 Hannover, Germany

Institute of Hematology and Medical Oncology "L. and A. Seragnoli"; 🇮🇹 Bologna, Italy

UO Ematologia Ospedale di Ravenna; 🇮🇹 Ravenna, Italy

Johannes Gutenberg - University Mainz; 🇩🇪 Mainz, Germany

Charitè-Campus Benjamin Franklin; 🇩🇪 Berlin, Germany

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Roswell Park Comprehensive Cancer Center; 🇺🇸 Buffalo, New York, United States

Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Queen Elizabeth II Health Sciences Centre; 🇨🇦 Halifax, Nova Scotia, Canada