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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2 First in Human Study of the Menin-MLL(KMT2A) Inhibitor KO-539 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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Mixed Phenotype Acute Leukemia, Advanced Malignant Neoplasm, Acute Myeloid Leukemia, Mixed Lineage Leukemia, Mixed Lineage Acute Leukemia, Acute Leukemia of Ambiguous Lineage

Intervention / Treatment
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* Drug: Ziftomenib


Participation Criteria
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Eligibility Criteria
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Key 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. Phase 1b: Patients with a documented lysine[K]-specific methyltransferase 2-rearrangement (KMT2A-r), or Patients with a documented nucleophosmin 1 mutation (NPM1-m) Phase 2: a. Patients with a documented nucleophosmin 1 mutation (NPM1-m) ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 2 months. Adequate liver and kidney function according to protocol requirements. Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receive hydroxyurea to control and maintain white blood cell count prior to enrollment. 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. 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: Diagnosis of acute promyelocytic leukemia. Diagnosis of chronic myelogenous leukemia in blast crisis. Donor lymphocyte infusion < 30 days prior to study entry. Clinically active central nervous system (CNS) leukemia. Undergone HSCT and have not had adequate hematologic recovery. Receiving immunosuppressive therapy post HSCT within 2 weeks of Cycle 1 Day 1. Grade ≥ 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity. 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. 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. 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. 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. 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). Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection. 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. Mean QTcF >480 ms on triplicate ECG. Major surgery within 4 weeks prior to the first dose of study treatment. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a - Dose Escalation<br> | Drug: Ziftomenib<br>* Oral administration<br>|
| Experimental: Phase 1b - Dose-Validation Expansion<br>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 | Drug: Ziftomenib<br>* Oral administration<br>|
| Experimental: Phase 2<br>NPM1-m patients will receive the recommended phase 2 dose determined in Phase 1 | Drug: Ziftomenib<br>* Oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Hematological malignancy, KMT2A, NPM1, Menin, MLLr, Leukemia, Acute Leukemia