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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04067336
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : May 15, 2023
Sponsor:
Information provided by (Responsible Party):
Kura Oncology, Inc.

Study Description
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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.

Condition or disease Intervention/treatment Phase
Advanced Malignant Neoplasm Acute Myeloid Leukemia Mixed Lineage Leukemia Mixed Lineage Acute Leukemia Acute Leukemia of Ambiguous Lineage Mixed Phenotype Acute Leukemia Drug: Ziftomenib Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 199 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 12, 2019
Estimated Primary Completion Date : September 30, 2024
Estimated Study Completion Date : September 30, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase 1a - Dose Escalation Drug: Ziftomenib
Oral administration
Experimental: Phase 1b - Dose-Validation Expansion

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
Oral administration
Experimental: Phase 2
NPM1-m patients will receive the recommended phase 2 dose determined in Phase 1
 Drug: Ziftomenib
Oral administration


Outcome Measures
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Primary Outcome Measures :
  1. Phase 1a: Maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) [ Time Frame: 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.

  2. Phase 1b: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs). [ Time Frame: 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

  3. Phase 1b: Minimal biologically effective dose [ Time Frame: 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

  4. Phase 2: Evidence of anti-leukemia activity [ Time Frame: 12 months following end of treatment ]
    Anti-leukemia activity is assessed by the CR (CR+CRh) rate


Secondary Outcome Measures :
  1. Phase 1a: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs). [ Time Frame: 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

  2. Phase 1a: Tmax [ Time Frame: Cycle 1 and Cycle 2. Each cycle is 28 days. ]
    Time to observed maximum plasma concentration of ziftomenib and/or its metabolites

  3. Phase 1a: AUC(0-last) [ Time Frame: 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

  4. Phase 1a: Cmax [ Time Frame: Cycle 1 and Cycle 2. Each cycle is 28 days. ]
    Maximum plasma concentration of ziftomenib and/or its metabolites

  5. Phases 1a, 1b, and 2: Composite definition of complete remission (CR) and complete remission with partial hematologic recovery (CRh) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess the CR (CR+CRh) rate

  6. Phases 1a, 1b, and 2: Complete response (CR) with and without minimal residual disease (MRD) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess the CR rate with and without MRD

  7. Phases 1a, 1b, and 2: Duration of remission (DOR) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess the DOR

  8. Phases 1a, 1b, and 2: Transfusion independence (TI) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess transfusion independence

  9. Phases 1a, 1b, and 2: Event-free survival (EFS) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess event-free survival

  10. Phases 1a, 1b, and 2: Overall survival [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess overall survival


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

  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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04067336


Contacts
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Contact: Clinical Operations 617 588 3755 KO-MEN-001@kuraoncology.com

Locations
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Sponsors and Collaborators
Kura Oncology, Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Kura Oncology, Inc.
ClinicalTrials.gov Identifier: NCT04067336    
Other Study ID Numbers: KO-MEN-001
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: May 15, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kura Oncology, Inc.:
AML
Hematological malignancy
KMT2A
NPM1
 Menin
MLLr
Leukemia
Acute Leukemia
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Biphenotypic, Acute
Acute Disease
Neoplasms by Histologic Type
Neoplasms
 Disease Attributes
Pathologic Processes
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases