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

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ClinicalTrials.gov Identifier: NCT04067336
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : March 15, 2024
Sponsor:
Information provided by (Responsible Party):
Kura Oncology, Inc.

Tracking Information
First Submitted Date  ICMJE June 25, 2019
First Posted Date  ICMJE August 26, 2019
Last Update Posted Date March 15, 2024
Actual Study Start Date  ICMJE September 12, 2019
Estimated Primary Completion Date September 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 23, 2023)
  • 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.
  • 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
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: August 22, 2019)
Determine the maximal tolerated dose (MTD) of KO-539 mono-therapy in 28-day cycle. [ Time Frame: DLTs will be evaluated during the first 28 days (1 cycle) of KO-539 mono-therapy and during subsequent cycles until approximately 28 days after last dose (End of Study), on average 3 to 6 months. ]
MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2023)
  • 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
  • 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
  • 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
  • Phase 1a: Cmax [ Time Frame: 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) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess the CR (CR+CRh) rate
  • 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
  • Phases 1a, 1b, and 2: Duration of remission (DOR) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess the DOR
  • Phases 1a, 1b, and 2: Transfusion independence (TI) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess transfusion independence
  • Phases 1a, 1b, and 2: Event-free survival (EFS) [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess event-free survival
  • Phases 1a, 1b, and 2: Overall survival [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess overall survival
Original Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2019)
  • 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. ]
    Adverse Events (AEs) and Serious Adverse Events (SAEs) will be graded according to the NCI-CTCAE v5.01.
  • Maximum observed plasma concentration (Cmax) of KO-539. [ Time Frame: Blood samples for determination of KO-539 concentration will be collected in Cycle 1 and Cycle 2. Each cycle is 28 days. ]
    Determine Cmax of KO-539.
  • Time to reach maximum observed concentration (Tmax). [ Time Frame: Blood samples for determination of KO-539 concentration will be collected in Cycle 1 and Cycle 2. Each cycle is 28 days. ]
    Determine Tmax of KO-539.
  • Area under plasma-concentration time curve from time 0 to time of last quantifiable concentration (AUC(0-last)). [ Time Frame: Blood samples for determination of KO-539 concentration will be collected in Cycle 1 and Cycle 2. Each cycle is 28 days. ]
    Determine AUC(0-last) of KO-539.
  • Early evidence of antitumor activity. [ Time Frame: Up to 6 months following end of treatment. ]
    Antitumor activity will be assessed according to the criteria proposed by the 2017 European Leukemia Network (ELN).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia
Official Title  ICMJE 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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Malignant Neoplasm
  • Acute Myeloid Leukemia
  • Mixed Lineage Leukemia
  • Mixed Lineage Acute Leukemia
  • Acute Leukemia of Ambiguous Lineage
  • Mixed Phenotype Acute Leukemia
Intervention  ICMJE Drug: Ziftomenib
Oral administration
Study Arms  ICMJE
  • Experimental: Phase 1a - Dose Escalation
    Intervention: Drug: Ziftomenib
  • 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

    Intervention: Drug: Ziftomenib
  • Experimental: Phase 2
    NPM1-m patients will receive the recommended phase 2 dose determined in Phase 1
    Intervention: Drug: Ziftomenib
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 23, 2023)
199
Original Estimated Enrollment  ICMJE
 (submitted: August 22, 2019)
30
Estimated Study Completion Date  ICMJE September 30, 2025
Estimated Primary Completion Date September 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Clinical Operations 858 500 8800 KO-MEN-001@kuraoncology.com
Listed Location Countries  ICMJE Belgium,   Canada,   France,   Germany,   Italy,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04067336
Other Study ID Numbers  ICMJE KO-MEN-001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Current Responsible Party Kura Oncology, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Kura Oncology, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Kura Oncology, Inc.
Verification Date March 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP