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First in Human Study of KO-539 in Relapsed or Refractory Acute Myeloid Leukemia

Sponsor
Kura Oncology, Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04067336
Collaborator
(none)
60
Enrollment
26
Locations
2
Arms
39.6
Anticipated Duration (Months)
2.3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess ziftomenib (KO-539), a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML).

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

This Phase 1/2a, first-in-human (FIH), open-label, dose-escalation and dose-validation/expansion study will assess ziftomenib (KO-539), a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML).

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

The dose-validation/expansion part of the study (part 1b) will determine the safety, tolerability, and minimal biologically effective dose of ziftomenib (KO-539) in dosing cohorts which have demonstrated early biological activity and have been determined to be safe in the dose-escalation part.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
60 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2A 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 :
Sep 12, 2019
Anticipated Primary Completion Date :
Jun 30, 2022
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1a: Dose-Escalation

Drug: Ziftomenib
Oral administration
Other Names:
  • KO-539

    		•
    Experimental: Part 1b: Dose-Validation Expansion

    Cohort 1: KMT2A-r / NPM1-m patients will receive a dose previously studied in Part 1a Cohort 2: KMT2A-r / NPM1-m patients will receive a dose previously studied in Part 1a

    Drug: Ziftomenib
    Oral administration
    Other Names:
  • KO-539

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Part 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.

    2. Part 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

    3. Part 1b: Minimal biologically effective dose [Up to 6 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

    Secondary Outcome Measures

    1. Part 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

    2. Part 1a: Tmax [Cycle 1 and Cycle 2. Each cycle is 28 days.]

      Time to observed maximum plasma concentration of ziftomenib (KO-539)

    3. Part 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 (KO-539)

    4. Part 1a: Cmax [Cycle 1 and Cycle 2. Each cycle is 28 days.]

      Maximum plasma concentration of ziftomenib (KO-539)

    5. Parts 1a and 1b: Composite definition of complete remission (CR) and complete remission with partial hematologic recovery (CRh) [Up to 6 months following discontinuation of treatment]

      To assess the CR (CR+CRh) rate

    6. Parts 1a and 1b: Complete response (CR) with and without minimal residual disease (MRD) [Up to 6 months following discontinuation of treatment]

      To assess the CR rate with and without MRD

    7. Parts 1a and 1b: Duration of remission (DOR) [Up to 6 months following discontinuation of treatment]

      To assess the DOR

    8. Part 1b: Transfusion independence (TI) [Up to 6 months following discontinuation of treatment]

      To assess transfusion independence

    9. Part 1b: Relapse-free survival (RFS) [Up to 6 months following discontinuation of treatment]

      To assess relapse-free survival

    10. Part 1b: Overall survival [Up to 12 months following discontinuation of treatment]

      To assess overall survival

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria (Parts 1a and 1b):

    1. 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.

    2. ≥ 18 years of age.

    3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

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

    5. Peripheral white blood cell (WBC) counts ≤ 30,000/μL.

    6. Women of childbearing potential must be willing to use a highly effective method of contraception throughout the study and for at least 187 days after the last dose of study treatment.

    7. Males with female partners of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 97 days after the last dose of study treatment.

    In Part 1b Dose-Validation /Cohort Expansion, patient must have documented specific genetic subtypes determined by testing and defined as either KMT2A-r or NPM1-m.

    Key Exclusion Criteria (Parts 1a and 1b):

    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 (i.e. ANC >1,000 and platelet count > 100,000).

    6. Receiving immunosuppressive therapy post HSCT at the time of screening (must be off all immunosuppression therapy for at least 2 weeks).

    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, or 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 (KO-539) or within 5 drug half-lives (whichever is longer) prior to the first dose of study drug.

    9. 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.

    10. Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection.

    11. Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection.

    12. 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

    1. 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.

    1. Mean QTcF >480 ms on triplicate ECG.

    2. Major surgery within 4 weeks prior to the first dose of study treatment.

    3. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Banner MD Anderson Cancer Center Gilbert Arizona United States 85234
    2 Mayo Clinic Phoenix Arizona United States 85054
    3 UCLA Bowyer Oncology Center Los Angeles California United States 90095
    4 Mayo Clinic Jacksonville Florida United States 32224
    5 Northwestern University Chicago Illinois United States 60611
    6 Indiana University Melvin and Bren Simon Comprehensive Cancer Center Indianapolis Indiana United States 46202
    7 University of Maryland Greenebaum Comprehensive Cancer Center Baltimore Maryland United States 21201
    8 Massachusetts General Hospital Boston Massachusetts United States 02114
    9 University of Michigan Hospitals Ann Arbor Michigan United States 48109
    10 Karmanos Cancer Institute Detroit Michigan United States 48201
    11 Mayo Clinic Rochester Minnesota United States 55905
    12 Roswell Park Comprehensive Cancer Center Buffalo New York United States 14203
    13 The Mount Sinai Hospital New York New York United States 10029
    14 Duke Cancer Institute Durham North Carolina United States 27710
    15 UPMC Hillman Cancer Center Pittsburgh Pennsylvania United States 15232
    16 Vanderbilt-Ingram Cancer Center Nashville Tennessee United States 37232
    17 Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center Dallas Texas United States 75390
    18 MD Anderson Cancer Center Houston Texas United States 77030
    19 Fred Hutchinson Cancer Research Center Seattle Washington United States 98109
    20 Hopital Saint Louis Paris France 75475
    21 Institut Gustave Roussy Villejuif France 94800
    22 Hospital Universitari Vall d'Hebron Barcelona Spain 08035
    23 Universitat de Barcelona Barcelona Spain 08035
    24 MD Anderson Cancer Center Madrid Spain 28033
    25 Hospital Universitario Central de Asturias Oviedo Spain 33011
    26 Hospital Universitari i Politecnic La Fe Valencia Spain 46026

    Sponsors and Collaborators

    • Kura Oncology, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Kura Oncology, Inc.
    ClinicalTrials.gov Identifier:
    NCT04067336
    Other Study ID Numbers:
    • KO-MEN-001
    First Posted:
    Aug 26, 2019
    Last Update Posted:
    May 2, 2022
    Last Verified:
    Apr 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    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:
    Leukemia
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute
    Leukemia, Biphenotypic, Acute
    Acute Disease

    Study Results

    No Results Posted as of May 2, 2022