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First in Human Study of KO-539 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. Identifier: NCT04067336
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : January 19, 2021
Information provided by (Responsible Party):
Kura Oncology, Inc.

Brief Summary:
This first-in-human (FIH) dose escalation and dose expansion study will determine the maximum tolerated dose (MTD) of KO-539, a menin-MLL(KMT2A) inhibitor, in patients with refractory or relapsed AML who have failed or are ineligible for any approved standard of care therapies, including HSCT.

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: KO-539 Phase 1 Phase 2

Detailed Description:
This Phase 1/2a, first-in-human (FIH), open-label, dose-escalation study of KO-539, a menin-MLL(KMT2A) inhibitor, will determine the safety and tolerability of escalating doses using a modified toxicity probability interval (mTPI) adaptive design when administered to patients with relapsed and/or refractory AML. If an maximum tolerated dose (MTD) cannot be identified, a recommended phase 2 dose (RP2D) will be determined. A expansion phase in patients with NPM1m and KMT2A-r R/R AML patients is planned following determination of the MTD/RP2D. KO-539 will be administered as a once daily oral dose in 28 continuous day cycles.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group 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 : September 12, 2019
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : August 1, 2022

Arm Intervention/treatment
Experimental: KO-539

Phase 1 Dose escalation - R/R AML

Phase 2A Dose Expansion Cohort 1- KMT2Ar R/R AML Cohort 2- NPM1m R/R AML

Drug: KO-539
Oral administration

Primary Outcome Measures :
  1. To determine the maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of KO-539 in patients with relapsed or refractory acute myeloid leukemia (AML) [ Time Frame: DLTs will be evaluated during the first 28 days (1 cycle) of KO-539 mono-therapy ]
    MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients.

Secondary Outcome Measures :
  1. 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.

  2. Early evidence of antileukemic activity according to 2017 European Leukemia Network (ELN) [ Time Frame: Up to 6 months following end of treatment. ]

    Key Secondary:

    • Complete remission (CR) with and without minimal residual disease (MRD)
    • Complete remission with incomplete hematology recovery (CRi)
    • Duration of remission (DOR) at 6 months

  3. 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.

  4. 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.

  5. 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.

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

Inclusion Criteria:

  1. Refractory or relapsed AML defined as the reappearance of > 5% blasts in the bone marrow and who have failed or are ineligible for any approved standard of care therapies, including HSCT.
  2. ≥ 18 years of age.
  3. Read, understood, and provided written informed consent and, if applicable, Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained and must be willing to comply with all study requirements and procedures including serial bone marrow and peripheral blood sampling.
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
  5. Adequate liver and kidney function
  6. Hydroxyurea will be allowed prior to enrollment and after the start of KO-539 to control and maintain peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients can continue on hydroxyurea through Cycle 1 Day 28 or until first disease assessment. After which, patients should be titrated off therapy.
  7. Both men and women enrolled in this trial must use adequate birth control measures during the course of the trial and for at least 28 days or hematologic recovery whichever is longest after discontinuing study treatment. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.

Exclusion Criteria:

  1. Patient has a diagnosis of acute promyelocytic leukemia.
  2. Patient has a diagnosis of chronic myelogenous leukemia in blast crisis.
  3. Donor lymphocyte infusion < 30 days prior to study entry.
  4. WBC count > 30,000/mm3.
  5. Clinically active central nervous system (CNS) leukemia.
  6. Patients who have undergone HSCT and have not had adequate hematologic recovery (i.e. ANC >1000 and platelet count > 100K) or patients on immunosuppressive therapy post HSCT at the time of screening (must be off all immunosuppression therapy for at least 2 weeks), or with Grade > 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity. The use of topical steroids for cutaneous GVHD is allowed and stable steroid doses less than or equal to 10 mg of prednisone daily is permitted with Medical Monitor approval.
  7. Patient has 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 KO-539 or within 5 drug half-lives (whichever is longer) prior to the first dose of study drug. Patients must have recovered to NCI CTCAE v. 5.01 ≤ Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the Investigator.
  8. Patient requires 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.
  9. Patient has a known positive test for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection.
  10. Patient has a 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).
  11. Patient has an 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 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.
  13. Mean QTcF >480 ms on triplicate electrocardiograms (ECGs) performed within 5 minutes of each other as a guide to known drugs associated with QTc prolongation, please refer to the following Credible Meds web page for a list of drugs that prolong QT and/or cause torsades de pointes,
  14. Major surgery within 4 weeks prior to the first dose of study treatment. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and patients should be recovered.
  15. Underlying medical condition that, in the Principal Investigator's opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or adverse events (AEs).
  16. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
  17. Known alcohol or drug abuse or dependence.

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 identifier (NCT number): NCT04067336

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Contact: Diana Hummel 617-588-2609
Contact: Bridget Martell, MD 858-500-8852

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United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 40411
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Christine Connolly   
United States, Michigan
University of Michigan Hospitals Recruiting
Ann Arbor, Michigan, United States, 48109
Contact    800-865-1125   
United States, New York
Roswell Park Comprehensive Cancer Center Recruiting
Buffalo, New York, United States, 14263
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Rachel Abramowicz   
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109
Contact: Kaysey Orlowski   
Hopital Saint Louis Recruiting
Paris, France, 75475
Institut Gustave Roussy Recruiting
Villejuif, France, 94800
Sponsors and Collaborators
Kura Oncology, Inc.
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Responsible Party: Kura Oncology, Inc. Identifier: NCT04067336    
Other Study ID Numbers: KO-MEN-001
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: January 19, 2021
Last Verified: January 2021
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.:
Hematological malignancy
Acute Leukemia
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Biphenotypic, Acute
Acute Disease
Neoplasms by Histologic Type
Disease Attributes
Pathologic Processes
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases