Clinical Trials /

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

NCT04067336

Description:

This first-in-human (FIH) dose escalation 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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: KO-MEN-001
  • NCT ID: NCT04067336

Conditions

  • Advanced Malignant Neoplasm

Interventions

DrugSynonymsArms
KO-539KO-539

Purpose

This first-in-human (FIH) dose escalation 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.

Detailed Description

      This Phase 1, 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
      specific genetic subgroups is planned following determination of the MTD/RP2D. KO-539 will be
      administered as a once daily oral dose in 28 continuous day cycles.
    

Trial Arms

NameTypeDescriptionInterventions
KO-539Experimentaldose escalation study - capsules
  • KO-539

Eligibility Criteria

        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 organ function: creatinine ≤ 2.0 × upper limit of normal (ULN); serum
             bilirubin ≤ 1.5 × ULN; aspartate aminotransferase and alanine aminotransferase ≤ 2.0 ×
             ULN.

          6. Adequate renal function: creatinine clearance (CLcr) ≥ 60 mL/min using the
             Cockcroft-Gault equation.

          7. 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.

          8. 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 or QTcB of >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,
             https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf.

         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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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

Measure: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.
Safety Issue:
Description:Adverse Events (AEs) and Serious Adverse Events (SAEs) will be graded according to the NCI-CTCAE v5.01.
Measure: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.
Safety Issue:
Description:Determine Cmax of KO-539.
Measure: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.
Safety Issue:
Description:Determine Tmax of KO-539.
Measure: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.
Safety Issue:
Description:Determine AUC(0-last) of KO-539.
Measure:Early evidence of antitumor activity.
Time Frame:Up to 6 months following end of treatment.
Safety Issue:
Description:Antitumor activity will be assessed according to the criteria proposed by the 2017 European Leukemia Network (ELN).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Kura Oncology, Inc.

Trial Keywords

  • AML
  • Hematological malignancy
  • KMT2A
  • NPM1

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