Description:
This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess
KO-539, a menin-MLL(KMT2A) inhibitor, in patients with refractory or relapsed acute myeloid
leukemia (AML).
Title
- Brief Title: First in Human Study of KO-539 in Relapsed or Refractory Acute Myeloid Leukemia
- 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
Clinical Trial IDs
- ORG STUDY ID:
KO-MEN-001
- NCT ID:
NCT04067336
Conditions
- Advanced Malignant Neoplasm
- Acute Myeloid Leukemia
- Mixed Lineage Leukemia
- Mixed Lineage Acute Leukemia
- Acute Leukemia of Ambiguous Lineage
- Mixed Phenotype Acute Leukemia
Interventions
Drug | Synonyms | Arms |
---|
KO-539 | | KO-539 |
Purpose
This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess
KO-539, a menin-MLL(KMT2A) inhibitor, in patients with refractory or relapsed acute myeloid
leukemia (AML).
Detailed Description
This Phase 1/2a, first-in-human (FIH), open-label, dose-escalation and
dose-validation/expansion study will assess KO-539, a menin-MLL(KMT2A) inhibitor, in patients
with refractory or relapsed acute myeloid leukemia (AML). The dose-escalation part of the
study (part 1a) will determine the maximal tolerated dose (MTD). The
dose-validation/expansion part of the study (part 1b) will determine the safety,
tolerability, and minimal biologically effective dose of KO-539 in dosing cohorts which have
demonstrated early biological activity and have been determined to be safe as part of the
dose-escalation part.
Trial Arms
Name | Type | Description | Interventions |
---|
KO-539 | Experimental | Part 1a: Dose Escalation
Part 1b: Dose-Validation/Expansion
Cohort 1: KMT2A/NPM1 patients will receive a dose previously studied in Part 1a
Cohort 2: KMT2A/NPM1 patients will receive a dose previously studied in Part 1a | |
Eligibility Criteria
Key Inclusion Criteria:
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. Patients are allowed to receive
hydroxyurea to control and maintain WBC count prior to enrollment.
6. Both men and women (of childbearing potential) enrolled in this trial must use
adequate birth control measures during the course of the trial and for at least 90
days after their last dose of study treatment.
Key Exclusion Criteria:
1. Donor lymphocyte infusion < 30 days prior to study entry.
2. Clinically active central nervous system (CNS) leukemia.
3. Undergone HSCT and have not had adequate hematologic recovery (i.e. ANC >1000 and
platelet count > 100,000).
4. Receiving immunosuppressive therapy post HSCT at the time of screening (must be off
all immunosuppression therapy for at least 2 weeks). The use of topical steroids for
cutaneous GVHD is allowed and stable steroid doses less than or equal to 20 mg of
prednisone daily is permitted.
5. Grade > 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic
GVHD, or extensive chronic GVHD of any severity.
6. 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.
7. 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.
8. Known detectable viral load for human immunodeficiency virus, hepatitis C, or
hepatitis B surface antigen indicative of active infection.
9. Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other
infection.
10. 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.
11. QTcF >480 ms.
12. Major surgery within 4 weeks prior to the first dose of study treatment.
13. Women who are pregnant or lactating. All female patients with reproductive potential
must have a negative pregnancy test prior to starting treatment.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Part 1a: Maximal tolerated dose (MTD). |
Time Frame: | Dose Limiting Toxicities (DLTs) will be evaluated during the first 28 days (1 cycle) |
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: | Part 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. |
Safety Issue: | |
Description: | Assessed by NCI-CTCAE v5.0 |
Measure: | Part 1a: Tmax |
Time Frame: | Cycle 1 and Cycle 2. Each cycle is 28 days. |
Safety Issue: | |
Description: | Time to observed maximum plasma concentration of KO-539 |
Measure: | Part 1a: AUC(0-last) |
Time Frame: | Cycle 1 and Cycle 2. Each cycle is 28 days. |
Safety Issue: | |
Description: | Area under the plasma concentration-time curve from time 0 to time of last measurable concentration of KO-539 |
Measure: | Part 1a: Cmax |
Time Frame: | Cycle 1 and Cycle 2. Each cycle is 28 days. |
Safety Issue: | |
Description: | Maximum plasma concentration of KO-539 |
Measure: | Parts 1a and 1b: Composite definition of complete remission (CR) and complete remission with partial hematologic recovery (CRh) |
Time Frame: | Up to 6 months following discontinuation of treatment |
Safety Issue: | |
Description: | To assess the CR (CR+CRh) rate |
Measure: | Parts 1a and 1b: Complete response (CR) with and without minimal residual disease (MRD) |
Time Frame: | Up to 6 months following discontinuation of treatment |
Safety Issue: | |
Description: | To assess the CR rate with and without MRD |
Measure: | Parts 1a and 1b: Duration of remission (DOR) |
Time Frame: | Up to 6 months following discontinuation of treatment |
Safety Issue: | |
Description: | To assess the DOR |
Measure: | Part 1b: Transfusion independence (TI) |
Time Frame: | Up to 6 months following discontinuation of treatment |
Safety Issue: | |
Description: | To assess transfusion independence |
Measure: | Part 1b: Relapse-free survival (RFS) |
Time Frame: | Up to 6 months following discontinuation of treatment |
Safety Issue: | |
Description: | To assess relapse-free survival |
Measure: | Part 1b: Overall survival |
Time Frame: | Up to 6 months following discontinuation of treatment |
Safety Issue: | |
Description: | To assess overall survival |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Kura Oncology, Inc. |
Trial Keywords
- AML
- Hematological malignancy
- KMT2A
- NPM1
- Menin
- MLLr
- Leukemia
- Acute Leukemia
Last Updated
August 24, 2021