First in Human Study of KO-539 in Relapsed or Refractory Acute Myeloid Leukemia
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| ClinicalTrials.gov Identifier: NCT04067336 |
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Recruitment Status :
Recruiting
First Posted : August 26, 2019
Last Update Posted : May 2, 2022
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Sponsor:
Kura Oncology, Inc.
Information provided by (Responsible Party):
Kura Oncology, Inc.
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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 |
|---|---|---|
| Advanced Malignant Neoplasm Acute Myeloid Leukemia Mixed Lineage Leukemia Mixed Lineage Acute Leukemia Acute Leukemia of Ambiguous Lineage Mixed Phenotype Acute Leukemia | Drug: Ziftomenib | Phase 1 Phase 2 |
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 Type : | Interventional (Clinical Trial) |
| Estimated 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 : | September 12, 2019 |
| Estimated Primary Completion Date : | June 30, 2022 |
| Estimated Study Completion Date : | December 31, 2022 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Familial acute myeloid leukemia with mutated CEBPA
Cytogenetically normal acute myeloid leukemia
Core binding factor acute myeloid leukemia
| Arm | Intervention/treatment |
|---|---|
| Experimental: Part 1a: Dose-Escalation |
Drug: Ziftomenib
Oral administration
Other Name: KO-539 |
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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 Name: KO-539 |
Primary Outcome Measures :
- Part 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.
- Part 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
- Part 1b: Minimal biologically effective dose [ Time Frame: 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 :
- 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. ]Assessed by NCI-CTCAE v5.0
- Part 1a: Tmax [ Time Frame: Cycle 1 and Cycle 2. Each cycle is 28 days. ]Time to observed maximum plasma concentration of ziftomenib (KO-539)
- Part 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 (KO-539)
- Part 1a: Cmax [ Time Frame: Cycle 1 and Cycle 2. Each cycle is 28 days. ]Maximum plasma concentration of ziftomenib (KO-539)
- 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 ]To assess the CR (CR+CRh) rate
- Parts 1a and 1b: Complete response (CR) with and without minimal residual disease (MRD) [ Time Frame: Up to 6 months following discontinuation of treatment ]To assess the CR rate with and without MRD
- Parts 1a and 1b: Duration of remission (DOR) [ Time Frame: Up to 6 months following discontinuation of treatment ]To assess the DOR
- Part 1b: Transfusion independence (TI) [ Time Frame: Up to 6 months following discontinuation of treatment ]To assess transfusion independence
- Part 1b: Relapse-free survival (RFS) [ Time Frame: Up to 6 months following discontinuation of treatment ]To assess relapse-free survival
- Part 1b: Overall survival [ Time Frame: Up to 12 months following discontinuation of treatment ]To assess overall survival
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Key Inclusion Criteria (Parts 1a and 1b):
- 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.
- ≥ 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- Adequate liver and kidney function according to protocol requirements.
- Peripheral white blood cell (WBC) counts ≤ 30,000/μL.
- 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.
- 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):
- Diagnosis of acute promyelocytic leukemia.
- Diagnosis of chronic myelogenous leukemia in blast crisis.
- Donor lymphocyte infusion < 30 days prior to study entry.
- Clinically active central nervous system (CNS) leukemia.
- Undergone HSCT and have not had adequate hematologic recovery (i.e. ANC >1,000 and platelet count > 100,000).
- Receiving immunosuppressive therapy post HSCT at the time of screening (must be off all immunosuppression therapy for at least 2 weeks).
- Grade ≥ 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.
- 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.
- 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.
- Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection.
- Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection.
- 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.
- Mean QTcF >480 ms on triplicate ECG.
- Major surgery within 4 weeks prior to the first dose of study treatment.
- Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
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 ClinicalTrials.gov identifier (NCT number): NCT04067336
Contacts
| Contact: Mary Pevear | 781-346-9905 | mpevear@kuraoncology.com | |
| Contact: Mollie Leoni, MD | 617-302-9755 | mleoni@kuraoncology.com |
Locations
Show 26 study locations
Sponsors and Collaborators
Kura Oncology, Inc.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Kura Oncology, Inc. |
| ClinicalTrials.gov Identifier: | NCT04067336 |
| Other Study ID Numbers: |
KO-MEN-001 |
| First Posted: | August 26, 2019 Key Record Dates |
| Last Update Posted: | May 2, 2022 |
| Last Verified: | April 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| 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.:
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AML Hematological malignancy KMT2A NPM1 |
Menin MLLr Leukemia Acute Leukemia |
Additional relevant MeSH terms:
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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Leukemia, Biphenotypic, Acute Acute Disease Neoplasms by Histologic Type Neoplasms |
Disease Attributes Pathologic Processes Leukemia, Lymphoid Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases |