Acute Myeloid Leukemia Clinical Trial
Official title:
A Phase 1/2 First in Human Study of the Menin-MLL(KMT2A) Inhibitor KO-539 in Patients With Relapsed or Refractory Acute Myeloid Leukemia
This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML) as part of Phase 1. In Phase 2, assessment of ziftomenib will continue in patients with NPM1-m AML.
Status | Recruiting |
Enrollment | 199 |
Est. completion date | September 30, 2025 |
Est. primary completion date | September 30, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Key Inclusion Criteria: Patients with 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. 1. Phase 1b: 1. Patients with a documented lysine[K]-specific methyltransferase 2-rearrangement (KMT2A-r), or 2. Patients with a documented nucleophosmin 1 mutation (NPM1-m) 2. Phase 2: a. Patients with a documented nucleophosmin 1 mutation (NPM1-m) 3. = 18 years of age. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 2 months. 5. Adequate liver and kidney function according to protocol requirements. 6. Peripheral white blood cell (WBC) counts = 30,000/µL. Patients may receive hydroxyurea to control and maintain white blood cell count prior to enrollment. 7. Women of childbearing potential must be willing to use a highly effective method of contraception throughout the study and for at least 180 days after the last dose of study treatment. 8. Males with female partners of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 90 days after the last dose of study treatment. Key Exclusion Criteria: 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. 6. Receiving immunosuppressive therapy post HSCT within 2 weeks of Cycle 1 Day 1. 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, 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 or within 5 drug half-lives prior to the first dose of study drug. 9. Not recovered to < Grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) from all acute toxicities or deemed back to a stable baseline. 10. 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. 11. Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection. Patients with controlled disease will not be excluded from study enrollment. 12. 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). 13. Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection. 14. 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. 15. Mean QTcF >480 ms on triplicate ECG. 16. Major surgery within 4 weeks prior to the first dose of study treatment. 17. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative serum pregnancy test within 72 hours prior to starting treatment. |
Country | Name | City | State |
---|---|---|---|
Belgium | UZ Brussel | Jette | |
Belgium | AZ Delta - Campus Rumbeke | Roeselare | |
Canada | Queen Elizabeth II Health Sciences Centre | Halifax | Nova Scotia |
Canada | Hopital Maisonneuve-Rosemont | Montréal | Quebec |
Canada | CHU de Quebec - Universite Laval, Hopital de l'Enfant - Jesus | Québec | Quebec |
Canada | Hopital de l'Enfant-Jesus - Centre Integre en Cancerologie du CHU de Quebec - Universite Laval | Québec | Quebec |
France | CHU de Lille | Lille | |
France | CHU de Nantes | Nantes | |
France | Hopital Saint Louis | Paris | |
France | Magendie Hopital Haut-Leveque | Pessac | |
France | Centre Hospitalier Lyon Sud | Pierre-Bénite | |
France | Institut Gustave Roussy | Villejuif | |
Germany | Charitè-Campus Benjamin Franklin | Berlin | |
Germany | University Medicine Greifswald | Greifswald | |
Germany | Medizinische Hochsschule Hannover | Hannover | |
Germany | Johannes Gutenberg - University Mainz | Mainz | |
Italy | Institute of Hematology and Medical Oncology "L. and A. Seragnoli" | Bologna | |
Italy | IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" | Meldola | |
Italy | UO Ematologia Ospedale di Ravenna | Ravenna | |
Italy | Institution Fondazione Policlinico Tor Vergata | Roma | |
Spain | Hospital Universitari Vall d'Hebron | Barcelona | |
Spain | Universitat de Barcelona | Barcelona | |
Spain | Hospital Universitario HM Sanchinarro | Madrid | |
Spain | MD Anderson Cancer Center | Madrid | |
Spain | Hospital Universitario Central de Asturias | Oviedo | |
Spain | Hospital Universitario Virgen del Rocio | Sevilla | |
Spain | Hospital Universitari i Politecnic La Fe | Valencia | |
United Kingdom | Beatson West of Scotland Cancer Centre | Glasgow | |
United Kingdom | St. George's Hospital | London | |
United States | University of Michigan Hospitals | Ann Arbor | Michigan |
United States | University of Maryland Greenebaum Comprehensive Cancer Center | Baltimore | Maryland |
United States | Massachusetts General Hospital | Boston | Massachusetts |
United States | Roswell Park Comprehensive Cancer Center | Buffalo | New York |
United States | Northwestern University | Chicago | Illinois |
United States | Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center | Dallas | Texas |
United States | Karmanos Cancer Institute | Detroit | Michigan |
United States | Duke Cancer Institute | Durham | North Carolina |
United States | Banner MD Anderson Cancer Center | Gilbert | Arizona |
United States | Hackensack University Medical Center - John Theurer Cancer Center | Hackensack | New Jersey |
United States | MD Anderson Cancer Center | Houston | Texas |
United States | Indiana University Melvin and Bren Simon Comprehensive Cancer Center | Indianapolis | Indiana |
United States | Mayo Clinic | Jacksonville | Florida |
United States | UCLA Bowyer Oncology Center | Los Angeles | California |
United States | University of Southern California | Los Angeles | California |
United States | Vanderbilt-Ingram Cancer Center | Nashville | Tennessee |
United States | The Mount Sinai Hospital | New York | New York |
United States | Weill Cornell Medical College - NY Presbyterian Hospital | New York | New York |
United States | Oklahoma University Health - Stephenson Cancer Center | Oklahoma City | Oklahoma |
United States | Mayo Clinic | Phoenix | Arizona |
United States | UPMC Hillman Cancer Center | Pittsburgh | Pennsylvania |
United States | Mayo Clinic | Rochester | Minnesota |
United States | Fred Hutchinson Cancer Research Center | Seattle | Washington |
Lead Sponsor | Collaborator |
---|---|
Kura Oncology, Inc. |
United States, Belgium, Canada, France, Germany, Italy, Spain, United Kingdom,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Phase 1a: Maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) | MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients. | Dose Limiting Toxicities (DLTs) will be evaluated during the first 28 days (1 cycle) | |
Primary | Phase 1b: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs). | Assessed by NCI-CTCAE v5.0 | During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first. | |
Primary | Phase 1b: Minimal biologically effective dose | 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 | Up to 12 months following end of treatment | |
Primary | Phase 2: Evidence of anti-leukemia activity | Anti-leukemia activity is assessed by the CR (CR+CRh) rate | 12 months following end of treatment | |
Secondary | Phase 1a: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs). | Assessed by NCI-CTCAE v5.0 | During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first. | |
Secondary | Phase 1a: Tmax | Time to observed maximum plasma concentration of ziftomenib and/or its metabolites | Cycle 1 and Cycle 2. Each cycle is 28 days. | |
Secondary | Phase 1a: AUC(0-last) | Area under the plasma concentration-time curve from time 0 to time of last measurable concentration of ziftomenib and/or its metabolites | Cycle 1 and Cycle 2. Each cycle is 28 days. | |
Secondary | Phase 1a: Cmax | Maximum plasma concentration of ziftomenib and/or its metabolites | Cycle 1 and Cycle 2. Each cycle is 28 days. | |
Secondary | Phases 1a, 1b, and 2: Composite definition of complete remission (CR) and complete remission with partial hematologic recovery (CRh) | To assess the CR (CR+CRh) rate | Up to 12 months following discontinuation of treatment | |
Secondary | Phases 1a, 1b, and 2: Complete response (CR) with and without minimal residual disease (MRD) | To assess the CR rate with and without MRD | Up to 12 months following discontinuation of treatment | |
Secondary | Phases 1a, 1b, and 2: Duration of remission (DOR) | To assess the DOR | Up to 12 months following discontinuation of treatment | |
Secondary | Phases 1a, 1b, and 2: Transfusion independence (TI) | To assess transfusion independence | Up to 12 months following discontinuation of treatment | |
Secondary | Phases 1a, 1b, and 2: Event-free survival (EFS) | To assess event-free survival | Up to 12 months following discontinuation of treatment | |
Secondary | Phases 1a, 1b, and 2: Overall survival | To assess overall survival | Up to 12 months following discontinuation of treatment |
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