First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04067336
• Other study ID #: KO-MEN-001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 12, 2019
• Est. completion date: September 30, 2025

Study information

• Verified date: March 2024
• Source: Kura Oncology, Inc.
• Contact: Clinical Operations
• Phone: 858 500 8800
• Email: KO-MEN-001[@]kuraoncology.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

This Phase 1/2, first-in-human (FIH), open-label, 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). The dose-escalation part of the study (Phase 1a) will determine the maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D). The dose-validation/expansion part of the study (Phase 1b) will determine the safety, tolerability, and minimal biologically effective dose of ziftomenib in dosing cohorts which have demonstrated early biological activity and have been determined to be safe in the dose-escalation phase. The Phase 2 portion of the study will determine the safety, tolerability, and anti-leukemia activity of ziftomenib in patients with NPM1-m AML.

Recruitment information / eligibility

• 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.

Related Conditions & MeSH terms

• Acute Disease
• Acute Leukemia of Ambiguous Lineage
• Acute Myeloid Leukemia
• Advanced Malignant Neoplasm
• Leukemia
• Leukemia, Biphenotypic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Mixed Lineage Acute Leukemia
• Mixed Lineage Leukemia
• Mixed Phenotype Acute Leukemia

Intervention

Drug:
• Ziftomenib
Oral administration

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Kura Oncology, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Italy,  Spain,  United Kingdom, 

Outcome

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