First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia (NCT04067336) — USA Trial Details

Condition(s) studied

Advanced Malignant NeoplasmAcute Myeloid LeukemiaMixed Lineage LeukemiaMixed Lineage Acute LeukemiaAcute Leukemia of Ambiguous LineageMixed Phenotype Acute LeukemiaAcute Lymphoblastic Leukemia

Investigational drug(s) / intervention(s)

ZiftomenibMidazolamItraconazole

Ziftomenib: Oral administration

Midazolam: Oral administration

Itraconazole: Oral administration

Study summary

In this trial, ziftomenib, a menin-MLL(KMT2A) inhibitor, will be tested in patients for the first time. The trial includes a Main Study and four sub-studies. In the Main Study (including Phase 1a, Phase 1b, and Phase 2 portions), ziftomenib will be evaluated in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The main study has completed enrollment.

In Sub-studies 1 and 2, the effects of taking ziftomenib and other common drugs at the same time will be investigated in AML patients. In Sub-study 3, ziftomenib will be evaluated in patients with R/R acute lymphoblastic leukemia (ALL). In Sub-study 4, ziftomenib will be evaluated in patients with R/R AML with certain genetic mutations.

Eligibility

Sex

ALL

Min age

18 Years

Max age

—

Healthy volunteers

No

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: * Patients with a documented lysine\[K\]-specific methyltransferase 2-rearrangement (KMT2A-r), or * Patients with a documented nucleophosmin 1 mutation (NPM1-m) 2. Phase 2: * Patients with a documented nucleophosmin 1 mutation (NPM1-m) 3. Sub-studies: * Sub-studies 1 and 2: Patients with R/R AML with NPM1-m or other mutations associated with MEIS1 overexpression. * Sub-study 3: Patients with R/R Acute Lymphoblastic Leukemia (ALL) with KMT2A-r. * Sub-study 4: Patients with R/R AML with mutations associated with MEIS1 overexpression. 4. ≥ 18 years of age. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 2 months. 6. Adequate liver and kidney function according to protocol requirements. 7. Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receive hydroxyurea to control and maintain white blood cell count prior to enrollment. 8. 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. 9. 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. 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), as follows: * Phase 1a, 1b, 2, and sub-studies 3 and 4: 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. * Sub-studies 1 and 2: No exceptions will be allowed except for the use of moderate CYP3A4 antifungal prophylaxis such as fluconazole or isavuconazole which is at steady state on Cycle 1 Day 1 and will continue through the completion of PKs on Cycle 1 Day 15 (for sub-study 1) or Cycle 1 Day 18 (for sub-study 2). 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. 18. For sub-studies 1 and 2: Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of ziftomenib until the end of Cycle 1. 19. For sub-studies 1 and 2: Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.

Primary outcome measure(s)

Phase 1a: Maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) — 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.
Phase 1b: Number of patients who experience Adverse Events (AEs) and Serious Adverse Events (SAEs) — 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
Phase 1b: Minimum biologically effective dose — For at least 12 months following end of treatment
Minimum biologically effective dose in dosing cohorts which have demonstrated biological activity and have been determined to be safe as a part of Part 1a
Phase 1a, 1b, and 2: Evidence of anti-leukemia activity — For at least 12 months following end of treatment
Assessed by the CR + CRh rate
Sub-study 1: Time to observed maximum plasma concentration (Tmax) of ziftomenib and midazolam — Cycle 1 on Days 1 and 15 at predose and postdose
Tmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
Sub-study 1: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and midazolam — Cycle 1 on Days 1 and 15 at predose and postdose
AUC0-t of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
Sub-study 1: Maximum observed plasma concentration (Cmax) of ziftomenib and midazolam — Cycle 1 on Days 1 and 15 at predose and postdose
Cmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
Sub-study 2: Time to observed maximum plasma concentration (Tmax) of ziftomenib and itraconazole — Cycle 1 on Days 1, 15, and 22 at predose and postdose
Tmax of ziftomenib, its metabolites, and itraconazole
Sub-study 2: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and itraconazole — Cycle 1 on Days 1, 15, and 22 at predose and postdose
AUC0-t of ziftomenib, its metabolites, and itraconazole
Sub-study 2: Maximum observed plasma concentration (Cmax) of ziftomenib and itraconazole — Cycle 1 on Days 1, 15, and 22 at predose and postdose
Cmax of ziftomenib, its metabolites, and itraconazole
Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D) — 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 the number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) per NCI-CTCAE v5.0
Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D) — For at least 12 months following end of treatment
Assessed by CR
Sub-study 3: Change in Eastern Cooperative Oncology Group (ECOG) status — Timeframe: from Baseline to End of Treatment
To assess the change in ECOG status
Sub-study 3: Time to observed maximum plasma concentration (Tmax) of ziftomenib — Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards
Tmax of ziftomenib
Sub-study 3: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib — Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards
AUC0-t of ziftomenib
Sub-study 3: Maximum observed plasma concentration (Cmax) of ziftomenib — Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards.
Cmax of ziftomenib
Sub-study 4: Complete remission (CR) and complete remission with partial hematologic recovery (CRh) — For at least 12 months following end of treatment
To assess the CR+CRh rate

Trial sites (43)

Facility	City	Region
Banner MD Anderson Cancer Center	Gilbert	Arizona
UCLA Ronald Reagan Medical Center	Los Angeles	California
Mayo Clinic	Jacksonville	Florida
Robert H. Lurie Comprehensive Cancer Center of Northwestern University	Chicago	Illinois
University of Maryland Greenebaum Comprehensive Cancer Center	Baltimore	Maryland
Massachusetts General Hospital	Boston	Massachusetts
University of Michigan Hospitals	Ann Arbor	Michigan
Karmanos Cancer Institute	Detroit	Michigan
Mayo Clinic	Rochester	Minnesota
Hackensack University Medical Center - John Theurer Cancer Center	Hackensack	New Jersey
Roswell Park Comprehensive Cancer Center	Buffalo	New York
Weill Cornell Medical College - NY Presbyterian Hospital	New York	New York
The Mount Sinai Hospital	New York	New York
Duke Cancer Institute	Durham	North Carolina
Oklahoma University Health - Stephenson Cancer Center	Oklahoma City	Oklahoma
UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center	Dallas	Texas
MD Anderson Cancer Center	Houston	Texas
Fred Hutchinson Cancer Research Center	Seattle	Washington
AZ Delta - Campus Rumbeke	Roeselare	Belgium
Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia
Hopital Maisonneuve-Rosemont	Montreal	Quebec
Hopital de l'Enfant-Jesus - Centre Integre en Cancerologie du CHU de Quebec - Universite Laval	Québec	Quebec
Centre Hospitalier Universitaire de Lille	Lille	France
Centre Hospitalier Universitaire 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	France
University Medicine Greifswald	Greifswald	Germany
Medizinische Hochsschule Hannover	Hanover	Germany
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	Italy
Hospital Universitari Vall d'Hebron	Barcelona	Spain
Universitat de Barcelona	Barcelona	Spain
MD Anderson Cancer Center	Madrid	Spain
Hospital Universitario HM Sanchinarro	Madrid	Spain

+ 3 more sites — see the full list on the official registry below.