Clinical trial NCT04067336: First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Malignant Neoplasm
Acute Myeloid Leukemia
Mixed Lineage Leukemia
Mixed Lineage Acute Leukemia
Acute Leukemia of Ambiguous Lineage
Mixed Phenotype Acute Leukemia
Acute Lymphoblastic Leukemia
Keywords: AML
Hematological malignancy
KMT2A
NPM1
Menin
Leukemia
Acute Leukemia
ALL
MLL
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
MEIS1
Lead sponsor: Kura Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2019-08-26
Enrollment: 263
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: This first-in-human (FIH), open-label study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The trial includes a Main Study and four sub-studies.

The Main Study is a Phase 1/2 dose-escalation and dose-validation/expansion study to assess ziftomenib in patients with R/R AML. The dose-escalation part of the study (Phase 1a) will determine the maximum 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 (MBED) of ziftomenib in biomarker-specific dosing cohorts from among doses that demonstrated early biological activity and are 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 nucleophosmin 1-mutant (NPM1-m) AML.

In Sub-study 1, the effects of co-administration of ziftomenib on the pharmacokinetics (PK) of midazolam will be studied in patients with R/R AML with certain genetic mutations.

In Sub-study 2, the effects of co-administration of itraconazole on the PK of ziftomenib will be studied in patients with R/R AML with certain genetic mutations.

In Sub-study 3, the safety, tolerability, and MBED/RP2D of ziftomenib will be studied in patients with R/R KMT2A-rearranged (KMT2A-r) ALL (Phase 1a dose escalation). These parameters will be investigated further for the RP2D in a Phase 1b dose-validation/cohort expansion part of the sub-study.

In Sub-study 4, the clinical activity of ziftomenib will be studied in patients with R/R AML with certain genetic mutations.

Eligibility criteria: 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 outcomes:
measure: Phase 1a: Maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D)
timeFrame: Dose Limiting Toxicities (DLTs) will be evaluated during the first 28 days (1 cycle)
measure: Phase 1b: Number of patients who experience Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.
measure: Phase 1b: Minimum biologically effective dose
timeFrame: For at least 12 months following end of treatment
measure: Phase 1a, 1b, and 2: Evidence of anti-leukemia activity
timeFrame: For at least 12 months following end of treatment
measure: Sub-study 1: Time to observed maximum plasma concentration (Tmax) of ziftomenib and midazolam
timeFrame: Cycle 1 on Days 1 and 15 at predose and postdose
measure: Sub-study 1: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and midazolam
timeFrame: Cycle 1 on Days 1 and 15 at predose and postdose
measure: Sub-study 1: Maximum observed plasma concentration (Cmax) of ziftomenib and midazolam
timeFrame: Cycle 1 on Days 1 and 15 at predose and postdose
measure: Sub-study 2: Time to observed maximum plasma concentration (Tmax) of ziftomenib and itraconazole
timeFrame: Cycle 1 on Days 1, 15, and 22 at predose and postdose
measure: Sub-study 2: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and itraconazole
timeFrame: Cycle 1 on Days 1, 15, and 22 at predose and postdose
measure: Sub-study 2: Maximum observed plasma concentration (Cmax) of ziftomenib and itraconazole
timeFrame: Cycle 1 on Days 1, 15, and 22 at predose and postdose
measure: Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D)
timeFrame: During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first
measure: Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D)
timeFrame: For at least 12 months following end of treatment
measure: Sub-study 3: Change in Eastern Cooperative Oncology Group (ECOG) status
timeFrame: Timeframe: from Baseline to End of Treatment
measure: Sub-study 3: Time to observed maximum plasma concentration (Tmax) of ziftomenib
timeFrame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards
measure: Sub-study 3: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib
timeFrame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards
measure: Sub-study 3: Maximum observed plasma concentration (Cmax) of ziftomenib
timeFrame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards.
measure: Sub-study 4: Complete remission (CR) and complete remission with partial hematologic recovery (CRh)
timeFrame: For at least 12 months following end of treatment
Secondary outcomes:
measure: Phase 1a and 2: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.
measure: Phase 1a: Tmax
timeFrame: Cycle 1 and Cycle 2. Each cycle is 28 days.
measure: Phase 1a: AUC(0-t)
timeFrame: Cycle 1 and Cycle 2. Each cycle is 28 days.
measure: Phase 1a: Cmax
timeFrame: Cycle 1 and Cycle 2. Each cycle is 28 days.
measure: Phases 1a, 1b, and 2: Complete remission (CR) and complete remission with partial hematologic recovery (CRh) measurable residual disease (MRD) negativity
timeFrame: For at least 12 months following discontinuation of treatment
measure: Phases 1a, 1b, and 2: Duration of response (DOR)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Phases 1a, 1b, and 2: Transfusion independence (TI)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Phases 1a, 1b, and 2: Overall response rate (ORR)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Phases 1a, 1b, and 2: Event-free survival (EFS)
timeFrame: For at least 12 months following end of treatment
measure: Phases 1a, 1b, and 2: Overall survival (OS)
timeFrame: For at least 12 months following end of treatment
measure: Phases 1a, 1b, and 2: Composite complete remission (CRc)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Phases 1b and 2: Composite complete remission (CRc) measurable residual disease (MRD) negativity
timeFrame: For at least 12 months following discontinuation of treatment
measure: Phases 1b and 2: Overall response rate (ORR) measurable residual disease (MRD) negativity
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-study 2: Corrected QT (QTc) intervals
timeFrame: During Cycle 1
measure: Sub-study 3: Complete remission (CR) measurable residual disease (MRD) negativity
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-studies 3 and 4: Composite complete remission (CRc)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-study 3: Duration of response (DOR)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-studies 3 and 4: Overall survival (OS)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-studies 3 and 4: Event-free survival (EFS)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-study 4: Transfusion independence (TI)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-studies 3 and 4: Overall response rate (ORR) measurable residual disease (MRD) negativity
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-study 4: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.
measure: Sub-study 4: Duration of response (DOR)
timeFrame: For at least 12 months following discontinuation of treatment
measure: Sub-study 4: Time to observed maximum plasma concentration (Tmax) of ziftomenib
timeFrame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
measure: Sub-study 4: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib
timeFrame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
measure: Sub-study 4: Maximum plasma concentration (Cmax) of ziftomenib
timeFrame: Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: UCLA Ronald Reagan Medical Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Comprehensive Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospitals
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University Medical Center - John Theurer Cancer Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College - NY Presbyterian Hospital
state: New York
city: New York
country: United States
facility: The Mount Sinai Hospital
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Oklahoma City
country: United States
facility: Oklahoma University Health - Stephenson Cancer Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Harold C. Simmons Comprehensive Cancer Center - UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Jette
country: Belgium
facility: UZ Brussel
city: Roeselare
country: Belgium
facility: AZ Delta - Campus Rumbeke
city: Yvoir
country: Belgium
facility: CHU UCL Namur
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster University Juravinski Cancer Centre
state: Ontario
city: Montréal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Québec
country: Canada
facility: Hopital de l'Enfant-Jesus - Centre Integre en Cancerologie du CHU de Quebec - Universite Laval
state: Quebec
city: Lille
country: France
facility: Centre Hospitalier Universitaire de Lille
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Paris
country: France
facility: Hopital Saint Louis
city: Pessac
country: France
facility: Magendie Hopital Haut-Leveque
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Berlin
country: Germany
facility: Charitè-Campus Benjamin Franklin
city: Greifswald
country: Germany
facility: University Medicine Greifswald
city: Hannover
country: Germany
facility: Medizinische Hochsschule Hannover
city: Mainz
country: Germany
facility: Johannes Gutenberg - University Mainz
city: Bologna
country: Italy
facility: Institute of Hematology and Medical Oncology "L. and A. Seragnoli"
city: Meldola
country: Italy
facility: IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
city: Ravenna
country: Italy
facility: UO Ematologia Ospedale di Ravenna
city: Roma
country: Italy
facility: Institution Fondazione Policlinico Tor Vergata
city: Toruń
country: Poland
facility: Nasz Lekarz Przychodnie Medyczne
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Universitat de Barcelona
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale University
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: St. George's Hospital
Study officials:
References:
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citation: Jimenez JA, Apfelbaum AA, Hawkins AG, Svoboda LK, Kumar A, Ruiz RO, Garcia AX, Haarer E, Nwosu ZC, Bradin J, Purohit T, Chen D, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma. Mol Cancer Res. 2021 Jul;19(7):1182-1195. doi: 10.1158/1541-7786.MCR-20-0679. Epub 2021 Mar 19.