A Study to Investigate the Safety and Tolerability of Ziftomenib in Combination With Venetoclax/Azacitidine, Venetoclax, 7+3, or 7+3+Quizartinib in Patients With AML

Official title

Phase 1 Study of Venetoclax/Azacitidine or Venetoclax in Combination With Ziftomenib or Standard Induction Cytarabine/Daunorubicin (7+3) Chemotherapy in Combination With Ziftomenib for the Treatment of Patients With Acute Myeloid Leukemia

Overview

Ziftomenib is an investigational drug in development for the treatment of patients with acute myeloid leukemia (AML) with certain genetic alterations. This protocol has 3 separate arms that will investigate the benefits and risks of adding ziftomenib to standard-of-care (SOC) drug treatments in patients who have AML with certain genetic mutations. Both newly diagnosed and relapsed refractory patients with AML will be assigned to different cohorts based on specific study criteria and physician discretion. The purpose of this study is to assess the safety, tolerability, and early signs of efficacy of ziftomenib in combination with SOC drugs to treat AML.

Interventions

• Drug Ziftomenib
  Oral Administration
• Drug Venetoclax
  Oral Administration
• Drug Azacitidine
  Subcutaneous or Intravenous Administration
• Drug Daunorubicin
  Intravenous Administration
• Drug Cytarabine
  Intravenous Administration
• Drug Quizartinib
  Oral Administration

Primary outcome measures

• Rate of dose limiting toxicities (DLTs) per dose level (Part 1a only) [Time frame: During the first 28 days of ziftomenib in combination with SOC backbone treatment (1 cycle)]
• Descriptive statistics of adverse events [Time frame: From Cycle 1 Day 1 up to and including 28 days following the end of 36 months of treatment]
• Complete remission (CR) rate [Time frame: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first]

Secondary outcome measures (12)

• Composite Complete Remission (CRc) [Time frame: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first]
• Morphologic leukemia-free state (MLFS) rate [Time frame: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever comes first]
• Measurable residual disease (MRD) [Time frame: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first]
• Median OS [Time frame: From Cycle 1 Day 1 to date of death from any cause, assessed up to 36 months of treatment]
• Proportion of patients alive [Time frame: From Cycle 1 Day 1 until death from any cause, assessed up to 1 year following start of treatment]
• Median EFS [Time frame: From Cycle 1 Day 1 to treatment failure, hematologic relapse following CR, or death from any cause, whichever comes first, assessed up to 36 months of treatment]
• EFS [Time frame: From Cycle 1 Day 1 to treatment failure, hematologic relapse following CR, or death from any cause, whichever comes first, assessed up to 1 year following start of treatment]
• Median DOR [Time frame: From time of first remission to relapse or death, whichever occurs first, assessed up to 36 months from start of treatment]
• Proportion of patients who undergo HSCT [Time frame: From Cycle 1 Day 1 until date of HSCT, assessed up to 36 months of treatment]
• TI [Time frame: From 28 days prior to Cycle 1 Day 1 up to and including 28 days following the end of 36 months of treatment]
• Cmax [Time frame: Cycle 1; each cycle is 28 days]
• Tmax [Time frame: Cycle 1; each cycle is 28 days]

Eligibility criteria

Inclusion criteria

• Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AML

• Those intending treatment with intensive chemotherapy in Arm C should be NPM1-m and FLT3-ITD+ with an allelic ratio ≥0.05 and eligible for FLT3-targeted treatment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Adequate liver, renal, and cardiac function according to protocol defined criteria
• A female of childbearing potential must agree to use adequate contraception as well as a double barrier method from the time of screening through 180 days following the last dose of study intervention. A male of childbearing potential must agree to use abstinence or use a double barrier method of contraception from the time of screening through 180 days following the last dose of study intervention

• Female patients of childbearing potential who receive quizartinib in Arm C should use a highly effective method of contraception during quizartinib treatment and for 7 months after the last dose

Exclusion criteria

• Diagnosis of either acute promyelocytic leukemia or blast phase chronic myeloid leukemia
• Known history of BCR-ABL alteration
• Advanced malignant hepatic tumor
• Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recovery
• Active central nervous system (CNS) involvement by AML.
• Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine if used per institutional SOC for control of leukocytosis are permitted to meet this criterion
• Not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopecia
• Known clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infection
• For newly diagnosed cohorts: received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine per institutional standards to control leukocytosis, or prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia
• For relapsed/refractory cohorts: received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug
• Uncontrolled intercurrent illness including, but not limited to, cardiac illness as defined in the protocol
• Mean QT interval corrected for heart rate by Fredericia's formula (QTcF)

• Arm A and Arm B: >480 ms on triplicate ECGs
• Arm C: >450 ms on triplicate ECGs
• Uncontrolled infection
• Women who are pregnant or lactating
• An active malignancy and currently receiving chemotherapy for that malignancy or disease that is uncontrolled/progressing
• Patients who have active GVHD requiring >0.5 mg/kg prednisone or any new or increase in immunosuppressants in the prior 2 weeks for GVHD treatment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 44 centers

• Mayo Clinic - Phoenix — Phoenix
• Moores UC San Diego Cancer Center — La Jolla
• USC / Norris Comprehensive Cancer Center — Los Angeles
• UCLA - Bowyer Oncology Center — Los Angeles
• UC Irvine Health Chao Family Comprehensive Cancer Center — Orange
• University of Colorado — Aurora
• Colorado Blood Cancer Institute — Denver
• Yale Cancer Center and Smilow Cancer Hospital — New Haven
• … and 36 more centers

Publications

• Wang ES, Erba HP, Zeidan AM, Roboz GJ, Altman JK, Advani AS, Lin TL, Strickland SA, Juckett MB, Pratz KW, Mangan JK, McMahon CM, Alsfeld LC, Balasubramanian SK, Guru Murthy GS, Rotta M, Palmisiano N, McCloskey J, Saliba AN, Khawandanah M, Madanat YF, Naqvi K, Qasrawi AH, Schiller GJ, Badar T, Gojo I, Yaghmour G, Osman D, Zhang H, Tian Y, Soifer HS, Riches M, Corum D, Leoni M, Fathi AT, Issa GC. Zi PMID 42227701

Identifiers

NCT: NCT05735184 · KO-MEN-007

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗