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

Phase 1RecruitingNCT05735184

Kura Oncology, Inc.420 enrolled

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

420

Conditions

Acute Myeloid Leukemia Mixed Lineage Leukemia Gene Mutation Refractory AML AML With Mutated NPM1

Interventions

ZiftomenibDRUG

Oral Administration

VenetoclaxDRUG

Oral Administration

AzacitidineDRUG

Subcutaneous or Intravenous Administration

DaunorubicinDRUG

Intravenous Administration

CytarabineDRUG

Intravenous Administration

QuizartinibDRUG

Oral Administration

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key 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 Key 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

Locations (44)

Mayo Clinic - Phoenix

Phoenix, Arizona, United States

RECRUITING

Moores UC San Diego Cancer Center

La Jolla, California, United States

RECRUITING

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States

RECRUITING

UCLA - Bowyer Oncology Center

Los Angeles, California, United States

Outcomes

Primary Outcomes

Rate of dose limiting toxicities (DLTs) per dose level (Part 1a only)

Assessed by the NCI-CTCAE v5.0

Time frame: During the first 28 days of ziftomenib in combination with SOC backbone treatment (1 cycle)

Descriptive statistics of adverse events

Assessed by the NCI-CTCAE v5.0

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

Assessed by the ELN 2022 criteria

Time frame: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first

Secondary Outcomes

Composite Complete Remission (CRc)

Assessed by the ELN 2022 criteria

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

Assessed by the ELN 2022 criteria

Time frame: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever comes first

Measurable residual disease (MRD)

Assessed by multiparameter flow cytometry (MFC) and/or molecular analysis (NGS, PCR)

Time frame: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first

Median OS

To assess overall survival of ziftomenib

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

To assess proportion of patients alive at 1 year following start of treatment with ziftomenib

Time frame: From Cycle 1 Day 1 until death from any cause, assessed up to 1 year following start of treatment

Median EFS

To assess median event free survival

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

To assess event free survival at 1 year

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

To assess median duration of remission

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

To assess proportion of patients who undergo hematopoietic stem cell transplant

Time frame: From Cycle 1 Day 1 until date of HSCT, assessed up to 36 months of treatment

To assess rate of transfusion independence

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

Maximum plasma concentration (Cmax) of ziftomenib and metabolites