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 1

Recruiting

• Conditions: Acute Myeloid Leukemia; NPM1 Mutation; Mixed Lineage Leukemia Gene Mutation; Refractory AML; AML With Mutated NPM1; Acute Myeloid Leukemia, in Relapse; Acute Myeloid Leukemia Recurrent; KMT2Ar; Myeloid Sarcoma; Nucleophosmin 1-mutated Acute Myeloid Leukemia
• Interventions: Drug: Ziftomenib; Drug: Venetoclax; Drug: Daunorubicin; Drug: Azacitidine; Drug: Cytarabine; Drug: Quizartinib

• Registration Number: NCT05735184
• Lead Sponsor: Kura Oncology, Inc.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-02-09
• Study First Submitted QC: 2023-02-09
• Study First Posted: 2023-02-21
• Study Start: 2023-07-18
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-09
• Last Update Posted: 2025-09-16
• Primary Completion: 2030-04
• Study Completion: 2030-04-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 420

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)	Ziftomenib	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)	Ziftomenib	Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio \<0.05
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)	Venetoclax	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)	Venetoclax	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with Venetoclax in R/R NPM1-m (A-3)	Venetoclax	Ziftomenib with Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)	Azacitidine	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)	Ziftomenib	Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio \<0.05
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4)	Ziftomenib	Ziftomenib with Venetoclax and Azacitidine in newly diagnosed NPM1-m AML patients
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)	Ziftomenib	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)	Daunorubicin	Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio \<0.05
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)	Azacitidine	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)	Daunorubicin	Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio \<0.05
Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)	Cytarabine	Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio \<0.05
Dose Validation/Expansion: Ziftomenib with Venetoclax in R/R NPM1-m (A-3)	Ziftomenib	Ziftomenib with Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)	Cytarabine	Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio \<0.05
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4)	Azacitidine	Ziftomenib with Venetoclax and Azacitidine in newly diagnosed NPM1-m AML patients
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)	Ziftomenib	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)	Cytarabine	Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive therapy
Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3)	Venetoclax	Ziftomenib with Venetoclax and Azacitidine in newly diagnosed KMT2A-r AML patients
Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)	Cytarabine	Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4)	Venetoclax	Ziftomenib with Venetoclax and Azacitidine in newly diagnosed NPM1-m AML patients
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)	Venetoclax	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)	Azacitidine	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)	Daunorubicin	Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive therapy
Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)	Quizartinib	Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)	Daunorubicin	Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)	Cytarabine	Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)	Ziftomenib	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)	Venetoclax	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)	Ziftomenib	Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy
Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)	Azacitidine	Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy
Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)	Cytarabine	Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy
Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3)	Azacitidine	Ziftomenib with Venetoclax and Azacitidine in newly diagnosed KMT2A-r AML patients
Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)	Daunorubicin	Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)	Ziftomenib	Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)	Daunorubicin	Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy
Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)	Ziftomenib	Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive therapy
Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3)	Ziftomenib	Ziftomenib with Venetoclax and Azacitidine in newly diagnosed KMT2A-r AML patients
Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)	Ziftomenib	Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy
Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)	Quizartinib	Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy

Primary Outcome Measures

Name	Time	Method
Rate of dose limiting toxicities (DLTs) per dose level (Part 1a only)	During the first 28 days of ziftomenib in combination with SOC backbone treatment (1 cycle)	Assessed by the NCI-CTCAE v5.0
Descriptive statistics of adverse events	From Cycle 1 Day 1 up to and including 28 days following the end of 36 months of treatment	Assessed by the NCI-CTCAE v5.0
Complete remission (CR) rate	Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first	Assessed by the ELN 2022 criteria

Secondary Outcome Measures

Name	Time	Method
TI	From 28 days prior to Cycle 1 Day 1 up to and including 28 days following the end of 36 months of treatment	To assess rate of transfusion independence
Accumulation ratio of ziftomenib and metabolites	Cycle 1; each cycle is 28 days	To assess accumulation ratio of ziftomenib and metabolites
Cmax of quizartinib	Cycle 1; each cycle is 28 days	Maximum plasma concentration (Cmax) of quizartinib
Tmax of quizartinib	Cycle 1; each cycle is 28 days	Time to maximum plasma concentration (Tmax) of quizartinib
AUCtau of quizartinib	Cycle 1; each cycle is 28 days	Area under the concentration-time curve over a dosing interval (AUCtau) of quizartinib
Median EFS	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	To assess median event free survival
Tmax	Cycle 1; each cycle is 28 days	Time to maximum plasma concentration (Tmax) of ziftomenib and metabolites
AUC0-last	Cycle 1; each cycle is 28 days	Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last) of ziftomenib and metabolites
AUCtau	Cycle 1; each cycle is 28 days	Area under the concentration-time curve over a dosing interval (AUCtau) of ziftomenib
AUCtau of venetoclax	Cycle 1; each cycle is 28 days	Area under the concentration-time curve over a dosing interval (AUCtau) of venetoclax
Composite Complete Remission (CRc)	Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first	Assessed by the ELN 2022 criteria
EFS	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	To assess event free survival at 1 year
Median DOR	From time of first remission to relapse or death, whichever occurs first, assessed up to 36 months from start of treatment	To assess median duration of remission
Proportion of patients who undergo HSCT	From Cycle 1 Day 1 until date of HSCT, assessed up to 36 months of treatment	To assess proportion of patients who undergo hematopoietic stem cell transplant
Cmax of venetoclax	Cycle 1; each cycle is 28 days	Maximum plasma concentration (Cmax) of venetoclax
AUC0-last of venetoclax	Cycle 1; each cycle is 28 days	Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last) of venetoclax
Measurable residual disease (MRD)	Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first	Assessed by multiparameter flow cytometry (MFC) and/or molecular analysis (NGS, PCR)
Median OS	From Cycle 1 Day 1 to date of death from any cause, assessed up to 36 months of treatment	To assess overall survival of ziftomenib
Proportion of patients alive	From Cycle 1 Day 1 until death from any cause, assessed up to 1 year following start of treatment	To assess proportion of patients alive at 1 year following start of treatment with ziftomenib
Cmax	Cycle 1; each cycle is 28 days	Maximum plasma concentration (Cmax) of ziftomenib and metabolites
Tmax of venetoclax	Cycle 1; each cycle is 28 days	Time to maximum plasma concentration (Tmax) of venetoclax
AUC0-last of quizartinib	Cycle 1; each cycle is 28 days	Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last) of quizartinib
Morphologic leukemia-free state (MLFS) rate	Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever comes first	Assessed by the ELN 2022 criteria

Trial Locations

Locations (44)

Mayo Clinic - Phoenix; 🇺🇸 Phoenix, Arizona, United States

Moores UC San Diego Cancer Center; 🇺🇸 La Jolla, California, United States

USC / Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

UCLA - Bowyer Oncology Center; 🇺🇸 Los Angeles, California, United States

UC Irvine Health Chao Family Comprehensive Cancer Center; 🇺🇸 Orange, California, United States

UC Health Blood Disorders and Cell Therapies Center - Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States

Colorado Blood Cancer Institute; 🇺🇸 Denver, Colorado, United States

Yale Cancer Center and Smilow Cancer Hospital; 🇺🇸 New Haven, Connecticut, United States

Mayo Clinic Jacksonville; 🇺🇸 Jacksonville, Florida, United States

Emory Healthcare - The Emory Clinic; 🇺🇸 Atlanta, Georgia, United States

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