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

NCT05735184 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: KO-MEN-007
• Study Type: interventional
• Target: 420
• Locations: 1 country
• Sites: 44

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.

Conditions

Acute Myeloid Leukemia; Mixed Lineage Leukemia Gene Mutation; Refractory AML; Acute Myeloid Leukemia Recurrent; Acute Myeloid Leukemia, in Relapse; NPM1 Mutation; KMT2Ar; Myeloid Sarcoma; AML With Mutated NPM1; Nucleophosmin 1-mutated Acute Myeloid Leukemia

Keywords

Leukemia; Myeloid; AML; Hematological malignancy; KMT2A; NPM1; Menin; Acute Leukemia; Newly diagnosed AML; Untreated AML; venetoclax; cytarabine; daunorubicin; KMT2A-r; NPM1 mutation; Refractory AML; Acute Myeloid Leukemia, in Relapse; quizartinib

Outcome Measures

Primary Outcomes (3)

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

  Assessed by the NCI-CTCAE v5.0

  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

  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

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

Secondary Outcomes (23)

• Composite Complete Remission (CRc)

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

• Morphologic leukemia-free state (MLFS) rate

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

• Measurable residual disease (MRD)

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

• Median OS

  From Cycle 1 Day 1 to date of death from any cause, assessed up to 36 months of treatment

• Proportion of patients alive

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

Study Arms (13)

Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)

EXPERIMENTAL

Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Drug: Ziftomenib; Drug: Venetoclax; Drug: Azacitidine

Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)

EXPERIMENTAL

Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Drug: Ziftomenib; Drug: Venetoclax; Drug: Azacitidine

Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)

EXPERIMENTAL

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

Drug: Ziftomenib; Drug: Daunorubicin; Drug: Cytarabine

Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2)

EXPERIMENTAL

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

Drug: Ziftomenib; Drug: Daunorubicin; Drug: Cytarabine

Dose Validation/Expansion: Ziftomenib with Venetoclax in R/R NPM1-m (A-3)

EXPERIMENTAL

Ziftomenib with Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Drug: Ziftomenib; Drug: Venetoclax

Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4)

EXPERIMENTAL

Ziftomenib with Venetoclax and Azacitidine in newly diagnosed NPM1-m AML patients

Drug: Ziftomenib; Drug: Venetoclax; Drug: Azacitidine

Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)

EXPERIMENTAL

Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy

Drug: Ziftomenib; Drug: Venetoclax; Drug: Azacitidine

Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1)

EXPERIMENTAL

Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy

Drug: Ziftomenib; Drug: Venetoclax; Drug: Azacitidine

Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)

EXPERIMENTAL

Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy

Drug: Ziftomenib; Drug: Daunorubicin; Drug: Cytarabine

Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2)

EXPERIMENTAL

Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive therapy

Drug: Ziftomenib; Drug: Daunorubicin; Drug: Cytarabine

Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3)

EXPERIMENTAL

Ziftomenib with Venetoclax and Azacitidine in newly diagnosed KMT2A-r AML patients

Drug: Ziftomenib; Drug: Venetoclax; Drug: Azacitidine

Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)

EXPERIMENTAL

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

Drug: Ziftomenib; Drug: Daunorubicin; Drug: Cytarabine; Drug: Quizartinib

Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)

EXPERIMENTAL

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

Drug: Ziftomenib; Drug: Daunorubicin; Drug: Cytarabine; Drug: Quizartinib

Interventions

Ziftomenib DRUG

Oral Administration

Also known as: KO-539

Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2); Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2); Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1); Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1); Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1); Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2); Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2); Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1); Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1); Dose Validation/Expansion: Ziftomenib with Venetoclax in R/R NPM1-m (A-3)

Venetoclax DRUG

Oral Administration

Also known as: Venclexta, Venclyxto

Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1); Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1); Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1); Dose Validation/Expansion: Ziftomenib with Venetoclax in R/R NPM1-m (A-3)

Azacitidine DRUG

Subcutaneous or Intravenous Administration

Also known as: Azadine, Vidaza

Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1); Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1); Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1); Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1)

Daunorubicin DRUG

Intravenous Administration

Also known as: Cerubidine, daunomycin

Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2); Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2); Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1); Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2); Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2); Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)

Cytarabine DRUG

Intravenous Administration

Also known as: cytosine arabinoside (ara-C), Cytosar-U, Tarabine PFS

Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2); Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2); Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1); Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2); Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2); Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)

Quizartinib DRUG

Oral Administration

Also known as: Vanflyta

Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1); Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Kura Oncology, Inc.: lead

Study Sites (44)

Mayo Clinic - Phoenix

Phoenix, Arizona, 85054, United States

RECRUITING

Moores UC San Diego Cancer Center

La Jolla, California, 92093, United States

RECRUITING

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

RECRUITING

UCLA - Bowyer Oncology Center

Los Angeles, California, 90095, United States

RECRUITING

UC Irvine Health Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

RECRUITING

University of Colorado

Aurora, Colorado, 80045, United States

RECRUITING

Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

RECRUITING

Yale Cancer Center and Smilow Cancer Hospital

New Haven, Connecticut, 06510, United States

RECRUITING

Mayo Clinic Jacksonville

Jacksonville, Florida, 32224, United States

RECRUITING

Emory Healthcare - The Emory Clinic

Atlanta, Georgia, 30308, United States

RECRUITING

Georgia Cancer Center at Augusta University

Augusta, Georgia, 30912, United States

RECRUITING

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, 60611, United States

RECRUITING

Loyola University Medical Center

Maywood, Illinois, 60153, United States

RECRUITING

University of Iowa Hospitals & Clinics

Iowa City, Iowa, 52242, United States

RECRUITING

The University of Kansas Medical Center Research Institute

Fairway, Kansas, 66205, United States

RECRUITING

University of Kentucky Markey Cancer Center

Louisville, Kentucky, 40202, United States

RECRUITING

Norton Cancer Institute - St. Matthews

Louisville, Kentucky, 40207, United States

RECRUITING

Ochsner MD Anderson Cancer Center

Jefferson, Louisiana, 70121, United States

RECRUITING

Johns Hopkins School of Medicine

Baltimore, Maryland, 21205, United States

RECRUITING

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

UMass Chan Medical School

Worcester, Massachusetts, 01655, United States

RECRUITING

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

RECRUITING

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

RECRUITING

University of Minnesota

Minneapolis, Minnesota, 55455, United States

RECRUITING

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

RECRUITING

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

RECRUITING

Rutgers Cancer Institute

New Brunswick, New Jersey, 08903, United States

RECRUITING

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14203, United States

RECRUITING

New York - Presbyterian / Weill Cornell Medicine

New York, New York, 10021, United States

RECRUITING

Mount Sinai - Ruttenberg Treatment Center

New York, New York, 10029, United States

RECRUITING

Columbia University Medical Center

New York, New York, 10032, United States

RECRUITING

Stony Brook University Hospital

Stony Brook, New York, 11794, United States

RECRUITING

Duke Blood Cancer Center

Durham, North Carolina, 27705, United States

RECRUITING

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

RECRUITING

Cleveland Clinic Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

RECRUITING

The James Cancer Hospital and Solove Research Institute

Columbus, Ohio, 43210, United States

RECRUITING

OU Health Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

RECRUITING

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

TriStar Bone Marrow Transplant

Nashville, Tennessee, 37203, United States

RECRUITING

Sarah Cannon Research Institute - St. David's South Austin Medical Center / Texas Oncology South Austin

Austin, Texas, 78704, United States

RECRUITING

UT Southwestern - Simmons Cancer Center

Dallas, Texas, 75235, United States

RECRUITING

MD Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

RECRUITING

Medical College of Wisconsin Cancer Center

Milwaukee, Wisconsin, 53226, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Sarcoma, Myeloid; Leukemia; Hematologic Neoplasms

Interventions

venetoclax; Azacitidine; Daunorubicin; Cytarabine; quizartinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Arabinonucleosides

Central Study Contacts

Kura Medical Information

CONTACT

844-KURAONC; medinfo@kuraoncology.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: February 9, 2023
• First Posted: February 21, 2023
• Study Start: July 18, 2023
• Primary Completion (Estimated): April 1, 2030
• Study Completion (Estimated): April 1, 2030
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (44)