A Study to Investigate the Safety and Tolerability of Ziftomenib in Combination with Venetoclax/Azacitidine, Venetoclax, or 7+3 in Patients with AML
- Conditions
- Acute Myeloid LeukemiaMixed Lineage Acute LeukemiaMixed Lineage Leukemia Gene MutationMixed Phenotype Acute LeukemiaRefractory AMLAML with Mutated NPM1Acute Myeloid Leukemia RecurrentAcute Myeloid Leukemia, in RelapseNPM1 MutationKMT2Ar
- Interventions
- Registration Number
- NCT05735184
- Lead Sponsor
- Kura Oncology, Inc.
- Brief Summary
This Phase 1 study will assess the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with venetoclax and azacitidine (ven/aza), ven, and 7+3 for two different molecularly-defined arms, NPM1-m and KMT2A-r.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 212
- Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AML
- 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 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 adequate contraception from the time of screening through 90 days following the last dose of study intervention
Key
- Diagnosis of either acute promyelocytic leukemia or blast chronic myelomonocytic leukemia
- Known history of BCR-ABL alteration
- Advanced malignant hepatic tumor [for patients receiving ven/aza combination]
- 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 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 to control leukocytosis, prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia, or non-HMA therapy for prior myelodysplastic syndrome
- 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 corrected QT interval corrected for heart rate by Fredericia's formula (QTcF) >480 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1) Ziftomenib Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/7+3 in 1L KMT2A-r (B-2) Ziftomenib Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1) Venetoclax Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1) Azacitidine Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy Dose Escalation: Ziftomenib/7+3 in 1L KMT2A-r (B-2) Cytarabine Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1) Ziftomenib Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1) Venetoclax Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1) Azacitidine Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/7+3 in 1L NPM1-m (A-2) Ziftomenib Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Validation/Expansion: Ziftomenib/7+3 in 1L NPM1-m (A-2) Daunorubicin Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Validation/Expansion: Ziftomenib/7+3 in 1L NPM1-m (A-2) Cytarabine Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Validation/Expansion: Ziftomenib/Venetoclax in R/R NPM1-m (A-3) Ziftomenib Ziftomenib/Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/Venetoclax in R/R NPM1-m (A-3) Venetoclax Ziftomenib/Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L NPM1-m (A-4) Ziftomenib Ziftomenib/Venetoclax/Azacitidine in newly diagnosed NPM1-m AML patients Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L NPM1-m (A-4) Venetoclax Ziftomenib/Venetoclax/Azacitidine in newly diagnosed NPM1-m AML patients Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L NPM1-m (A-4) Azacitidine Ziftomenib/Venetoclax/Azacitidine in newly diagnosed NPM1-m AML patients Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1) Ziftomenib Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/7+3 in 1L KMT2A-r (B-2) Cytarabine Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L KMT2A-r (B-3) Ziftomenib Ziftomenib/Venetoclax/Azacitidine in newly diagnosed KMT2A-r AML patients Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1) Venetoclax Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L KMT2A-r (B-3) Venetoclax Ziftomenib/Venetoclax/Azacitidine in newly diagnosed KMT2A-r AML patients Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L KMT2A-r (B-3) Azacitidine Ziftomenib/Venetoclax/Azacitidine in newly diagnosed KMT2A-r AML patients Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1) Ziftomenib Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy Dose Escalation: Ziftomenib/7+3 in 1L NPM1-m (A-2) Ziftomenib Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Escalation: Ziftomenib/7+3 in 1L NPM1-m (A-2) Daunorubicin Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Escalation: Ziftomenib/7+3 in 1L NPM1-m (A-2) Cytarabine Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1) Venetoclax Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1) Azacitidine Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy Dose Escalation: Ziftomenib/7+3 in 1L KMT2A-r (B-2) Ziftomenib Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Escalation: Ziftomenib/7+3 in 1L KMT2A-r (B-2) Daunorubicin Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1) Azacitidine Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy Dose Validation/Expansion: Ziftomenib/7+3 in 1L KMT2A-r (B-2) Daunorubicin Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy
- Primary Outcome Measures
Name Time Method Rate of dose limiting toxicities (DLTs) per dose level 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 First dose of ziftomenib up to and including 28 days after last dose of ziftomenib, or if the patient is lost to follow-up, whichever comes first Assessed by the NCI-CTCAE v5.0
Complete remission (CR) rate Up to 1 year following end of treatment with ziftomenib Assessed by the ELN 2022 criteria
- Secondary Outcome Measures
Name Time Method Composite Complete Remission (CRc) or MLFS rate Up to 1 year following end of treatment with ziftomenib Assessed by the ELN 2022 criteria
Measurable residual disease (MRD) Up to 1 year following end of treatment with ziftomenib Assessed by multiparameter flow cytometry (MFC) and molecular analysis
Median OS Up to 1 year following end of treatment with ziftomenib To assess overall survival of ziftomenib
Proportion of patients alive 1 year following end of treatment with ziftomenib To assess proportion of patients alive at 1 year following treatment with ziftomenib
Median EFS Up to 1 year following end of treatment with ziftomenib To assess median event free survival
EFS 1 year following end of treatment with ziftomenib To assess event free survival
Median DOR Up to 1 year following end of treatment with ziftomenib To assess median duration of remission
Proportion of patients who undergo HSCT Up to 1 year following end of treatment with ziftomenib To assess proportion of patients who undergo hematopoietic stem cell transplant
TI Up to 1 year following end of treatment with ziftomenib To assess rate of transfusion independence
Cmax Cycle 1. Each cycle is 28 days. Maximum plasma concentration (Cmax) of ziftomenib and metabolites
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
Accumulation ratio of ziftomenib and metabolites Cycle 1. Each cycle is 28 days. To assess accumulation ratio of ziftomenib and metabolites
Cmax of venetoclax Cycle 1. Each cycle is 28 days. Maximum plasma concentration (Cmax) of venetoclax
Tmax of venetoclax Cycle 1. Each cycle is 28 days. Time to maximum plasma concentration (Tmax) 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
AUCtau of venetoclax Cycle 1. Each cycle is 28 days. Area under the concentration-time curve over a dosing interval (AUCtau) of venetoclax
Trial Locations
- Locations (28)
Moores UC San Diego Cancer Center
🇺🇸La Jolla, California, United States
USC University of Southern California / Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
UCLA - Bowyer Oncology Center
🇺🇸Los Angeles, California, United States
UCI 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
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
🇺🇸Chicago, Illinois, United States
The University of Kansas Cancer Center
🇺🇸Fairway, Kansas, United States
Norton Cancer Institute - St. Matthews
🇺🇸Louisville, Kentucky, United States
Ochsner MD Anderson Cancer Center
🇺🇸Jefferson, Louisiana, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Rutgers Cancer Institute
🇺🇸New Brunswick, New Jersey, United States
Roswell Park Comprehensive Cancer Center
🇺🇸Buffalo, New York, United States
New York - Presbyterian / Weill Cornell Medicine
🇺🇸New York, New York, United States
Mount Sinai - Ruttenberg Treatment Center
🇺🇸New York, New York, United States
Stony Brook Cancer Center
🇺🇸Stony Brook, New York, United States
Duke Blood Cancer Center
🇺🇸Durham, North Carolina, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
OU Health Stephenson Cancer Center
🇺🇸Oklahoma City, Oklahoma, United States
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
TriStar Bone Marrow Transplant
🇺🇸Nashville, Tennessee, United States
Sarah Cannon Research Institute - St. David's South Austin Medical Center / Texas Oncology South Austin
🇺🇸Austin, Texas, United States
UT Southwestern - Simmons Cancer Center
🇺🇸Dallas, Texas, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
UW Health - Carbone Cancer Center
🇺🇸Madison, Wisconsin, United States