Safety and Tolerability of Ziftomenib Combinations in Patients with Relapsed/Refractory Acute Myeloid Leukemia
- Conditions
- AMLAML with Mutated NPM1Hematologic MalignancyKMT2ArNPM1 MutationMLL RearrangementLeukemiaAcute Myeloid LeukemiaLeukemia, MyeloidLeukemia, Myeloid, Acute
- Interventions
- Biological: Granulocyte colony-stimulating factor
- Registration Number
- NCT06001788
- Lead Sponsor
- Kura Oncology, Inc.
- Brief Summary
The safety, tolerability, and antileukemic response of ziftomenib in combination with standard of care treatments for patients with relapsed/refractory acute myeloid leukemia will be examined with the following agents: FLAG-IDA, low-dose cytarabine, and gilteritinib.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 171
- Has been diagnosed with relapsed/refractory AML.
- Has a documented NPM1 mutation or KMT2A rearrangement.
- Has a documented FLT3 mutation (cohort A-3 only).
- Has an Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2.
- Has adequate hepatic and renal function as defined per protocol.
- Has an ejection fraction above a protocol defined limit.
- Participant, or legally authorized representative, must be able to understand and provide written informed consent prior to the first screening procedure.
- Has agreed to use contraception as defined per protocol.
Key
- Has a diagnosis of acute promyelocytic leukemia or blast chronic myeloid leukemia.
- Has clinically active central nervous system leukemia.
- Has an active and uncontrolled infection.
- Has a mean corrected QT interval (QTcF) > 480ms.
- Has uncontrolled intercurrent illness, including, but not limited to protocol defined cardiac disease.
- Has received radiation, chemotherapy, immunotherapy, or any other anticancer therapy including investigational therapy <14 days or within 5 drug half-lives prior to the first dose of study intervention.
- Has had major surgery within 4 weeks prior to the first dose of study intervention.
- Has received a hematopoietic stem cell transplant (HSCT) and has not previously had adequate recovery per protocol defined criteria.
- Has active graft-versus-host disease (GvHD) and or on immunosuppressive drugs for the treatment of GvHD.
- Participant is pregnant or lactating.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 1b Ziftomenib Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1a Granulocyte colony-stimulating factor Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1b Granulocyte colony-stimulating factor Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1a Ziftomenib Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1a Fludarabine Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1a Idarubicin Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1a Cytarabine Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1b Idarubicin Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1a Gilteritinib Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1b Fludarabine Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1b Cytarabine Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC) Phase 1b Gilteritinib Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)
- 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 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
- Secondary Outcome Measures
Name Time Method OS Up to 12 months following discontinuation of treatment To assess overall survival
Complete remission (CR) rate for cohorts A-1, A-2, B-1, and B-2 Up to 12 months following discontinuation of treatment Assessed by ELN 2022 criteria
Gilteritinib AUC(0-last) Cycle 1 (Each cycle is 28 days) To assess the area under the plasma concentration-time-curve from time 0 to time of last measurable concentration of gilteritinib
Complete remission (CR) / Complete remission with partial hematologic recovery (CRh) rate for cohort A-3 Up to 12 months following discontinuation of treatment Assessed by ELN 2022 criteria
Composite complete remission (CRc) rate Up to 12 months following discontinuation of treatment Assessed by ELN 2022 criteria
6-month OS Up to 6 months following discontinuation of treatment To assess proportion of patients alive at 6 months
DOR Up to 12 months following discontinuation of treatment To assess duration of remission
Ziftomenib Cmax Cycle 1 (Each cycle is 28 days) To assess the maximum plasma combination of ziftomenib and its metabolites
Gilteritinib Cmax Cycle 1 (Each cycle is 28 days) To assess the maximum plasma combination of gilteritinib
Morphologic leukemia-free state (MLFS) rate Up to 12 months following discontinuation of treatment Assessed by ELN 2022 criteria
MRD assessment Up to 12 months following discontinuation of treatment To assess minimum residual disease in bone marrow as assessed by multiparameter flow cytometry (MFC) and molecular analysis
HSCT Up to 12 months following discontinuation of treatment To assess proportion of patients that undergo a hematopoietic stem-cell transplant
Ziftomenib AUC(0-last) Cycle 1 (Each cycle is 28 days) To assess the area under the plasma concentration-time-curve from time 0 to time of last measurable concentration of ziftomenib and its metabolites
Ziftomenib AUC(tau) Cycle 1 (Each cycle is 28 days) To assess the area under the plasma concentration-time-curve over a dosing interval for ziftomenib and its metabolites
Median EFS Up to 12 months following discontinuation of treatment To assess median event free survival
6-month EFS Up to 6 months following discontinuation of treatment To assess 6-month event free survival
Transfusion independence Up to 12 months following discontinuation of treatment To assess rate of transfusion independence
Gilteritinib Tmax Cycle 1 (Each cycle is 28 days) To assess the time to observed maximum plasma concentration of gilteritinib
Gilteritinib AUC(tau) Cycle 1 (Each cycle is 28 days) To assess the area under the plasma concentration-time-curve over a dosing interval for gilteritinib
Ziftomenib Tmax Cycle 1 (Each cycle is 28 days) To assess the time to observed maximum plasma concentration of ziftomenib and its metabolites
Trial Locations
- Locations (25)
Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States
USC Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
UCLA Health - Bowyer Oncology Center
🇺🇸Los Angeles, California, United States
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
Smilow Cancer Hospital at Yale New Haven
🇺🇸New Haven, Connecticut, United States
The University of Kansas
🇺🇸Kansas City, Kansas, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Henry Ford Cancer Institute
🇺🇸Detroit, Michigan, United States
UCI Health Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Roswell Park Comprehensive Cancer Center
🇺🇸Buffalo, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Stony Brook Cancer Center
🇺🇸Stony Brook, New York, United States
Atrium Health Levine Cancer Center
🇺🇸Charlotte, North Carolina, United States
OU Health Stephenson Cancer Center
🇺🇸Oklahoma City, Oklahoma, United States
Lehigh Valley Topper Cancer Institute
🇺🇸Allentown, Pennsylvania, United States
Prisma Health
🇺🇸Greenville, South Carolina, United States
Texas Oncology - Baylor Charles A. Sammons Cancer Center
🇺🇸Dallas, Texas, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
IRCCS Azienda Ospedaliero-Universitaria do Bologna - Policlinico di Sant'Orsola
🇮🇹Bologna, Italy
Ospedale Santa Maria delle Croci
🇮🇹Ravenna, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Roma, Italy
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario Central de Asturias
🇪🇸Oviedo, Spain
Hospital Universitari y Politecnic La Fe
🇪🇸Valencia, Spain