Safety and Tolerability of Ziftomenib Combinations in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase 1a 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) |
Drug: Ziftomenib
Oral administration
Other Names:
Drug: Fludarabine
Intravenous infusion
Drug: Idarubicin
Intravenous infusion
Drug: Cytarabine
Intravenous Infusion
Drug: Gilteritinib
Oral administration
Other Names:
Biological: Granulocyte colony-stimulating factor
Subcutaneous injection
|
| Experimental: Phase 1b 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) |
Drug: Ziftomenib
Oral administration
Other Names:
Drug: Fludarabine
Intravenous infusion
Drug: Idarubicin
Intravenous infusion
Drug: Cytarabine
Intravenous Infusion
Drug: Gilteritinib
Oral administration
Other Names:
Biological: Granulocyte colony-stimulating factor
Subcutaneous injection
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
- 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
- Morphologic leukemia-free state (MLFS) rate [Up to 12 months following discontinuation of treatment]
Assessed by ELN 2022 criteria
- OS [Up to 12 months following discontinuation of treatment]
To assess overall survival
- 6-month OS [Up to 6 months following discontinuation of treatment]
To assess proportion of patients alive at 6 months
- 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
- DOR [Up to 12 months following discontinuation of treatment]
To assess duration of remission
- MRD assessment [Up to 12 months following discontinuation of treatment]
To assess minimum residual disease in bone marrow
- HSCT [Up to 12 months following discontinuation of treatment]
To assess proportion of patients that undergo a hematopoietic stem-cell transplant
- Transfusion independence [Up to 12 months following discontinuation of treatment]
To assess transfusion independence
- Ziftomenib Cmax [Cycle 1 (Each cycle is 28 days)]
To assess the maximum plasma combination of ziftomenib and its metabolites
- Ziftomenib Tmax [Cycle 1 (Each cycle is 28 days)]
To assess the time to observed maximum plasma concentration of ziftomenib and its metabolites
- 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
- Gilteritinib Cmax [Cycle 1 (Each cycle is 28 days)]
To assess the maximum plasma combination of gilteritinib
- Gilteritinib Tmax [Cycle 1 (Each cycle is 28 days)]
To assess the time to observed maximum plasma concentration of gilteritinib
- 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
- 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
Eligibility Criteria
Criteria
Key Inclusion Criteria:
-
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 Exclusion Criteria:
-
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.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Kura Oncology, Inc.
Investigators
- Study Director: Clinical Development, Kura Oncology
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- KO-MEN-008