Safety and Tolerability of Ziftomenib Combinations in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Official Title
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Phase 1 Study to Determine the Safety and Tolerability of Ziftomenib Combinations for the Treatment of KMT2A-rearranged or NPM1-mutant Relapsed/Refractory Acute Myeloid Leukemia

Conditions
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AML, AML With Mutated NPM1, Hematologic Malignancy, KMT2Ar, NPM1 Mutation, MLL Rearrangement, Leukemia, Acute Myeloid Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute, Acute Leukemia, Neoplasms by Histologic Type

Intervention / Treatment
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* Drug: Ziftomenib
* Drug: Fludarabine
* Drug: Idarubicin
* Drug: Cytarabine
* Drug: Gilteritinib
* Biological: Granulocyte colony-stimulating factor


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a<br>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<br>* Oral administration<br>* Other names: KO-539;Drug: Fludarabine<br>* Intravenous infusion<br>Drug: Idarubicin<br>* Intravenous infusion<br>Drug: Cytarabine<br>* Intravenous Infusion<br>Drug: Gilteritinib<br>* Oral administration<br>* Other names: Xospata;Biological: Granulocyte colony-stimulating factor<br>* Subcutaneous injection<br>|
| Experimental: Phase 1b<br>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<br>* Oral administration<br>* Other names: KO-539;Drug: Fludarabine<br>* Intravenous infusion<br>Drug: Idarubicin<br>* Intravenous infusion<br>Drug: Cytarabine<br>* Intravenous Infusion<br>Drug: Gilteritinib<br>* Oral administration<br>* Other names: Xospata;Biological: Granulocyte colony-stimulating factor<br>* Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of dose limiting toxicities (DLTs) per dose level | Assessed by the NCI-CTCAE v5.0 | During the first 28 days of ziftomenib in combination with SOC treatment (1 cycle) | 
| Descriptive statistics of adverse events | Assessed by the NCI-CTCAE v5.0 | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission (CR) rate for cohorts A-1, A-2, B-1, and B-2 | Assessed by ELN 2022 criteria | Up to 12 months following discontinuation of treatment | 
| Complete remission (CR) / Complete remission with partial hematologic recovery (CRh) rate for cohort A-3 | Assessed by ELN 2022 criteria | Up to 12 months following discontinuation of treatment | 
| Composite complete remission (CRc) rate | Assessed by ELN 2022 criteria | Up to 12 months following discontinuation of treatment | 
| Morphologic leukemia-free state (MLFS) rate | Assessed by ELN 2022 criteria | Up to 12 months following discontinuation of treatment | 
| OS | To assess overall survival | Up to 12 months following discontinuation of treatment | 
| 6-month OS | To assess proportion of patients alive at 6 months | Up to 6 months following discontinuation of treatment | 
| Median EFS | To assess median event free survival | Up to 12 months following discontinuation of treatment | 
| 6-month EFS | To assess 6-month event free survival | Up to 6 months following discontinuation of treatment | 
| DOR | To assess duration of remission | Up to 12 months following discontinuation of treatment | 
| MRD assessment | To assess minimum residual disease in bone marrow | Up to 12 months following discontinuation of treatment | 
| HSCT | To assess proportion of patients that undergo a hematopoietic stem-cell transplant | Up to 12 months following discontinuation of treatment | 
| Transfusion independence | To assess transfusion independence | Up to 12 months following discontinuation of treatment | 
| Ziftomenib Cmax | To assess the maximum plasma combination of ziftomenib and its metabolites | Cycle 1 (Each cycle is 28 days) | 
| Ziftomenib Tmax | To assess the time to observed maximum plasma concentration of ziftomenib and its metabolites | Cycle 1 (Each cycle is 28 days) | 
| Ziftomenib AUC(0-last) | To assess the area under the plasma concentration-time-curve from time 0 to time of last measurable concentration of ziftomenib and its metabolites | Cycle 1 (Each cycle is 28 days) | 
| Ziftomenib AUC(tau) | To assess the area under the plasma concentration-time-curve over a dosing interval for ziftomenib and its metabolites | Cycle 1 (Each cycle is 28 days) | 
| Gilteritinib Cmax | To assess the maximum plasma combination of gilteritinib | Cycle 1 (Each cycle is 28 days) | 
| Gilteritinib Tmax | To assess the time to observed maximum plasma concentration of gilteritinib | Cycle 1 (Each cycle is 28 days) | 
| Gilteritinib AUC(0-last) | To assess the area under the plasma concentration-time-curve from time 0 to time of last measurable concentration of gilteritinib | Cycle 1 (Each cycle is 28 days) | 
| Gilteritinib AUC(tau) | To assess the area under the plasma concentration-time-curve over a dosing interval for gilteritinib | Cycle 1 (Each cycle is 28 days) |