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

Kura Oncology

Status and phase: Enrolling; Phase 1

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

Treatments: Drug: Gilteritinib; Biological: Granulocyte colony-stimulating factor; Drug: Idarubicin; Drug: Ziftomenib; Drug: Cytarabine; Drug: Fludarabine

Study type: Interventional

Funder types: Industry

Identifiers

NCT06001788

KO-MEN-008

Details and patient eligibility

About

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.

Enrollment: 171 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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171 participants in 2 patient groups

Phase 1a

Experimental group

Description:

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)

Treatment:

Drug: Fludarabine

Drug: Cytarabine

Drug: Ziftomenib

Drug: Idarubicin

Biological: Granulocyte colony-stimulating factor

Drug: Gilteritinib

Phase 1b

Experimental group

Description:

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)

Treatment:

Drug: Fludarabine

Drug: Cytarabine

Drug: Ziftomenib

Drug: Idarubicin

Biological: Granulocyte colony-stimulating factor

Drug: Gilteritinib