A Study to Investigate the Safety and Tolerability of Ziftomenib in Combination with Venetoclax/Azacitidine, Venetoclax, or 7+3 in Patients with AML

Kura Oncology

Status and phase: Enrolling; Phase 1

Conditions: Myeloid Sarcoma; Mixed Phenotype Acute Leukemia; AML with Mutated NPM1; KMT2Ar; NPM1 Mutation; Acute Myeloid Leukemia, in Relapse; Acute Myeloid Leukemia Recurrent; Refractory AML; Mixed Lineage Acute Leukemia; Mixed Lineage Leukemia Gene Mutation; Acute Myeloid Leukemia

Treatments: Drug: Daunorubicin; Drug: Cytarabine; Drug: Venetoclax; Drug: Ziftomenib; Drug: Azacitidine

Study type: Interventional

Funder types: Industry

Identifiers

NCT05735184

KO-MEN-007

Details and patient eligibility

About

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.

Enrollment: 212 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria:

• 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 Exclusion Criteria:

• 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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212 participants in 11 patient groups

Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1)

Experimental group

Description:

Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Treatment:

Drug: Azacitidine

Drug: Ziftomenib

Drug: Venetoclax

Dose Escalation: Ziftomenib/7+3 in 1L NPM1-m (A-2)

Experimental group

Description:

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

Treatment:

Drug: Ziftomenib

Drug: Cytarabine

Drug: Daunorubicin

Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1)

Experimental group

Description:

Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy

Treatment:

Drug: Azacitidine

Drug: Ziftomenib

Drug: Venetoclax

Dose Escalation: Ziftomenib/7+3 in 1L KMT2A-r (B-2)

Experimental group

Description:

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

Treatment:

Drug: Ziftomenib

Drug: Cytarabine

Drug: Daunorubicin

Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1)

Experimental group

Description:

Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Treatment:

Drug: Azacitidine

Drug: Ziftomenib

Drug: Venetoclax

Dose Validation/Expansion: Ziftomenib/7+3 in 1L NPM1-m (A-2)

Experimental group

Description:

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

Treatment:

Drug: Ziftomenib

Drug: Cytarabine

Drug: Daunorubicin

Dose Validation/Expansion: Ziftomenib/Venetoclax in R/R NPM1-m (A-3)

Experimental group

Description:

Ziftomenib/Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Treatment:

Drug: Ziftomenib

Drug: Venetoclax

Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L NPM1-m (A-4)

Experimental group

Description:

Ziftomenib/Venetoclax/Azacitidine in newly diagnosed NPM1-m AML patients

Treatment:

Drug: Azacitidine

Drug: Ziftomenib

Drug: Venetoclax

Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1)

Experimental group

Description:

Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy

Treatment:

Drug: Azacitidine

Drug: Ziftomenib

Drug: Venetoclax

Dose Validation/Expansion: Ziftomenib/7+3 in 1L KMT2A-r (B-2)

Experimental group

Description:

Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy

Treatment:

Drug: Ziftomenib

Drug: Cytarabine

Drug: Daunorubicin

Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L KMT2A-r (B-3)

Experimental group

Description:

Ziftomenib/Venetoclax/Azacitidine in newly diagnosed KMT2A-r AML patients

Treatment:

Drug: Azacitidine

Drug: Ziftomenib

Drug: Venetoclax