Mass General - Division of Clinical Research

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

Purpose

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.

Conditions

Acute Myeloid Leukemia
Mixed Lineage Acute Leukemia
Mixed Lineage Leukemia Gene Mutation
Mixed Phenotype Acute Leukemia
Refractory AML
AML With Mutated NPM1
Acute Myeloid Leukemia Recurrent
Acute Myeloid Leukemia, in Relapse
NPM1 Mutation
KMT2Ar
Myeloid Sarcoma

Eligibility

Eligible Ages: Over 18 Years
Eligible Genders: All
Accepts Healthy Volunteers: No

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

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

Study Design

Phase: Phase 1
Study Type: Interventional
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
Masking: None (Open Label)

Arm Groups

Arm	Description	Assigned Intervention
Experimental Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1)	Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy	Drug: Ziftomenib Oral Administration Drug: Venetoclax Oral Administration Drug: Azacitidine Subcutaneous or Intravenous Administration
Experimental Dose Escalation: Ziftomenib/7+3 in 1L NPM1-m (A-2)	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	Drug: Ziftomenib Oral Administration Drug: Daunorubicin Intravenous Administration Drug: Cytarabine Intravenous Administration
Experimental Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1)	Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy	Drug: Ziftomenib Oral Administration Drug: Venetoclax Oral Administration Drug: Azacitidine Subcutaneous or Intravenous Administration
Experimental Dose Escalation: Ziftomenib/7+3 in 1L KMT2A-r (B-2)	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	Drug: Ziftomenib Oral Administration Drug: Daunorubicin Intravenous Administration Drug: Cytarabine Intravenous Administration
Experimental Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1)	Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy	Drug: Ziftomenib Oral Administration Drug: Venetoclax Oral Administration Drug: Azacitidine Subcutaneous or Intravenous Administration
Experimental Dose Validation/Expansion: Ziftomenib/7+3 in 1L NPM1-m (A-2)	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	Drug: Ziftomenib Oral Administration Drug: Daunorubicin Intravenous Administration Drug: Cytarabine Intravenous Administration
Experimental Dose Validation/Expansion: Ziftomenib/Venetoclax in R/R NPM1-m (A-3)	Ziftomenib/Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy	Drug: Ziftomenib Oral Administration Drug: Venetoclax Oral Administration
Experimental Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L NPM1-m (A-4)	Ziftomenib/Venetoclax/Azacitidine in newly diagnosed NPM1-m AML patients	Drug: Ziftomenib Oral Administration Drug: Venetoclax Oral Administration Drug: Azacitidine Subcutaneous or Intravenous Administration
Experimental Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1)	Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy	Drug: Ziftomenib Oral Administration Drug: Venetoclax Oral Administration Drug: Azacitidine Subcutaneous or Intravenous Administration
Experimental Dose Validation/Expansion: Ziftomenib/7+3 in 1L KMT2A-r (B-2)	Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy	Drug: Ziftomenib Oral Administration Drug: Daunorubicin Intravenous Administration Drug: Cytarabine Intravenous Administration
Experimental Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L KMT2A-r (B-3)	Ziftomenib/Venetoclax/Azacitidine in newly diagnosed KMT2A-r AML patients	Drug: Ziftomenib Oral Administration Drug: Venetoclax Oral Administration Drug: Azacitidine Subcutaneous or Intravenous Administration

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 02114

Contact:
Amir Fathi, MD
617-724-1124

More Details

Status: Recruiting
Sponsor: Kura Oncology, Inc.

Study Contact

Clinical Operations
858 500 8800
KO-MEN-007@kuraoncology.com