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

Sponsor

Kura Oncology, Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05735184

Collaborator

(none)

212

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Ziftomenib Drug: Venetoclax Drug: Azacitidine Drug: Daunorubicin Drug: Cytarabine	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

212 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 1 Study of Venetoclax/Azacitidine or Venetoclax in Combination With Ziftomenib or Standard Induction Cytarabine/Daunorubicin (7+3) Chemotherapy in Combination With Ziftomenib for the Treatment of Patients With Acute Myeloid Leukemia

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

May 1, 2026

Anticipated Study Completion Date :

May 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
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

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 backbone 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
Complete remission (CR) rate [Up to 1 year following end of treatment with ziftomenib]
Assessed by the ELN 2022 criteria

Secondary Outcome Measures

Composite Complete Remission (CRc) or MLFS rate [Up to 1 year following end of treatment with ziftomenib]
Assessed by the ELN 2022 criteria
Measurable residual disease (MRD) [Up to 1 year following end of treatment with ziftomenib]
Assessed by multiparameter flow cytometry (MFC) and molecular analysis
Median OS [Up to 1 year following end of treatment with ziftomenib]
To assess overall survival of ziftomenib
Proportion of patients alive [1 year following end of treatment with ziftomenib]
To assess proportion of patients alive at 1 year following treatment with ziftomenib
Median EFS [Up to 1 year following end of treatment with ziftomenib]
To assess median event free survival
EFS [1 year following end of treatment with ziftomenib]
To assess event free survival
Median DOR [Up to 1 year following end of treatment with ziftomenib]
To assess median duration of remission
Proportion of patients who undergo HSCT [Up to 1 year following end of treatment with ziftomenib]
To assess proportion of patients who undergo hematopoietic stem cell transplant
TI [Up to 1 year following end of treatment with ziftomenib]
To assess rate of transfusion independence
Cmax [Cycle 1. Each cycle is 28 days.]
Maximum plasma concentration (Cmax) of ziftomenib and metabolites
Tmax [Cycle 1. Each cycle is 28 days.]
Time to maximum plasma concentration (Tmax) of ziftomenib and metabolites
AUC0-last [Cycle 1. Each cycle is 28 days.]
Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last) of ziftomenib and metabolites
AUCtau [Cycle 1. Each cycle is 28 days.]
Area under the concentration-time curve over a dosing interval (AUCtau) of ziftomenib
Accumulation ratio of ziftomenib and metabolites [Cycle 1. Each cycle is 28 days.]
To assess accumulation ratio of ziftomenib and metabolites
Cmax of venetoclax [Cycle 1. Each cycle is 28 days.]
Maximum plasma concentration (Cmax) of venetoclax
Tmax of venetoclax [Cycle 1. Each cycle is 28 days.]
Time to maximum plasma concentration (Tmax) of venetoclax
AUC0-last of venetoclax [Cycle 1. Each cycle is 28 days.]
Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last) of venetoclax
AUCtau of venetoclax [Cycle 1. Each cycle is 28 days.]
Area under the concentration-time curve over a dosing interval (AUCtau) of venetoclax

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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