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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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NPM1 Mutation, 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, KMT2Ar, Myeloid Sarcoma

Intervention / Treatment
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* Drug: Ziftomenib
* Drug: Venetoclax
* Drug: Azacitidine
* Drug: Daunorubicin
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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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

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: Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1)<br>Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy | Drug: Ziftomenib<br>* Oral Administration<br>Drug: Venetoclax<br>* Oral Administration<br>Drug: Azacitidine<br>* Subcutaneous or Intravenous Administration<br>|
| Experimental: Dose Escalation: Ziftomenib/7+3 in 1L NPM1-m (A-2)<br>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<br>* Oral Administration<br>Drug: Daunorubicin<br>* Intravenous Administration<br>Drug: Cytarabine<br>* Intravenous Administration<br>|
| Experimental: Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1)<br>Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy | Drug: Ziftomenib<br>* Oral Administration<br>Drug: Venetoclax<br>* Oral Administration<br>Drug: Azacitidine<br>* Subcutaneous or Intravenous Administration<br>|
| Experimental: Dose Escalation: Ziftomenib/7+3 in 1L KMT2A-r (B-2)<br>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<br>* Oral Administration<br>Drug: Daunorubicin<br>* Intravenous Administration<br>Drug: Cytarabine<br>* Intravenous Administration<br>|
| Experimental: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1)<br>Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy | Drug: Ziftomenib<br>* Oral Administration<br>Drug: Venetoclax<br>* Oral Administration<br>Drug: Azacitidine<br>* Subcutaneous or Intravenous Administration<br>|
| Experimental: Dose Validation/Expansion: Ziftomenib/7+3 in 1L NPM1-m (A-2)<br>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<br>* Oral Administration<br>Drug: Daunorubicin<br>* Intravenous Administration<br>Drug: Cytarabine<br>* Intravenous Administration<br>|
| Experimental: Dose Validation/Expansion: Ziftomenib/Venetoclax in R/R NPM1-m (A-3)<br>Ziftomenib/Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy | Drug: Ziftomenib<br>* Oral Administration<br>Drug: Venetoclax<br>* Oral Administration<br>|
| Experimental: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L NPM1-m (A-4)<br>Ziftomenib/Venetoclax/Azacitidine in newly diagnosed NPM1-m AML patients | Drug: Ziftomenib<br>* Oral Administration<br>Drug: Venetoclax<br>* Oral Administration<br>Drug: Azacitidine<br>* Subcutaneous or Intravenous Administration<br>|
| Experimental: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1)<br>Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy | Drug: Ziftomenib<br>* Oral Administration<br>Drug: Venetoclax<br>* Oral Administration<br>Drug: Azacitidine<br>* Subcutaneous or Intravenous Administration<br>|
| Experimental: Dose Validation/Expansion: Ziftomenib/7+3 in 1L KMT2A-r (B-2)<br>Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy | Drug: Ziftomenib<br>* Oral Administration<br>Drug: Daunorubicin<br>* Intravenous Administration<br>Drug: Cytarabine<br>* Intravenous Administration<br>|
| Experimental: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L KMT2A-r (B-3)<br>Ziftomenib/Venetoclax/Azacitidine in newly diagnosed KMT2A-r AML patients | Drug: Ziftomenib<br>* Oral Administration<br>Drug: Venetoclax<br>* Oral Administration<br>Drug: Azacitidine<br>* Subcutaneous or Intravenous Administration<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 backbone 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 | 
| Complete remission (CR) rate | Assessed by the ELN 2022 criteria | Up to 1 year following end of treatment with ziftomenib | 

Secondary Outcome Measures

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