BAY1436032 in Patients With Mutant IDH1(mIDH1) Advanced Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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To determine the maximum tolerated and / or recommended Phase II dose of oral mutant IDH1 (mIDH1) inhibitor BAY1436032 and to characterize its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy in patients with mIDH1-R132X advanced acute myeloid leukemia (AML)

Official Title
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An Open-label, Non-randomized, Multicenter Phase I Study to Determine the Maximum Tolerated and / or Recommended Phase II Dose of Oral Mutant IDH1 (mIDH1) Inhibitor BAY1436032 and to Characterize Its Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Efficacy in Patients With mIDH1-R132X Advanced Acute Myeloid Leukemia (AML)

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: BAY1436032


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with advanced AML that harbors IDH1 mutation Patients are relapsed from or refractory to at least 1 previous line of therapy Good kidney and liver function Male or female patients Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Women must have a negative serum pregnancy test within 7 days prior to the first dose of study drug or be surgically or biologically sterile or postmenopausal Exclusion Criteria: Previously treated with any prior mIDH1 targeted therapy Extramedullary disease only History of clinically significant or active cardiac disease Active clinically significant infection Unresolved chronic toxicity of previous AML treatment Taking known strong cytochrome P450 (CYP) 2C8 inducers or inhibitors Pregnancy or breast-feeding

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAY1436032<br>Dose escalation: Various doses of study drug will be tested on a small number of patients/dose with the goal of identifying the most appropriate dose(s) for further evaluation in dose expansion. The MTD of the study drug may or may not be identified. It is anticipated that 3-4 patients will be treated at each dose of study drug to be tested and that 15-20 total patients will be treated in this part of the trial. Dose expansion: Up to 2 different doses of study drug will be tested on up to 30 patients/dose with the goal of identifying the most appropriate RP2D for further clinical development. The doses to be evaluated in this part of the trial will be selected based on information obtained during dose escalation. | Drug: BAY1436032<br>* BAY1436032 administered continuously as a single agent dosed twice a day orally on Days 1 to 28 of a 28-day cycle. Patients may continue treatment with BAY1436032 until disease progression, development of other unacceptable toxicity or Investigator discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) or RP2D of BAY1436032 | If the MTD is not reached during dose escalation, the primary variable will be the recommended phase 2 dose (RP2D) of BAY1436032 | Within first 4 weeks of first dose | 
| Number of participants with Adverse Events as a Measure of | As a measure of safety and tolerability | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective efficacy response | Response assessment for AML in this study will be based on the modified Cheson criteria. The following categories are used to capture the investigator's AML response evaluation: Complete remission (CR) Morphologic CR with CRh (morphologic CR with incomplete hematological recovery) and the response category CRp (morphologic CR with incomplete platelet recovery) Partial remission (PR) Response categories for morphologic leukemia-free state (MLFS), stable disease and progressive disease Progressive disease | Up to 12 weeks | 
| Duration of response | Efficacy data | Up to 12 weeks | 
| Event-free survival (EFS) | EFS defined as time from start of treatment to treatment failure, relapse, or death due to any cause. | Up to 12 weeks | 
| Change of 2 hydroxyglutarate (2-HG) level obtained at baseline and post-baseline | Assess pharmacodynamic (PD) effects and evidence of clinical efficacy associated with BAY 1436032 administration in patients. Change from baseline and percent change from baseline will be calculated. | Up to 12 weeks | 
| Cmax (maximum observed drug concentration in plasma after a single dose) | As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients. PK parameters normalized for dose and / or dose and body weight will be calculated. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hour post-dose (each cycle is 28 days) | 
| AUC(0-8) (AUC from time 0 to 8 h after a single dose) | As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients. PK parameters normalized for dose and / or dose and body weight will be calculated. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hour post-dose (each cycle is 28 days) | 
| AUC(0-12) (AUC from time 0 to 12 h after a single dose) | if feasible | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hour post-dose (each cycle is 28 days) | 
| Cmax,md (Cmax after multiple doses) | As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients. PK parameters normalized for dose and / or dose and body weight will be calculated. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, and 12 hour post-dose on Day 15; (each cycle is 28 days) | 
| AUC(0-8)md (AUC from time 0 to 8 h after multiple doses) | As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients. PK parameters normalized for dose and / or dose and body weight will be calculated. | Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hour post-dose on Day 15; (each cycle is 28 days) | 
| AUC(0-12)md (AUC from time 0 to 12 h after multiple doses) | if feasible | Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hour post-dose on Day 15; (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, mIDH1, IDH1 mutation, mIDH1 inhibitor