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

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)

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)

Study Overview

• Status: Completed
• Conditions: Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: BAY1436032

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12200
    • Universitätsklinikum Charite zu Berlin
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg Eppendorf (UKE)
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Universitatsklinikum Heidelberg
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover (MHH)
  • Sachsen
    • Leipzig, Sachsen, Germany
      • Universitätsklinikum Leipzig AöR
• United States
  • New York
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Comprehensive Cancer Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: BAY1436032; 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; 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.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Bayer

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2017
• Primary Completion (Actual): December 6, 2018
• Study Completion (Actual): March 15, 2019

Study Registration Dates

• First Submitted: April 6, 2017
• First Submitted That Met QC Criteria: April 20, 2017
• First Posted (Actual): April 25, 2017

Study Record Updates

• Last Update Posted (Actual): May 14, 2019
• Last Update Submitted That Met QC Criteria: May 13, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Phase 1; IDH1 mutation; mIDH1; mIDH1 inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: 19036; 2016-004095-22 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No