Back to resultsA Study to Investigate BAY2402234, a Dihydroorotate Dehydrogenase (DHODH) Inhibitor, in Myeloid Malignancies
Primary Purpose
Leukemia
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
BAY2402234
Sponsored by
About this trial
This is an interventional treatment trial for Leukemia focused on measuring Acute myeloid leukemia, Myelodysplastic Syndromes, Chronic myelomonocytic leukemia, Dihydroorotate dehydrogenase (DHODH) inhibitor
Eligibility Criteria
Inclusion Criteria:
- Patients with relapsed or refractory AML. Relapsed AML is defined as relapse after achieving a response to initial therapy and refractory AML is defined as failure to achieve a response after one previous line of therapy. Response is defined as per IWG criteria (CR, CRi or CRp). Patients who are not candidates to receive or who decline standard of care therapy are also eligible.
- Patients with intermediate-1 or higher risk MDS who have failed therapy with a hypomethylating agent, or have failed lenalidomide therapy if harboring a 5q-chromosomal deletion.
- Patients with relapsed/refractory CMML.
- Estimated glomerular filtration rate (eGFR) > 40 mL per 1.73 m^2
- Patients must have adequate coagulation (international normalized ratio [INR] ≤ 1.5; activated partial thromboplastin time [aPTT] ≤1.5 X the upper limit of normal [ULN]; patients on chronic anticoagulation therapy at investigator's discretion; patients on chronic use of direct-acting oral anticoagulants who have acceptable benefit-risk ratio at investigator's discretion)
- Adequate liver function (total bilirubin ≤1.5 X ULN (or ≤3 X ULN in patients with documented Gilbert's syndrome or for patients with hyperbilirubinemia considered due to myeloid disease), alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≤3 X ULN (or ≤5 X ULN for patients with liver involvement of their myeloid disease)
Exclusion Criteria:
- Patients eligible for hematopoietic stem cell transplantation
- Clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia
- Human immunodeficiency virus (HIV) infection
- Chronic or active hepatitis B or C if not controlled by antiviral therapy
- History of organ allograft (allogeneic bone marrow or stem cell transplant) within 3 months prior to first dose of study drug
- Serious, uncontrolled infection requiring systemic antibiotic, antifungal or antiviral therapy. Prophylactic antibiotic, antifungal and/or antiviral therapy is permitted
- Left ventricular ejection fraction (LVEF) <40%
Sites / Locations
- Montefiore Medical Center
- Memorial Sloan-Kettering Cancer Center
- Thomas Jefferson University
- Vanderbilt University Medical Center
- Institut Gustave Roussy
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Dose Escalation
Dose Expansion: AML
Dose Expansion: MDS
Arm Description
Dose escalation with sequential cohorts enrolling patients with AML, MDS, or CMML. Patients will be treated in 28-day cycles with once daily oral administration of BAY2402234
After completion of dose escalation, an expansion cohort comprised of patients with AML will start. These patients will be treated in 28 day cycles with once daily oral administration of BAY2402234 at the maximum tolerated dose or pharmacologically active dose.
After completion of dose escalation, an expansion cohort comprised of patients with MDS will start. These patients will be treated in 28 day cycles with once daily oral administration of BAY2402234 at the maximum tolerated dose or pharmacologically active dose.
Outcomes
Primary Outcome Measures
Maximum tolerated dose (MTD)
The MTD was defined as the maximum dose administered during Cycle 1 at which the estimated dose-limiting toxicity (DLT) probability is closest to 30%.
Number of subjects with DLTs
A dose-limiting toxicity (DLT) was defined as any of the events that are clearly unrelated to underlying disease and occurring at any particular dose level during the first 28 days (i.e. Cycle 1) of treatment for non-hematological DLTs, or 42 days after the start of treatment, in the absence of active disease (i.e. < 5% blasts in bone marrow and absence of leukemic blasts in peripheral blood) for hematological DLTs. The National Cancer Institute Common Terminology Criteria for Adverse Events Version (CTCAE) v4.03 will be used to assess toxicities.
AUC(0-24) (area under the concentration versus time curve from time zero to 24 hours) after single dose on Cycle 1 Day 1 (C1D1)
Cmax (maximum observed drug concentration in plasma after single dose administration) on C1D1
AUC(0-24)md (AUC(0-24) after multiple dose) on Cycle 1 Day 15 (C1D15)
Cmax,md (Cmax after multiple dose) on C1D15
Number of subjects with Treatment Emergent Adverse Events (TEAEs)
An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study.
Secondary Outcome Measures
Number of acute myeloid leukemia (AML) patients with complete remission (CR) and complete response with partial recovery of peripheral blood counts (CRh)
Number of myelodysplastic syndrome (MDS) patients with hematologic improvement (erythroid response, platelet response, and neutrophil response)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03404726
Brief Title
A Study to Investigate BAY2402234, a Dihydroorotate Dehydrogenase (DHODH) Inhibitor, in Myeloid Malignancies
Official Title
An Open-label, Multicenter Phase 1 Study to Characterize the Safety, Tolerability, Preliminary Antileukemic Activity, Pharmacokinetics, and Maximum Tolerated Dose or Pharmacological Active Dose of BAY2402234 in Patients With Advanced Myeloid Malignancies
Study Type
Interventional
2. Study Status
Record Verification Date
December 2021
Overall Recruitment Status
Terminated
Why Stopped
Lack of sufficient clinical benefit
Study Start Date
March 29, 2018 (Actual)
Primary Completion Date
January 26, 2021 (Actual)
Study Completion Date
January 26, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary objective is to determine the safety, tolerability, pharmacokinetics, maximum tolerated dose (MTD), or pharmacological active dose (PAD) of BAY2402234 in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML).
The secondary objective is to evaluate evidence of clinical efficacy associated with BAY2402234 in patients with AML (defined as Complete remission, Complete remission with partial hematologic recovery), and MDS (defined as hematological improvement).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia
Keywords
Acute myeloid leukemia, Myelodysplastic Syndromes, Chronic myelomonocytic leukemia, Dihydroorotate dehydrogenase (DHODH) inhibitor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Dose Escalation
Arm Type
Experimental
Arm Description
Dose escalation with sequential cohorts enrolling patients with AML, MDS, or CMML. Patients will be treated in 28-day cycles with once daily oral administration of BAY2402234
Arm Title
Dose Expansion: AML
Arm Type
Experimental
Arm Description
After completion of dose escalation, an expansion cohort comprised of patients with AML will start. These patients will be treated in 28 day cycles with once daily oral administration of BAY2402234 at the maximum tolerated dose or pharmacologically active dose.
Arm Title
Dose Expansion: MDS
Arm Type
Experimental
Arm Description
After completion of dose escalation, an expansion cohort comprised of patients with MDS will start. These patients will be treated in 28 day cycles with once daily oral administration of BAY2402234 at the maximum tolerated dose or pharmacologically active dose.
Intervention Type
Drug
Intervention Name(s)
BAY2402234
Intervention Description
BAY2402234 is a potent and selective small molecule inhibitor of dihydroorotate dehydrogenase. A solution of BAY2402234 will be available to initiate the trial and there are plans to transition to a tablet form of BAY2402234 once it becomes available. Both liquid and tablet formulations of BAY2402234 will be continually administered once daily by mouth in 28 day cycles.
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD)
Description
The MTD was defined as the maximum dose administered during Cycle 1 at which the estimated dose-limiting toxicity (DLT) probability is closest to 30%.
Time Frame
Up to 42 days after the first dose
Title
Number of subjects with DLTs
Description
A dose-limiting toxicity (DLT) was defined as any of the events that are clearly unrelated to underlying disease and occurring at any particular dose level during the first 28 days (i.e. Cycle 1) of treatment for non-hematological DLTs, or 42 days after the start of treatment, in the absence of active disease (i.e. < 5% blasts in bone marrow and absence of leukemic blasts in peripheral blood) for hematological DLTs. The National Cancer Institute Common Terminology Criteria for Adverse Events Version (CTCAE) v4.03 will be used to assess toxicities.
Time Frame
Up to 42 days after the first dose
Title
AUC(0-24) (area under the concentration versus time curve from time zero to 24 hours) after single dose on Cycle 1 Day 1 (C1D1)
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after dose administration at C1D1
Title
Cmax (maximum observed drug concentration in plasma after single dose administration) on C1D1
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours (QD cohorts=until 24 hours; BID cohort=until 12 hours) after dose administration at C1D1
Title
AUC(0-24)md (AUC(0-24) after multiple dose) on Cycle 1 Day 15 (C1D15)
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after dose administration at C1D15
Title
Cmax,md (Cmax after multiple dose) on C1D15
Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours (QD cohorts=until 24 hours; BID cohort=until 12 hours) after dose administration at C1D1
Title
Number of subjects with Treatment Emergent Adverse Events (TEAEs)
Description
An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study.
Time Frame
From first application of study intervention up to 30 days after end of treatment
Secondary Outcome Measure Information:
Title
Number of acute myeloid leukemia (AML) patients with complete remission (CR) and complete response with partial recovery of peripheral blood counts (CRh)
Time Frame
Up to 6 months on average
Title
Number of myelodysplastic syndrome (MDS) patients with hematologic improvement (erythroid response, platelet response, and neutrophil response)
Time Frame
Every month until disease progression or patient was withdrawn from study, up to 6 months on average
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients with relapsed or refractory AML. Relapsed AML is defined as relapse after achieving a response to initial therapy and refractory AML is defined as failure to achieve a response after one previous line of therapy. Response is defined as per IWG criteria (CR, CRi or CRp). Patients who are not candidates to receive or who decline standard of care therapy are also eligible.
Patients with intermediate-1 or higher risk MDS who have failed therapy with a hypomethylating agent, or have failed lenalidomide therapy if harboring a 5q-chromosomal deletion.
Patients with relapsed/refractory CMML.
Estimated glomerular filtration rate (eGFR) > 40 mL per 1.73 m^2
Patients must have adequate coagulation (international normalized ratio [INR] ≤ 1.5; activated partial thromboplastin time [aPTT] ≤1.5 X the upper limit of normal [ULN]; patients on chronic anticoagulation therapy at investigator's discretion; patients on chronic use of direct-acting oral anticoagulants who have acceptable benefit-risk ratio at investigator's discretion)
Adequate liver function (total bilirubin ≤1.5 X ULN (or ≤3 X ULN in patients with documented Gilbert's syndrome or for patients with hyperbilirubinemia considered due to myeloid disease), alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≤3 X ULN (or ≤5 X ULN for patients with liver involvement of their myeloid disease)
Exclusion Criteria:
Patients eligible for hematopoietic stem cell transplantation
Clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia
Human immunodeficiency virus (HIV) infection
Chronic or active hepatitis B or C if not controlled by antiviral therapy
History of organ allograft (allogeneic bone marrow or stem cell transplant) within 3 months prior to first dose of study drug
Serious, uncontrolled infection requiring systemic antibiotic, antifungal or antiviral therapy. Prophylactic antibiotic, antifungal and/or antiviral therapy is permitted
Left ventricular ejection fraction (LVEF) <40%
Facility Information:
Facility Name
Montefiore Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467-2490
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Institut Gustave Roussy
City
Villejuif Cedex
ZIP/Postal Code
94805
Country
France
12. IPD Sharing Statement
Links:
URL
http://www.clinicaltrialsregister.eu/
Description
Click here to find information about studies related to Bayer Healthcare products conducted in Europe.
URL
https://clinicaltrials.bayer.com/
Description
Click here to find results for studies related to Bayer Healthcare products.
Learn more about this trial
A Study to Investigate BAY2402234, a Dihydroorotate Dehydrogenase (DHODH) Inhibitor, in Myeloid Malignancies
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