A Study to Investigate BAY2402234, a Dihydroorotate Dehydrogenase (DHODH) Inhibitor, in Myeloid Malignancies

Sponsor

Bayer (Industry)

Overall Status

Terminated

CT.gov ID

NCT03404726

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: BAY2402234	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 29, 2018

Actual Primary Completion Date :

Jan 26, 2021

Actual Study Completion Date :

Jan 26, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation 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	Drug: BAY2402234 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.
Experimental: Dose Expansion: AML 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.	Drug: BAY2402234 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.
Experimental: Dose Expansion: MDS 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.	Drug: BAY2402234 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.

Arm

Intervention/Treatment

Experimental: Dose Escalation

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

Drug: BAY2402234

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.

Experimental: Dose Expansion: AML

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.

Drug: BAY2402234

Experimental: Dose Expansion: MDS

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.

Drug: BAY2402234

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) [Up to 42 days after the first dose]
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 [Up to 42 days after the first dose]
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) [Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after dose administration at C1D1]
Cmax (maximum observed drug concentration in plasma after single dose administration) on C1D1 [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]
AUC(0-24)md (AUC(0-24) after multiple dose) on Cycle 1 Day 15 (C1D15) [Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after dose administration at C1D15]
Cmax,md (Cmax after multiple dose) on C1D15 [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]
Number of subjects with Treatment Emergent Adverse Events (TEAEs) [From first application of study intervention up to 30 days after end of treatment]
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) [Up to 6 months on average]
Number of myelodysplastic syndrome (MDS) patients with hematologic improvement (erythroid response, platelet response, and neutrophil response) [Every month until disease progression or patient was withdrawn from study, up to 6 months on average]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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%

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Montefiore Medical Center	Bronx	New York	United States	10467-2490
2	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
3	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
4	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
5	Institut Gustave Roussy	Villejuif Cedex		France	94805

Sponsors and Collaborators

Bayer

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.

Responsible Party:

Bayer

ClinicalTrials.gov Identifier:

NCT03404726

Other Study ID Numbers:

19420
2017-002896-24

First Posted:

Jan 19, 2018

Last Update Posted:

Jan 11, 2022

Last Verified:

Dec 1, 2021

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Bayer

Acute myeloid leukemia

Myelodysplastic Syndromes

Chronic myelomonocytic leukemia

Dihydroorotate dehydrogenase (DHODH) inhibitor

Additional relevant MeSH terms:

Leukemia

Study Results

No Results Posted as of Jan 11, 2022