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

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ClinicalTrials.gov Identifier: NCT03404726
Recruitment Status : Terminated (Lack of sufficient clinical benefit)
First Posted : January 19, 2018
Last Update Posted : March 5, 2021
Sponsor:
Information provided by (Responsible Party):
Bayer

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

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Study Type : Interventional  (Clinical Trial)
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 : March 29, 2018
Actual Primary Completion Date : January 26, 2021
Actual Study Completion Date : January 26, 2021


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.




Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: Up to 42 days after the first dose ]
    Phase 1 dose escalation study with increasing doses of study drug (BAY2402234). Maximum tolerated dose will be defined as the maximum dose administered during Cycle 1 at which the incidence of dose limiting toxicities is closest to 30%.

  2. Number of Adverse Events as a measure of safety and tolerability [ Time Frame: Up to 6 months on average ]
  3. AUC (0-24) (Area under the curve) [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 hours after dose administration at Cycle 1 Day 1 and Cycle 1 Day 15 ]
  4. Cmax (Maximum concentration) [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 hours after dose administration at Cycle 1 Day 1 and Cycle 1 Day 15 ]

Secondary Outcome Measures :
  1. Composite endpoint: Number of 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 ]
    Response criteria according to modified IWG 2003. CRh is defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter)

  2. Change in erythroid response as Histological Improvement criteria for patients with MDS and CMML [ Time Frame: Every month until disease progression or patient is withdrawn from study, up to 6 months on average ]
    Response criteria according to IWG 2006.

  3. Change in platelet response as Histological Improvement criteria for patients with MDS and CMML [ Time Frame: Every month until disease progression or patient is withdrawn from study, up to 6 months on average ]
    Response criteria according to IWG 2006.

  4. Change in neutrophil response as Histological Improvement criteria for patients with MDS and CMML [ Time Frame: Every month until disease progression or patient is withdrawn from study, up to 6 months on average ]
    Response criteria according to IWG 2006.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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%

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03404726


Locations
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United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467-2490
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
France
Institut Gustave Roussy
Villejuif Cedex, France, 94805
Sponsors and Collaborators
Bayer
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT03404726    
Other Study ID Numbers: 19420
2017-002896-24 ( EudraCT Number )
First Posted: January 19, 2018    Key Record Dates
Last Update Posted: March 5, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Acute myeloid leukemia
Myelodysplastic Syndromes
Chronic myelomonocytic leukemia
Dihydroorotate dehydrogenase (DHODH) inhibitor
Additional relevant MeSH terms:
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Leukemia
Neoplasms by Histologic Type
Neoplasms