Clinical trial NCT03404726: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: Leukemia
Keywords: Acute myeloid leukemia
Myelodysplastic Syndromes
Chronic myelomonocytic leukemia
Dihydroorotate dehydrogenase (DHODH) inhibitor
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2018-01-19
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


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%

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: Up to 42 days after the first dose
measure: Number of subjects with DLTs
timeFrame: Up to 42 days after the first dose
measure: 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)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after dose administration at C1D1
measure: Cmax (maximum observed drug concentration in plasma after single dose administration) on C1D1
timeFrame: 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
measure: AUC(0-24)md (AUC(0-24) after multiple dose) on Cycle 1 Day 15 (C1D15)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after dose administration at C1D15
measure: Cmax,md (Cmax after multiple dose) on C1D15
timeFrame: 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
measure: Number of subjects with Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first application of study intervention up to 30 days after end of treatment
Secondary outcomes:
measure: Number of acute myeloid leukemia (AML) patients with complete remission (CR) and complete response with partial recovery of peripheral blood counts (CRh)
timeFrame: Up to 6 months on average
measure: Number of myelodysplastic syndrome (MDS) patients with hematologic improvement (erythroid response, platelet response, and neutrophil response)
timeFrame: Every month until disease progression or patient was withdrawn from study, up to 6 months on average
Other outcomes:
Locations:
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy
Study officials:
References: