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).
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).
Brief Title
A Study to Investigate BAY2402234, a Dihydroorotate Dehydrogenase (DHODH) Inhibitor, in Myeloid Malignancies
Categories
Completion Date
Completion Date Type
Actual
Conditions
Leukemia
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%
* 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%
Inclusion 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)
* 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)
Gender
All
Gender Based
false
Keywords
Acute myeloid leukemia
Myelodysplastic Syndromes
Chronic myelomonocytic leukemia
Dihydroorotate dehydrogenase (DHODH) inhibitor
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT03404726
Org Class
Industry
Org Full Name
Bayer
Org Study Id
19420
Overall Status
Terminated
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome 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%.
Outcome Measure
Maximum tolerated dose (MTD)
Outcome Time Frame
Up to 42 days after the first dose
Outcome 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.
Outcome Measure
Number of subjects with DLTs
Outcome Time Frame
Up to 42 days after the first dose
Outcome 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)
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after dose administration at C1D1
Outcome Measure
Cmax (maximum observed drug concentration in plasma after single dose administration) on C1D1
Outcome 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
Outcome Measure
AUC(0-24)md (AUC(0-24) after multiple dose) on Cycle 1 Day 15 (C1D15)
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after dose administration at C1D15
Outcome Measure
Cmax,md (Cmax after multiple dose) on C1D15
Outcome 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
Outcome 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.
Outcome Measure
Number of subjects with Treatment Emergent Adverse Events (TEAEs)
Outcome Time Frame
From first application of study intervention up to 30 days after end of treatment
Secondary Ids
Secondary Id
2017-002896-24
Secondary Outcomes
Outcome Time Frame
Up to 6 months on average
Outcome Measure
Number of acute myeloid leukemia (AML) patients with complete remission (CR) and complete response with partial recovery of peripheral blood counts (CRh)
Outcome Time Frame
Every month until disease progression or patient was withdrawn from study, up to 6 months on average
Outcome Measure
Number of myelodysplastic syndrome (MDS) patients with hematologic improvement (erythroid response, platelet response, and neutrophil response)
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Aditi Shastri
Investigator Email
ASHASTRI@montefiore.org
Investigator Phone
718-920-4826
Categories Mesh Debug
Cancer --- LEUKEMIA
Blood & Bone Marrow Cancers --- LEUKEMIA
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID, ACUTE
Blood & Bone Marrow Cancers --- MYELODYSPLASTIC SYNDROMES
Cancer --- NEOPLASMS
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID
Blood & Bone Marrow Cancers --- BONE MARROW DISEASES
Blood & Bone Marrow Cancers --- MYELODYSPLASTIC-MYELOPROLIFERATIVE DISEASES
MeSH Terms
LEUKEMIA
LEUKEMIA, MYELOID, ACUTE
MYELODYSPLASTIC SYNDROMES
LEUKEMIA, MYELOMONOCYTIC, CHRONIC
NEOPLASMS BY HISTOLOGIC TYPE
NEOPLASMS
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
LEUKEMIA, MYELOID
BONE MARROW DISEASES
MYELODYSPLASTIC-MYELOPROLIFERATIVE DISEASES
CHRONIC DISEASE
DISEASE ATTRIBUTES
PATHOLOGIC PROCESSES
PATHOLOGICAL CONDITIONS, SIGNS AND SYMPTOMS
ORLUDODSTAT