An Open-label Phase I Dose-escalation Study to Characterize the Safety, Tolerability, Pharmacokinetics, and Maximum Tolerated Dose of BAY1143572 Given in a Once-daily or an Intermittent Dosing Schedule in Subjects With Advanced Acute Leukemia
Overview
- Phase
- Phase 1
- Intervention
- Atuveciclib, BAY1143572
- Conditions
- Leukemia
- Sponsor
- Bayer
- Enrollment
- 42
- Locations
- 7
- Primary Endpoint
- Maximum Total Observed Drug Concentration of BAY1143572 after Multiple Dose Administration in Plasma (Cmax,md)
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
To determine the safety, tolerability, pharmacokinetics, maximum tolerated dose, and recommended Phase II dose of BAY1143572 in a once-daily or an intermittent dosing schedule in subjects with advanced acute leukemia
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female subjects aged \>/=18 years
- •Subjects with a histologically or cytologically confirmed acute leukemia who are refractory to or have exhausted all available therapies
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- •Life expectancy of at least 12 weeks
- •Adequate liver and renal functions as assessed by the following laboratory requirements to be conducted within 14 days before the first dose of study drug:
- •Total bilirubin \</=1.5 times the upper limit of normal (ULN)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \</=2.5 times ULN (\</=5 times ULN for subjects with liver involvement of their cancer)
- •International normalized ratio (INR) \</=1.5 times ULN
- •Estimated glomerular filtration rate (eGFR) \>/=50 mL/min per 1.73 m2 according to the Modification of Diet in Renal Disease Study Group (MDRD) formula
- •Negative serum or urine pregnancy test must be obtained within 7 days before the first dose of study drug in women of childbearing potential. Negative results must be available before study drug administration
Exclusion Criteria
- •Known hypersensitivity to the study drug or excipients of the preparation or any agent given in association with this study
- •History of cardiac disease including congestive heart failure New York Heart Association (NYHA) Class \>/=III, unstable angina (anginal symptoms at rest) or new-onset angina (within the last 6 months) or myocardial infarction within the past 6 months or cardiac arrhythmias requiring anti-arrhythmic therapy except for beta-blockers and digoxin; evidence for uncontrolled coronary artery disease (e.g. major regional wall motion abnormalities on baseline echocardiography or a left ventricular ejection fraction (LVEF) \<45%)
- •Previous pulmonary embolism within 12 months before study entry
- •Uncontrolled hypertension defined as systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg, despite optimal medical management and stable antihypertensive treatment for more than 7 days before the first dose of study drug
- •Moderate or severe hepatic impairment, i.e. Child-Pugh class B or C
- •Known history of human immunodeficiency virus (HIV) infection
- •Chronic or active hepatitis B or C, requiring antiviral therapy
- •Serious, uncontrolled infection requiring systemic antibiotic, antifungal or antiviral therapy
- •Uncontrolled meningeal leukemia
- •Prior allogeneic hematopoietic stem cell transplant within \</=4 months before first dose of study drug (Subjects must have completed immunosuppressive therapy before enrollment.
Arms & Interventions
20 mg BAY1143572
Subjects received 20 milligram (mg) BAY1143572 tablet orally once daily from Cycle 1 Day 1 of each cycle.
Intervention: Atuveciclib, BAY1143572
40 mg BAY1143572
Subjects received 40 mg BAY1143572 tablet orally once daily from Cycle 1 Day 1 of each cycle.
Intervention: Atuveciclib, BAY1143572
80 mg BAY1143572
Subjects received BAY1143572 80 mg tablet orally once daily from Cycle 1 Day 1 of each cycle.
Intervention: Atuveciclib, BAY1143572
120 mg BAY1143572
Subjects received BAY1143572 120 mg tablet orally once daily from Cycle 1 Day 1 of each cycle.
Intervention: Atuveciclib, BAY1143572
160 mg BAY1143572
Subjects received BAY1143572 160 mg tablet orally once daily from Cycle 1 Day 1 of each cycle.
Intervention: Atuveciclib, BAY1143572
200 mg BAY1143572
Subjects received BAY1143572 200 mg tablet orally once daily from Cycle 1 Day 1 of each cycle.
Intervention: Atuveciclib, BAY1143572
240 mg BAY1143572
Subjects received BAY1143572 240 mg tablet orally once daily from Cycle 1 Day 1 of each cycle.
Intervention: Atuveciclib, BAY1143572
Outcomes
Primary Outcomes
Maximum Total Observed Drug Concentration of BAY1143572 after Multiple Dose Administration in Plasma (Cmax,md)
Time Frame: Pre-dose up to 24 hours post-dose on Cycle 1 Day 15
Maximum total observed drug concentration of BAY1143572 after multiple dose administration in plasma was measured.
Maximum Tolerated Dose (MTD) of BAY1143572 in Advanced Acute Leukemia Subjects
Time Frame: After the first 28 days of treatment (cycle 1)
The MTD was defined as the highest dose that could be given such that not more than 20% of subjects experience a dose limiting toxicity (DLT) during Cycle 1. The study was terminated prior to the determination of MTD and hence no data was presented.
Area Under the Concentration Versus Time Curve from Zero to 24 hours of BAY1143572 in Plasma after Multiple Dose Administration (AUC[O-24h]md)
Time Frame: Pre-dose up to 24 hours post-dose on Cycle 1 Day 15
Area under the concentration versus time curve from zero to 24 hours of BAY1143572 in plasma after multiple dose administration was measured.
Area Under the Concentration Versus Time Curve from Zero to Last Data Point Greater than Lower Limit of Quantitation (LLOQ) of BAY1143572 in Plasma (AUC[0-tlast]) after Single Dose Administration
Time Frame: Pre-dose up to 24 hours post-dose on Cycle 1 Day 1
Area under the concentration versus time curve from zero to last data point greater than lower limit of quantitation of BAY1143572 in plasma after single dose administration was measured.
Time to Reach Maximum Drug Concentration of BAY1143572 in Plasma after Multiple Dose Administration (tmax,md)
Time Frame: Pre-dose up to 24 hours post-dose on Cycle 1 Day 15
Time to reach maximum drug concentration of BAY1143572 in plasma after multiple dose administration was measured.
Maximum Total Observed Drug Concentration (Cmax) of BAY1143572 after Single Dose Administration in Plasma
Time Frame: Pre-dose up to 24 hours post-dose on Cycle1 Day 1
Maximum total observed drug concentration of BAY1143572 after single dose administration in plasma was measured.
Area Under the Concentration Versus Time Curve from Zero to 24 hours (AUC[0-24h]) of BAY1143572 in Plasma After Single Dose Administration
Time Frame: Pre-dose up to 24 hours post-dose on Cycle1 Day 1
Area under the concentration versus time curve from zero to 24 hours of BAY1143572 in plasma after single dose administration was measured.
Time to Reach Maximum Drug Concentration (tmax) of BAY1143572 in Plasma after Single Dose Administration
Time Frame: pre-dose up to 24 hours post-dose on Cycle 1 Day 1
Time to reach maximum drug concentration of BAY1143572 in plasma after single dose administration was measured.
Secondary Outcomes
- Number of Subjects with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)(From start of study drug administration up to 30 days after the last dose of study drug administration (approximately 2.5 years))
- Number of Subjects With Leukemia Response(From start of treatment of the first subject until 28 days)
- Area Under the Concentration Versus Time Curve from Zero to Infinity (AUC) of BAY1143572 after Single Dose Administration in Plasma(Pre-dose up to 24 hours post-dose on C1D1)