Neoplasms
Conditions
Keywords
Safety, Tolerability, Pharmacokinetics
Brief summary
The PI3K (phosphoinositol 3-Kinase) inhibitor Copanlisib and the MEK (mitogen-activated protein kinase) inhibitor Refametinib (BAY86-9766)have both been tested as single agent treatments in other phase I studies. This study will test the combination of these two drugs to try and answer the following questions: 1. What are the side effects of the combination of Copanlisib and Refametinib (BAY86-9766)when given together at different/increasing dose levels? 2. What dose level of Copanlisib and Refametinib (BAY86-9766) should be tested in future clinical research studies? 3. How much Copanlisib is in the blood at specific times after administration and does adding Refametinib (BAY86-9766) have an affect? 4. How much Refametinib (BAY86-9766) is in the blood at specific times after administration and does adding Copanlisib have an affect? 5. Does the combination of Refametinib (BAY86-9766) and Copanlisib have an effect on tumors?
Interventions
DRUGCopanlisib + Refametinib (BAY86-9766)
Copanlisib will be administered as an IV infusion weekly for 3 weeks in combination with Refametinib (BAY86-9766) at varying dose levels. Refametinib (BAY86-9766) is administered orally twice a day starting at Day 4 of Cycle 1.
Sponsors
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than/equal to 18 years old * ECOG Performance Status of 0 - 1 * Life expectancy of at least 12 weeks * Patients with advanced, histologically or cytologically confirmed solid tumors, refractory to any standard therapy or have no standard therapy available * LVEF (left ventricular ejection fraction) \> or = to the lower limit of normal for the institution * Radiographically or clinically evaluable tumor * Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 14 days prior to start of first dose: * Hemoglobin \> 9.0 g/dL * Absolute neutrophil count (ANC) \> or = 1500/mm3 * Platelet count \> or = 100,000 /mm3 * Total bilirubin \< or = 1.5 times the upper limit of normal * ALT (alanine aminotransferase) and AST (aspartate aminotransferase) \< or = 2.5 x upper limit of normal (\< or = 5 x upper limit of normal for patients with liver involvement) * PT-INR (prothrombin-international normalized ratio) and PTT (partial thromboplastin time) \< or = 1.5 times the upper limit of normal * Serum creatinine \< or = 1.5 times the upper limit of normal
Exclusion criteria
* History of impaired cardiac function or clinically significant cardiac disease (i.e. congestive heart failure (CHF) NYHA (New York Heart Association) Class III or IV); active coronary artery disease, myocardial infarction within 6 months of study entry; new onset or unstable angina within 3 months of study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy * Type 1 or type 2 diabetes mellitus or fasting glucose \> 125 mg/dL or HgBA1c \> or = 7.0 * Use of systemic corticosteroids within 2 weeks of study entry * History of retinal vein occlusion * Known glucose-6-phosphate dehydrogenase (G6PD) deficiency * Active clinically serious infection * Uncontrolled hypertension * Positive for HIV, or chronic Hepatitis B or C * Subjects undergoing renal dialysis * Known bleeding diathesis * Ongoing substance abuse * Pregnant or breast-feeding women
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Tolerated Dose | 2 years |
| Comparison of the Copanlisib AUC when given alone with the AUC when given with Refametinib (BAY86-9766) | At day 15 |
| Comparison of the Refametinib (BAY86-9766) AUC when given alone with the AUC when given with Copanlisib | At day 15 |
Secondary
| Measure | Time frame |
|---|---|
| Tumor Response as measured by RECIST 1.1 criteria | 3 years |
| Pharmacodynamic biomarker evaluation analysis using paired tumor biopsies | 3 years |
| Biomarker evaluation including analysis of pathway activation in blood and plasma | 3 years |
| Tumor Response as measured by FDG-PET at MTD and expansion cohort(s) | 3 years |
Countries
Germany, Netherlands, United States
Outcome results
None listed