This is an open-label, four-arm, Phase I, dose escalation study to evaluate the safety and tolerability and to determine the optimal tolerated regimen (OTR) of pazopanib in combination with epirubicin or doxorubicin in patients with advanced solid tumors. Patients will be enrolled in cohorts of 3 to receive escalating doses of pazopanib and epirubicin or doxorubicin. Dose escalation schemas for each study arm are described in the protocol. For each arm, the OTR will be defined as the highest dose combination of the agents where no more than one out of six patients experiences a dose-limiting toxicity. Twelve additional patients in each arm will be studied with the OTR to evaluate toxicity and pharmacokinetics. This will allow an assessment of potential drug-drug interactions. Antitumor activity will be assessed using RECIST criteria.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
111
Arm D - doxorubicin given as a intravenous bolus injection on Day 1 or Day 3 depending on schedule selected from Arm A, B or C - starting dose 60 mg/m2 and increase to 75mg/m2
Arm A - daily administration of pazopanib on Days 1 through 21 starting at 200mg with a maximum dose of 800mg; Arm B daily administration of pazopanib on Days 1 through 8 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm C daily dose of pazopanib on Days 14 through 21 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm D once daily administration of pazopanib (according to schedule selected from Arm A, B, or C) starting at 400mg escalating to a maximum dose of 800mg
Arm A and Arm B - epirubicin given as a bolus intravenous injection on Day 3 starting dose 60mg/m2 increase to 90mg/m2 if tolerated; Arm C - epirubicin given as a bolus intravenous injection on Day 1 starting dose 60mg/m2 increase to 90mg/m2 if tolerated
GSK Investigational Site
Milan, Lombardy, Italy
GSK Investigational Site
Bellinzona, Switzerland
GSK Investigational Site
Lausanne, Switzerland
GSK Investigational Site
Sankt Gallen, Switzerland
Optimum tolerated regimen (OTR) for each combination regimen in each arm of the study.OTR determined by evaluation of AEs and change in lab values.OTR defined as highest dosing regimen that results in dose limiting toxicity in no more than 1 of 6 subject
Time frame: Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Safety assessments, including routine physical exam findings, vital signs, clinical laboratory tests (chemistry and hematology to include coagulation factors), clinical monitoring and/or observation, and adverse event reporting.
Time frame: Safety assessment timing is noted on the Time and Events Table. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Safety and tolerability endpoints will include cardiac function (left ventricular ejection fraction) monitored by either MUGA or ECHO. A 12-lead ECG will also be monitored.
Time frame: Safety assessment timing is noted on the Time and Events Table. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Pharmacokinetic endpoints will be AUC, Cmax, Tmax, and t1/2 of pazopanib, epirubicin, and doxorubicin, and clearance of epirubicin and doxorubicin if data are sufficient.
Time frame: PK samples will only be collected in Cycle 1 and Cycle 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Assessment of anti-tumor activity using RECIST criteria will be recorded as complete response, partial response, stable disease, or progressive disease.
Time frame: Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Levels of circulating cytokine and angiogenic factors (CAF) biomarkers (such as IL 2, IL-10, VEGF, sVEGFR2) in plasma will be determined.
Time frame: Biomarker samples will only be collected in Cycles 1, 2, and 3. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Assessment of circulating BMD angiogenic cells in cancer peripheral blood in patients before and during treatment with oral pazopanib (continuous and intermittent regimens) and epirubicin or doxorubicin.
Time frame: Biomarker samples will only be collected in Cycles 1 and 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Gene expression profiling in selected subpopulations of BMD angiogenic cells in peripheral blood of cancer patients before and during treatment with pazopanib (continuous or intermittent regimens) in combination with epirubicin or doxorubicin.
Time frame: Biomarker samples will only be collected in Cycles 1 and 2. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
Genetic variants in candidate genes in the host DNA will be evaluated
Time frame: One pharmacogenetic sample will be collected during the study ideally in Cycle 1. Subjects will continue on the study until disease progression occurs or one of the discontinuation criteria is met up to approximately 48 months.
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