This is an open-label, two-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 gemcitabine (Arm A) or pazopanib, gemcitabine, and cisplatin (Arm B) in patients with advanced solid tumors. Patients will be enrolled in cohorts of 3 to receive escalating doses of pazopanib and gemcitabine or pazopanib, gemcitabine and cisplatin. 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. Six to 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
22
initial dose 400mg daily in 21-day cycles; increase in dose up to 800mg daily following evaluation of safety and tolerability
Gemcitabine on Days 1 and 8 of each cycle; initial dose 600 mg/m2 increase to 1,000mg/m2 after evaluation of safety and tolerability; increase to 1250mg/m2 after evaluation of safety and tolerability
Cisplatin on Day 1 of each 21-day cycle initial dose 60mg/m2; increase to 80mg/m2 after evaluation of safety and tolerability
GSK Investigational Site
Essen, North Rhine-Westphalia, Germany
GSK Investigational Site
Newcastle upon Tyne, Northumberland, United Kingdom
Optimum tolerated regimen (OTR) for each regimen in each arm of the study. OTR determined evaluation of AEs and change in lab values. OTR defined as the highest dosing regimen that results in dose limiting toxicity in no more than 1 of 6 subjects
Time frame: Until disease progression
Anti-tumor activity evaluated using RECIST criteria (if subjects have measurable disease). Assessments of disease every 6 to 12 weeks, recorded as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD).
Time frame: Until Disease progression
Pharmacokinetic parameters AUC(0-24), Cmax, and tmax of pazopanib, gemcitabine, and ultrafilterable platinum.
Time frame: Dose Expansion - Cycle; Dose-Expansion Cycle 2
Levels of circulating cytokine and angiogenic factors (CAF) biomarkers (such as IL 2, IL-10, VEGF, sVEGFR2) in plasma will be determined
Time frame: Day 1 of each cycle until disease progression
Genetic variants in select candidate genes in the host DNA will be evaluated
Time frame: Day 1 of first cycle
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