This phase I trial studies the side effects and best dose of dabrafenib and pazopanib hydrochloride when given together in treating patients with advanced malignant tumors. Dabrafenib and pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
PRIMARY OBJECTIVES: I. To assess the safety and tolerability of GSK2118436 (dabrafenib) given with pazopanib (pazopanib hydrochloride) as well as determining the maximum tolerated dosing regimen in patients with BRAF mutated advanced malignant tumors. SECONDARY OBJECTIVES: I. Evaluate pharmacokinetics of the two study drugs and identify potential drug-drug interactions. II. Determine pharmacogenomics with microarray testing. III. Perform genotyping of tumors and if objective tumor response rates are identified. IV. Assess objective tumor response rates. OUTLINE: This is a dose-escalation study. Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 (once daily on day 1 and BID on days 3-28 of course 1), and pazopanib hydrochloride PO once daily (QD) on days 1-28 (days 2-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
23
Given PO
Given PO
Pharmacokinetic studies: Blood draw for various time points: Cycle 1 Days 1, 2, 3, 4 and 15; Cycle 2 Days 1, 2; and day 1 of Cycles 4, 6 and 12 * Pharmacogenomic studies: Blood draw on Cycle 1 Day 1 * Tumor genotyping: Archival tumor blocks or unstained slides * BRAF mutation quantification in circulating plasma DNA: Blood draw on Cycles 1-7 Day 1 and every other cycle thereafter; and at time of progression
Ohio State University Medical Center
Columbus, Ohio, United States
University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States
Incidence of adverse events using Common Terminology Criteria for Adverse Events (CTCAE) v4
We will summarize observed adverse events and their grade and attribution for each dose level, and patterns reflecting tolerability of the regimen explored through graphical analysis and descriptive summaries.
Time frame: 28 days
Maximum tolerated dose, defined as the dose below the dose where at least 2 dose limiting toxicities (DLTs) are observed, graded using CTCAE v4
Time frame: 28 days
Pharmacokinetics of the two study drugs (including Cmax, Css, clearance, t1/2 alpha, t1/2 beta, central volume of distribution, and steady state volume of distribution) and drug-drug interactions
Comparisons of groups of patients based on clinical response or toxicity will involve the use of analysis of variance for continuous data and categorical methods such as Fisher's exact test and chi-square tests for discrete data.
Time frame: Pre-dose, .5, 1, 2, 3, 4, 8, 24 hours
Pharmacogenomics determined with microarray testing on blood samples
Descriptive data will be computed and compared using analysis of variance and nonparametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.
Time frame: Day 1 of course 1
Genotype of tumor tissue samples
Descriptive data will be computed and compared using analysis of variance and nonparametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.
Time frame: Baseline
Objective tumor response rates with clinical assessment, tumor marker measurements and imaging studies as appropriate for each patient, as determined according to the Response Evaluation Criteria in Solid Tumors (RECIST), v1.1
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Descriptive data will be computed and compared using analysis of variance and nonparametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.
Time frame: Up to 4 weeks after completion of study treatment