This phase I trial is studying the side effects and best dose of dovitinib lactate when given together with gemcitabine hydrochloride and capecitabine in treating patients with advanced or metastatic solid tumors or advanced pancreatic cancer. Dovitinib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving dovitinib lactate together with combination chemotherapy may kill more tumor cells
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose and recommended phase II dose of dovitinib (dovitinib lactate) when administered concurrently with gemcitabine (gemcitabine hydrochloride) and capecitabine in patients with advanced solid malignancies. II. To characterize the safety profile of dovitinib, gemcitabine and capecitabine combination in patients with advanced solid malignancies. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetic profile of dovitinib, capecitabine, gemcitabine and their metabolites when administered concurrently in patients with advanced solid malignancies. II. To determine the preliminary efficacy of the study combination in patients with advanced adenocarcinoma of the pancreas or biliary tract. III. To explore serum and tumor biomarkers predictive of efficacy to the study combination. OUTLINE: This is a dose-escalation study of dovitinib lactate. Patients receive dovitinib lactate orally (PO) on days 1-5, 8-12, and 15-19, gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, and capecitabine PO twice daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks and then every 3 months for 1 year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
26
Roswell Park Cancer Institute
Buffalo, New York, United States
Maximum tolerated dose (MTD) is defined as the highest dose level at which less than 33% of patients experience study treatment-related dose limiting toxicities (DLT)
All toxicities and adverse events will be summarized with frequencies and descriptive measures, and tabulated according to body system, severity and relation to treatment.
Time frame: First course, 21 days
Overall safety profile characterized by type, frequency, severity (according to National Cancer Institute [NCI] CTCAE version 4.0), timing, seriousness and relationship to study treatment
All toxicities and adverse events will be summarized with frequencies and descriptive measures, and tabulated according to body system, severity and relation to treatment.
Time frame: Up to 30 days post-treatment
Plasma pharmacokinetic parameters of dovitinib lactate, gemcitabine hydrochloride, capecitabine and their metabolites
Differences in biomarkers between responders and non-responders will be explored with frequencies and summary statistics. Biomarkers will be tested with Fisher's exact test. Pharmacokinetic parameters will be summarized for each cohort of patients. Comparison of pharmacokinetic parameters among the dose levels will be performed using non-parametric statistical methods for K-independent samples. Drug-drug interaction will be examined comparing pharmacokinetic parameters using nonparametric statistical methods.
Time frame: Day 1 and 19 of course 1, day 8 of course 2 (Part A); day -14, day 19 of course 1,and day 8 of course 2 (Part B)
Solid tumor/dose-finding cohort: response rate, progression free survival
Tumor response will be defined according to the RECIST criteria version 1.1.
Time frame: Up to 1 year
Pancreas cancer cohort: survival, response rate and progression free survival
Tumor response will be defined according to the RECIST criteria version 1.1. Overall survival for patients enrolled to Part B will be estimated using Kaplan-Meier method.
Time frame: At 6 months
Pharmacodynamic effects of dovitinib lactate and Gem-Cap combination on vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptors (FGFR) dynamics in serum and tumor specimens
Time frame: Day 1, 12, and 19 of course (Part A); days -14, -3, and days 12 and 19 of course 1 (Part B)
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