Phase I Study of Dovitinib (TKI258) in Combination With Gemcitabine and Capecitabine in Advanced Solid Tumors, Pancreatic Cancer and Biliary Cancers
Overview
- Phase
- Phase 1
- Intervention
- gemcitabine hydrochloride
- Conditions
- Adenocarcinoma of the Pancreas
- Sponsor
- Roswell Park Cancer Institute
- Enrollment
- 26
- Locations
- 1
- Primary Endpoint
- 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)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
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
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Part A: histologically or cytologically confirmed solid tumors that ale advanced or metastatic that the gemcitabine combination is considered standard therapy or a rational option
- •Part B: histologically or cytologically confirmed adenocarcinoma of the pancreas or the biliary tract (cholangiocarcinoma)that is advanced or metastatic
- •Part B: must have tumor lesions amenable to safe biopsy and willing to consent to tumor biopsies
- •Patients with at least one measurable site of disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 that have not been previously irradiated
- •Eastern Cooperative Oncology Group (ECOG) Performance Status =\< 1
- •Life expectancy \>= 3 months
- •Absolute neutrophil count (ANC) \>= 1,500 cells/mm\^3
- •Platelets \>= 100,000 cells/mm\^3
- •Hemoglobin \>= 9.0 g/dL
- •Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) =\< 1.5 x Upper Limit of Normal (ULN)
Exclusion Criteria
- •Part B: Patients with history of another malignancy within the last three years prior to study entry, with exception of adequately treated in-situ carcinoma of the uterine cervix, or skin cancer (such as basal cell carcinoma, squamous cell carcinoma, or non-melanomatous skin cancer)
- •Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding nitrosourea, mitomycin-C, targeted therapy and radiation) =\< 4 weeks prior to starting study drug, or who have not recovered from side effects of such therapy
- •Patients who have received the last administration of nitrosourea or mitomycin-C =\< 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
- •Patients who have received targeted therapy (e.g. sunitinib, sorafenib, pazopanib) =\< 2 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
- •Patients who have had radiotherapy =\< 4 weeks prior to starting study drug, or =\< weeks prior to starting study drug in the case of localized radiotherapy (e.g. for analgesic purpose or for lytic lesions at risk of fracture), or who have not recovered from radiotherapy toxicities
- •Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury =\< 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device =\< 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
- •History or presence of serious uncontrolled ventricular arrhythmias or presence of serious uncontrolled atrial fibrillation
- •Clinically significant resting bradycardia
- •Known left ventricular ejection fraction (LVEF) assessed by 2-D echocardiogram (ECHO) \< 50% or lower limit of normal (whichever is higher) or multiple gated acquisition scan (MUGA) \< 45% or lower limit of normal (whichever is higher)
- •Any of the following within 6 months prior to study entry: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)
Arms & Interventions
Treatment (dovitinib lactate, gemcitabine, and capecitabine)
Patients receive dovitinib lactate PO on days 1-5, 8-12, and 15-19, gemcitabine hydrochloride 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.
Intervention: gemcitabine hydrochloride
Treatment (dovitinib lactate, gemcitabine, and capecitabine)
Patients receive dovitinib lactate PO on days 1-5, 8-12, and 15-19, gemcitabine hydrochloride 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.
Intervention: dovitinib lactate
Treatment (dovitinib lactate, gemcitabine, and capecitabine)
Patients receive dovitinib lactate PO on days 1-5, 8-12, and 15-19, gemcitabine hydrochloride 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.
Intervention: capecitabine
Treatment (dovitinib lactate, gemcitabine, and capecitabine)
Patients receive dovitinib lactate PO on days 1-5, 8-12, and 15-19, gemcitabine hydrochloride 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.
Intervention: laboratory biomarker analysis
Treatment (dovitinib lactate, gemcitabine, and capecitabine)
Patients receive dovitinib lactate PO on days 1-5, 8-12, and 15-19, gemcitabine hydrochloride 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.
Intervention: enzyme-linked immunosorbent assay
Treatment (dovitinib lactate, gemcitabine, and capecitabine)
Patients receive dovitinib lactate PO on days 1-5, 8-12, and 15-19, gemcitabine hydrochloride 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.
Intervention: pharmacological study
Outcomes
Primary Outcomes
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)
Time Frame: First course, 21 days
All toxicities and adverse events will be summarized with frequencies and descriptive measures, and tabulated according to body system, severity and relation to treatment.
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
Time Frame: Up to 30 days post-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.
Secondary Outcomes
- Plasma pharmacokinetic parameters of dovitinib lactate, gemcitabine hydrochloride, capecitabine and their metabolites(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(Up to 1 year)
- Pancreas cancer cohort: survival, response rate and progression free survival(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(Day 1, 12, and 19 of course (Part A); days -14, -3, and days 12 and 19 of course 1 (Part B))