Phase I study of sunitinib malate continuously dosed and standard-infusion gemcitabine in solid tumors.

Background: Sunitinib malate (S) is an oral multi-targeted tyrosine kinase inhibitor (TKIs) with affinity for VEGFRs, PDGFRs, KIT, RET, and Flt3. These targets are significant in several malignancies based on pre-clinical and clinical data. Cytotoxic chemotherapy and targeted angiogenesis inhibition concomitently may enhance tumor control. In this phase I trial gemcitabine (G) was combined with S in a continuous dosing schema to assess maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and tumor response.

Methods: Eligible patients had no curative therapy options, adequate organ function, and no prior anti-angiogenic treatments. The first dose level administered G 800 mg/m2 intravenously (IV) weekly x 3 every 28 days and S 25 mg orally every day. Any treatment-related grade 4 toxicity, grade 3 cardiac or venous thrombosis, unresolved non-cardiac grade 3 event, or uncontrolled hypertension was defined as DLT.

Results: Six patients (3 unresectable pancreas,1 metastatic pancreas, 1 pleural mesothelioma, 1 germ cell) with a median age of 65 years (range 39 to 73) and ECOG performance status of 0 - 2 were treated on dose level one. Only the mesothelioma and germ cell patients had prior therapy. Patient 2 experienced DLT of asymptomatic neutropenia, requiring expansion of the cohort; no further DLTs were seen at this dose level. Other toxicities included grade 4 dyspnea due to progressive disease and grade 3 hyponatremia, hypokalemia, and neutropenia, experienced by one pateint each. Two patients had grade 3 leucopenia. Two of the unresectable pancreas patients experienced confirmed partial responses (PRs). Patients are accrued to dose level two (S 37.5 mg orally per day and G 800 mg/m2 IV weekly x 3 every 28 days ).

Conclusions: Continuous dosing of S with G appears tolerable. Safety monitoring continues; it is anticipated that higher dose levels will have greater myelosuppression based on known mechanisms of action. Two unresectable pancreas cancer patients have confirmed PRs; the regimen merits continued assessment in this population. Supported by NIH/Cancer Therapy Evaluation Program U01 CA62502.

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