Phase I expansion study of sunitinib and bevacizumab in patients with advanced solid malignancies.
e13521 Background: The vascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) and the VEGF receptor (VEGFR) inhibitor sunitinib are efficacious agents in many malignancies. This combination has been previously evaluated in phase I studies of advanced solid tumors. In addition to renal cell carcinoma (RCC), objective responses in the previous phase I occurred in melanoma and adrenal carcinoma. An expansion phase of the phase I study was undertaken primarily to obtain further safety data in these tumor types. Methods: Patients (pts) with metastatic solid tumors with ECOG performance status 0-1 were enrolled on a phase I trial of sunitinib (37.5 mg daily weeks 1-4) and Bev (5 mg/kg iv on days 1, 15 and 29) of a 6 week cycle. Responses were assessed by CT scans performed at baseline and every 12 weeks based on RECIST criteria v1.0. Results: Twenty-two pts were enrolled (10 males, 12 females; median age 58 years) in the expansion cohort. Tumor types included melanoma (11), RCC (5), adrenal cancer (5) and angiosarcoma (1). Prior systemic treatment included chemotherapy (41%) and immunotherapy (27%). Common all grade toxicities included fatigue (77%), hypertension (73%), thrombocytopenia (68%), nausea (59%) and oral mucositis (55%). Grade 3 or higher toxicities occurred in 15 pts (68%); including hypertension (41%), thrombocytopenia (23%) and fatigue (14%). Seven pts developed hemorrhagic events, all grade 1 or 2. Two pts experienced grade 4 thrombocytopenia, 3 RCC pts developed grade 1 thrombotic microangiopathy (TMA); while 1 melanoma patient developed decreased haptoglobin (grade 1) with associated thrombocytopenia (grade 4) and schistocytes consistent with TMA. A median of 2 cycles were completed (range, 1-8). Best response in 19 evaluable pts included partial response 21% (4/19; melanoma (2), adrenal (1), and RCC(1)); stable disease 21% (4/19) and progressive disease 58% (11/19). Overall, 6 pts (31.5%) had measurable reduction in tumor burden. Conclusions: The safety profile of Bev plus sunitinib in melanoma and adrenal carcinoma pts is similar to the previously evaluated toxicities in RCC pts. Although reversible, combined VEGF and VEGFR inhibition may lead to microangiopathy even in non-RCC pts. Clinical trial information: NCT00357318.