A clinical and translational phase II trial of sequential axitinib and carboplatin/paclitaxel in advanced melanoma

8580 Background: Several clinical trials adding VEGF signaling inhibitors to chemotherapy have not demonstrated any benefit over chemotherapy alone in advanced melanoma potentially due to decreased tumor cell proliferation induced by VEGF blockade. We tested the hypothesis that sequential administration of axitinib followed by carboplatin and paclitaxel may be more effective than chemotherapy alone in metastatic melanoma. Methods: We conducted a prospective phase II trial of this combination in previously treated metastatic melanoma patients. Patients had an ECOG PS 0-1, and normal organ function. Axitinib 5 mg PO bid was taken on days 1 through 14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg/m2) was administered on day 1 starting with cycle 2. FLT-PET scans were performed on 6 patients to assess tumor cell proliferation on days 1, 14, 17, and 20 of cycle 1. Results: Treatment has been well tolerated. The most common grade 3 AEs have been neutropenia, hypertension, and gastrointestinal events. Grade 4 non-hematologic AEs have not been observed. 4 of 5 patients completing FLT-PET scans to date showed increases (23% to 92%) in SUV values during the axitinib holiday. The fifth patient had a single, minimally FLT avid lesion at baseline (SUV=1.9). In 30 evaluable patients, there have been 4 confirmed PRs, 2 unconfirmed PRs, and 3 patients with 28.6, 29.3, and 29.5% decreases in tumor size by RECIST. Overall, 19 patients have had SD and 5 have had PD as the best response. With a median follow-up of 8.3 months and 17 patients still active, the median PFS is 6.9 months, and 23 patients (77%) are still alive. 26 of 30 evaluable patients have been wild type for BRAF-V600E/K mutations. Conclusions: Axitinib followed by carboplatin and paclitaxel has been well tolerated and effective in a largely BRAF wild-type metastatic melanoma population. Given the urgent need for effective therapies in this population, this regimen warrants phase III testing.