Phase II trial of vorinostat in advanced melanoma.

INTRODUCTION: Vorinostat is a small molecule inhibitor of class I and II histone deacetylases with preclinical activity in melanoma. METHODS: We evaluated 32 patients with advanced primary cutaneous or ocular melanoma in a multi-institutional setting (PMH Phase II Consortium) with continuous daily oral vorinostat 400 mg. The primary endpoint was response rate by RECIST, with time to progression as a secondary endpoint. The study was designed to distinguish a response rate of 20 % from a RR of 5 % and to distinguish a 2 month median progression-free survival (PFS), from one of 3.1 months. The study proceeded to stage 2 following 2 of 16 responses.. We also assessed VEGF, FGF levels, P52 polymorphisms and chromatin-associated proteins as potential biomarkers. RESULTS: Therapy was associated with significant side effects, including fatigue, nausea, lymphopenia, and hyperglycemia. Eleven patients experienced at least one grade 3 or higher adverse event. There were two confirmed PRs in patients with cutaneous melanoma. Sixteen patients had stable disease and 14 patients had progressive disease for best response. In addition, two patients with cutaneous melanoma scored as stable disease had early unconfirmed partial responses with subsequent progression. Patients with stable disease or partial response (n = 18) had a median progression free survival of 5 months. (range 2-12 months). CONCLUSIONS: Vorinostat demonstrated some early responses and a high proportion of patients with stable disease, but did not meet its primary endpoint of response. Different schedules of this agent with BRAF mutation status and markers of histone acetylation could be explored in melanoma.

A phase II study single agent of aflibercept (VEGF Trap) in patients with recurrent or metastatic gynecologic carcinosarcomas and uterine leiomyosarcoma. A trial of the Princess Margaret Hospital, Chicago and California Cancer Phase II Consortia.

OBJECTIVE: The aim of this multi-institutional non randomized phase II trial was to determine the efficacy and safety of single agent aflibercept (VEGF Trap), a recombinant fusion protein that blocks multiple vascular endothelial growth factor isoforms, in women with gynecologic soft tissue sarcoma. METHODS: Patients were enrolled in two cohorts each with Simon two stage designs: uterine leiomyosarcoma and carcinosarcoma of endometrial, ovarian or fallopian tube origin. Eligibility criteria included ≤2 prior lines of chemotherapy for metastatic disease and ECOG performance status of ≤2. Aflibercept 4mg/kg was administered intravenously on day 1 of a 14 day cycle. Primary endpoints were objective response and disease stabilization (Progression Free Survival (PFS) at 6 months). RESULTS: 41 patients with uterine leiomyosarcoma and 22 patients with carcinosarcoma (19 uterine, 3 ovarian) were enrolled on study. In the leiomyosarcoma cohort, eleven (27%) patients had stable disease (SD), 4 with SD lasting at least 24 weeks. The 6 month PFS was 17%, with median time to progression (TTP) of 1.8 (95% CI:1.6-2.1) months. In the carcinosarcoma cohort, two (9%) patients had SD, one lasting >24 weeks, median TTP was 1.6 months (95%CI: 1.1-1.7) No partial responses were observed in patients from either cohort. Grade 3 or more aflibercept related toxicity was uncommon and included hypertension, fatigue, headache and abdominal pain. CONCLUSIONS: Single agent aflibercept has modest activity in patients with uterine leiomyosarcoma and minimal activity in women with carcinosarcoma.