A Phase II Trial of Sorafenib and Dacarbazine for Leiomyosarcoma, Synovial Sarcoma, and Malignant Peripheral Nerve Sheath Tumors.

BACKGROUND: Sorafenib and dacarbazine have low single-agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes. MATERIALS AND METHODS: Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3-week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m2 intravenously (later reduced to 850 mg/m2). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes. RESULTS: The study included 37 patients (19 female); median age was 55 years (range 26-87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression-free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m2, only 3 of the final 12 (25%) patients required dose reduction. CONCLUSION: This phase II study met its primary endpoint with an 18-week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest. IMPLICATIONS FOR PRACTICE: Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease-control rates; however, it also increases the potential for significant toxicity.

A Phase Ib/II Study of Gemcitabine and Docetaxel in Combination With Pazopanib for the Neoadjuvant Treatment of Soft Tissue Sarcomas.

LESSONS LEARNED: Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations. BACKGROUND: For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS. METHODS: Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m(2) gemcitabine on days 1 and 8, 75 mg/m(2) docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response. RESULTS: The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥ 90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed. CONCLUSION: GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.