BACKGROUND: Combined treatment approaches targeting tumor cells as well as stromal cells may control chemorefractory malignancies. In the current study, the authors sought to test one such combined approach in the treatment of chemorefractory melanoma and soft tissue sarcoma. METHODS: A Phase II trial was initiated to analyze the activity of a continuously administered molecularly targeted treatment regimen (daily pioglitazone [45 mg administered orally] and rofecoxib [25 mg administered orally]) combined with sequentially added angiostatic chemotherapy for patients with previously treated metastatic melanoma (n = 19) or soft tissue sarcoma (n = 21). Angiostatic chemotherapy consisted of trofosfamide (50 mg) administered orally 3 times daily beginning on the 15th day after the start of molecularly targeted therapy. RESULTS: Forty patients were evaluable for response and toxicity. Major side effects (World Health Organization Grade 3 or 4) were not observed. Objective responses and disease stabilization lasting longer than 6 months were noted in 11% and 11%, respectively, of all patients with melanoma and in 19% and 14%, respectively, of all patients with soft tissue sarcoma. Complete remission was noted in one patient with melanoma and in three patients with sarcoma. Both normal C-reactive protein (CRP) levels and CRP levels that decreased by > 30% during the 14-day biomodulator pretreatment period were found to be predictive of prolonged progression-free survival. CONCLUSIONS: To our knowledge, the current study is the first to demonstrate that a novel, completely orally administered combined biomodulator/metronomic chemotherapy regimen may be active and well tolerated in patients with chemorefractory malignancies.