Phase II Clinical Trial Results Involving Treatment with Low-Dose Daily Oral Cyclophosphamide, Weekly Vinblastine, and Rofecoxib in Patients with Advanced Solid Tumors

Abstract

Preclinical studies indicate that conventional chemotherapeutic agents given continuously at low doses (metronomic chemotherapy) may provide an improved therapeutic index. Cyclophosphamide and vinblastine have been best studied in experimental models, where tumor growth inhibition is achieved, at least in part, through antiangiogenic mechanisms. Fifty patients with advanced solid tumors were enrolled in this phase II trial, 43 of whom had received at least one prior chemotherapy regimen. Patients were required to have Eastern Cooperative Oncology Group performance status of < or = 2, a life expectancy of >3 months, and at least one measurable lesion. All patients received oral cyclophosphamide (50 mg) and rofecoxib (25 mg) daily in addition to weekly injections of vinblastine (3 mg/m2). Half of the patients also received minocycline (100 mg) orally twice daily with the intent of further inhibiting tumor angiogenesis. The primary end point of the study was clinical benefit, defined as the percentage of patients experiencing an objective response or exhibiting stable disease for at least 6 months. For the 47 eligible patients, there were two (4%) complete responses and four (9%) partial responses, for an overall objective response rate of 13%. An additional eight patients achieved disease stabilization (stable disease > or = 6 months) (17%). The primary end point of clinical benefit was therefore 30%, (95% confidence interval, 16-44%). The median progression-free survival for all patients was 103 days and 289 days for patients experiencing clinical benefit. The incidence of patients experiencing grade 3/4 toxicities were as follows: neutropenia (10/2), anemia (2/0), and thrombocytopenia (1/0). No patients developed grade 3 or 4 nausea, vomiting, mucositis, or alopecia. This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population and indicate that this approach merits further investigation in specific disease site studies.