Author(s): Read WL, Baggstrom MQ, Fracasso PM, Govindan R
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Abstract BACKGROUND: Preclinical studies have shown that binding of PPAR-gamma (polysome-proliferator activated receptor gamma) and retinoid-X receptor (RXR) to their ligands can slow growth and promote differentiation of malignant cells. Rosiglitazone, a PPAR-gamma ligand, is approved for treatment of insulin-resistant diabetes, and bexarotene, a RXR ligand, is approved for treatment of cutaneous T-cell lymphoma. After binding to its ligand, the PPAR-gamma receptor heterodimerizes with the RXR resulting in synergistic effects in preclinical models. We conducted a phase I study of bexarotene and rosiglitazone to define the MTD of rosiglitazone in this combination regimen. METHODS: Patients with resistant solid tumors received bexarotene 300 mg/m(2)/day. The starting dose of rosiglitazone was 4 mg/day and was escalated in five cohorts by 2-mg increments up to 12 mg/day. Both drugs were continued until disease progression or toxicity was observed. Patients received atorvastatin 10 mg/day to control bexarotene-related hypertriglyceridemia. RESULTS: Twenty-three patients were enrolled, with a median of 4 prior regimens (range 0-8). The study was closed after completing the 12 mg/day cohort without encountering dose-limiting toxicity. The most common grade 3 or 4 toxicities were hypertriglyceridemia (17\%), dyspnea (9\%), nausea (9\%), and dehydration (9\%). No objective responses were observed. CONCLUSIONS: The combination of bexarotene (300 mg/m(2)/day) and rosiglitazone (12 mg/day) is safe and feasible but did not result in objective responses in heavily pretreated patients with solid tumors. This combination is suitable for evaluation in other conditions such as hematologic malignancies and inflammatory diseases. (c) 2008 S. Karger AG, Basel.
This article was published in Chemotherapy
and referenced in Journal of Cytology & Histology