Phase I clinical trial of temsirolimus (T) and vinorelbine (V) in advanced solid tumors.

Abstract

e13084 Background: T, an mTOR inhibitor that regulates a signaling cascade which controls growth factor-induced cell proliferation was combined with V, an anti-mitotic drug in a phase I study. Synergistic effects have been reported with this combination. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to evaluate safety and tolerability. Methods: Eligible pts had advanced solid tumors, performance status 0-2, adequate organ function, and signed consent. Pts were treated with escalating doses of T and V. A 3+3 design was used. 4 dose levels were planned: Level I (T 20mg + V 20 mg/m2), Level II (T 25 + V 20), Level III (T 25 + V 25) and Level IV (T 25 + V 30). T was administered IV on days 1, 8, 15, and 22 while V was administered IV on days 1 and 15. Cycles were repeated every 28 days. MTD was defined as the highest dose tested in which fewer than 33% of pts experienced dose-limiting toxicity (DLT). DLTs included grade 3-4 non-hematologic toxicity (excluding inadequately treated nausea, vomiting, diarrhea, alopecia, myalgia, fatigue), hyperglycemia, hypertriglyceridemia, and grade 4 neutropenia or thrombocytopenia lasting more than 7 days. Results: Nineteen pts were enrolled (10 female, 9 male, median age 62 (35-79)), tumor types: lung (5), bladder (2), endometrial (7), prostate (2), neuroendocrine (1), vagina (2) and received a total of 50 cycles. All pts had received prior chemotherapy. Six pts were inevaluable and replaced (1 disease progression, 4 missed doses, 1 withdrew consent). Four pts were enrolled at dose level I, 9 to dose level II and 6 to dose level III. There was 1 DLT at level II (1 pt with grade 3 anorexia and dehydration) and 2 at level III (1 pt grade 3 hypokalemia; 1 pt grade 4 neutropenia). Two pts died on dose level III (1 not study related, disease progression; 1 study related, grade 4 neutropenia). Grade 3/4 toxicities were anemia (2), edema (1), hyperglycemia (1), anorexia (1), dehydration (1), hypertriglyceridemia (1), hypokalemia (2), and neutropenia (1). Dose level II was the MTD. One pt had a partial response (prostate), 6 stable disease. Conclusions: The recommended phase II dose of T + V is T 25mg and V 20mg/m2. At this dose, treatment was well tolerated.