Phase I study of everolimus (E; RAD001) + low-dose weekly cisplatin (C) for patients with advanced solid tumors: Preliminary results

Abstract

e14527 Background: Preclinical studies demonstrate synergistic anti-tumor activity with the combination of E + C. Methods: Patients received E per oral for days 1–21 of a 28 day cycle. E was dose escalated though 4 planned dose levels (DLs): 2.5 mg/day, 5 mg/day, 7.5 mg/day, and 10 mg/day. Cisplatin dose was fixed at 20 mg/m2 intravenously on days 1, 8, 15. A standard 3 + 3 dose escalation scheme was used. Blood samples for pharmacokinetics were collected on Day 1 and Day 8 of Cycle 1. Response was assessed by RECIST after 2 cycles. Results: 24 patients enrolled: 13 M, 11F; median age 62 (32–77); median number of prior cytotoxic chemotherapy regimens 1 (0–3; 75% with prior RT). At DL1, 3 patients were inevaluable (1 withdrawal of consent prior to treatment, 1 disease progression during cycle 1, 1 recurrent diverticulitis during cycle 1) and were replaced. DL 1 was expanded after a patient with melanoma metastatic to liver had sudden death of unclear cause, and the protocol was amended to exclude patients with hepatic dysfunction. At DL2, one patient experienced grade 3 small bowel obstruction of uncertain etiology, and the dose level was expanded to 6 evaluable patients without additional DLT. No DLTs occurred at DL3. No DLTs have occurred to date among 6 patients enrolled at DL 4. Adverse events per cycle (total n = 63 cycles; 20 patients evaluable for toxicity) include: lymphopenia G3 (19%), AST G3 (3.2%), alkaline phosphatase G3 (3.2%), ALT G3 (1.6%), hyponatremia (1.6%). Median cycles per patient, 2 (range <1 to 10+). Minor response seen in pulmonary carcinoid (n = 1); prolonged SD ≥ 6 cycles seen in pulmonary carcinoid (n=2), basal cell carcinoma (n=1), and esthesioneuroblastoma (n=1). Conclusions: Pending safety analysis at the final planned dose level, the phase II recommended dose is E 10 mg/day (days 1 - 21) + C 20 mg/m2 (days 1, 8, and 15) on a 28-day cycle. [Table: see text]