Lenalidomide and irinotecan in adults with recurrent malignant gliomas: Phase I results of the phase I/II trial.

Abstract

2036 Background: Patients with recurrent malignant gliomas have limited treatment options. We previously reported promising results using 6 month progression free survival [PFS6] endpoint combining irinotecan and thalidomide compared to historical controls. In this study, we tested the tolerability and efficacy of Irinotecan combined with Lenalidomide, a more potent thalidomide analogue with unique antiangiogenic and immunomodulatory properties. Methods: This phase I portion of the phase I/II study aimed to determine the maximum tolerated doses (MTD) of irinotecan and lenalidomide. Eligible patients were adults (>=18 y) with recurrent WHO Grade 3 or 4 gliomas who were not on EIAED, had failed prior radiation therapy, had a KPS>=60, had adequate marrow, renal and hepatic organ function, no major medical illnesses and no other concurrent malignancies. Each cycle was designated as 4 weeks in duration. Results: Two of the 4 patients enrolled at the starting dose level of Lenalidomide 10 mg/day on days 1-21 and irinotecan 200 mg/m2 q2 weeks developed rash as dose limiting toxicity (DLT). The trial was restarted with no change in irinotecan dose but with a lowered Lenalidomide dose of 7.5 mg/day for cycle 1 with escalation to 10 mg/day for cycle 2 and beyond. Of 3 eligible patients enrolled, no DLTs were noted even after cycle 2. The dose was hence escalated to Lenalidomide 10 mg/day with unchanged irinotecan dose. Only 1/6 patients experienced a DLT (pulmonary embolism); however, it was noted that 4/6 patients required dose reduction of irinotecan to 150 mg/m2 after cycle 1. One patient died during cycle 2 of unknown causes (autopsy declined) without reports of preceding toxicities. Non DLT toxicities included neutropenia, leukopenia, hypokalemia, diarrhea, fatigue and nausea/vomiting. Lenalidomide pharmacokinetic data, obtained by serial blood draws initially after one dose of the drug on day 0 and subsequently after irinotecan and lenalidomide dose on day 1 to examine drug interactions, will be presented. Conclusions: Based on these results, the maximum tolerated dose was Lenalidomide 10 mg/day on days 1-21 and irinotecan 150 mg/m2 q 2 weeks every 28 days which will be used in the phase II study that will open shortly.