Phase I of high dose (HD) temozolomide (TMZ) with peripheral blood stem cell support (PBSCS) rescue in recurrent high grade glioma (HGG)

Abstract

12518 Background: Despite improvements obtained with frontline treatments prognosis of recurrent HGG still remains dismal. HD chemotherapy (CT) suggested a dose-effect relationship in lymphoma and germ cell tumors. HD of TMZ could be a promising way to overcome resistance of HGG to standard schedule of CT Methods: This phase I had as principal objective to determine the Maximal Tolerated Dose (MTD) of HD of TMZ with PBSCS rescue in patients with recurrent HGG under 60 year. The MTD was defined as dose level which 50% of patients (pts) treated experienced a DLT (Dose Limiting Toxicity).The dose escalation was planned for eight dose levels from 300 to 650mg/m2/day over 5 days with CSP reinfusion at D7 according to the Modified Continual Reassessment Method (MCRM). Treatment was administered for one cycle. Results: Eighteen eligible pts were treated with HD of TMZ, all had received prior radiotherapy, 11 pts previous CT. Overall HD TMZ was well tolerated for the 7 evaluated dose levels. The MTD was not yet reached. Not dose limiting toxicities were reported in 12 pts: grade 2: fatigue (6pts), cephalalgia (3pts), nausea (3pts) , skin eruption (2pts), mucositis, FUO, vomiting, diarrhea, zoster, dental abcess, lung infection, septicemia, hepatic. grade 3 bilirubinemia, grade 4 neutropenia (13pts) and thrombocytopenia (4pts). Dose Limiting Toxicities were reported in 2 pts, gr3 cytolysis at level 3 (400mg/m2/day ) 1pt and gr 3 arthritis at level 7 (600mg/m2) 1pt respectively . Main hematological toxicities were gr 4 neutropenia in 13 pts median duration was 8 days, 4 pts had gr4 thrombocytopenia lasting 5 days. All patients were evaluable for tumor response, 2 partial responses were observed at 550 and 600mg/m2 level, 5 pts had a stabilization and a disease progression was reported in 11 patients. Conclusions: This interim analysis demonstrated that HD of TMZ with CSP reinfusion is feasible and well tolerated in patients with recurrent HGG. Nevertheless limited activity reported could be related to a less depletion of O6 alkylguanine transferase with HD than with a protracted schedule. Accrual is still ongoing. No significant financial relationships to disclose.