Final results of a phase I study using oral temozolomide (TMZ) daily for 14 days with weekly paclitaxel in patients (pts) with advanced malignancies

Abstract

12020 Background: TMZ is an alkylating agent with activity in a variety of neoplasms. The optimal schedule of administration for TMZ has not been established and only a few studies have studied it in combination with other agents. Repair of TMZ-induced DNA damage is associated with the activity of O-6 alkylguanine-DNA-alkyl transferase (AGT). Preclinical and clinical data indicate that prolonged exposure to TMZ results, not only in enhanced DNA alkylation, but also in depletion of AGT. This serves as the rationale to study TMZ using protracted schedules. Methods: The aim of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of oral TMZ given daily for 14 days with weekly paclitaxel in pts with advanced cancers. Forty-five pts received 136 cycles of TMZ at escalating doses (50, 75, 100, 125 and 150 mg/m2/day × 14 days) plus paclitaxel at 80 mg/m2 on days 1, 8, and 15. Pts were stratified as lightly (LP) or heavily (HP) pretreated and MTD defined as the dose level (DL) at which 1/6 patients developed DLT. Results: Twenty-four LP patients were treated at 5 DLs with all but one evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD in this group was the 125 mg/m2/day level. Twenty-six HP were treated at 5 DLs and 21 were evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD for this group was also 125 mg/m2/day. Thirty-eight (84%) pts were evaluable for response after 2 cycles of therapy. Three (8%) pts had a partial response (lung, lymphoma, ependymoma), 20 (53%) remained stable and 15 (39%) developed disease progression. Six (16%) pts remained stable for 6 cycles or more (2 sarcomas, 2 lung, 1 pancreas, 1 glioblastoma). Conclusions: We concluded that combining oral TMZ at a dose of 125 mg/m2/day for 14 days with standard-dose weekly paclitaxel is safe in both HP and LP pts. [Table: see text]