Phase I. Trial of irinotecan and temozolomide in patients with solid tumors

This phase I study was conducted to determine the dose-limiting toxicity, maximum tolerated doses, and recommended phase II doses of the combination of irinotecan (CPT-11, Camptosar) and temozolomide (Temodar). Patients have received irinotecan and temozolomide on one of three different dosing schedules: (1) oral temozolomide on days 1-14 plus a single i.v. dose of irinotecan on day 8 every 28 days (arm 1); (2) weekly i.v. irinotecan on days 1, 8, 15, and 22 plus oral temozolomide on days 1-7 and 15-21 every 42 days (arm 2); and (3) every-other-week i.v. irinotecan on days 1 and 15 plus oral temozolomide on days 1-7 and 15-21 every 28 days (arm 3). A total of 49 patients have received 112+ cycles of therapy on all three dosing schedules to date. Dose-limiting toxicity consisting of diarrhea, neutropenia, and thrombocytopenia was encountered at a temozolomide dose of 125 mg/m2/d and an irinotecan dose of 250 mg/m2 on treatment arm 1. As a result, the protocol has been amended to explore lower doses of temozolomide in combination with higher doses of irinotecan, and patient accrual is currently continuing. Dose-limiting grade 3 diarrhea, nausea, and vomiting were reported in 7/12 patients enrolled on the two dose levels explored on treatment arm 2, so this dosing regimen was considered intolerable. Patient accrual currently continues at dose level 1 of treatment arm 3, so it is too early to determine dose-limiting toxicities and recommended phase II doses for this treatment schedule. Two partial responses have been reported to date in patients with glioblastoma and head and neck cancer, respectively. One evaluable response has also been observed in a patient with metastatic colorectal cancer. Irinotecan weekly x 4 plus temozolomide on days 1-7 and 15-21 is intolerable due to the development of dose-limiting gastrointestinal toxicities. The recommended phase II doses of irinotecan and temozolomide on treatment arms 1 and 3 remain to be determined as patient accrual is currently ongoing.