A Phase I trial of protracted oral fixed-dose temozolomide.

BACKGROUND: The current Phase I trial was conducted to determine the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended Phase II dose of oral fixed-dose temozolomide when administered for 5 of every 7 days on a continuous basis. METHODS: Patients received a fixed dose of temozolomide daily for 5 of every 7 days continuously. Four weeks of treatment were considered 1 treatment cycle. Patients were accrued at 7 different dose levels ranging from 100 mg/day to 360 mg/day. RESULTS: Forty-six patients received 111 cycles of therapy. DLT consisted of myelosuppression, particularly thrombocytopenia. The primary nonhematologic toxicities were nausea and emesis, which were easily controlled with antiemetics. CONCLUSIONS: Protracted administration of temozolomide at a fixed dose of 300 mg/day for 5 of every 7 days continuously was well tolerated and allowed greater dose intensity compared with various other schedules. This regimen could potentially increase antitumor activity as protracted temozolomide schedules inhibit DNA repair by depletion of the repair protein O6-methylguanine-DNA methyltransferase.

Phase I. Trial of irinotecan plus carboplatin in two dose schedules.

A phase I study of carboplatin (Paraplatin) administered in two different dosing schedules (single dose every 4 weeks and weekly dosing) in combination with weekly irinotecan (CPT-11, Camptosar) was conducted in patients with relapsed or refractory advanced malignancies. Fifty-three patients with a variety of tumor types were randomly enrolled on the two different treatment regimens and have received a total of 163 cycles of treatment to date. Twenty-six patients received weekly irinotecan in combination with a single fixed dose of every-4-week carboplatin (arm 1). Initially, patients received irinotecan on days 1, 8, and 15, in combination with fixed-dose carboplatin at an area under the concentration-time curve (AUC) of 5.5 (Calvert formula) on day 1 every 28 days. Due to dose-limiting toxicities encountered at the first two dose levels, the protocol was amended to decrease the fixed dose of carboplatin to an AUC of 4.0 every 4 weeks. Dose-limiting toxicity was again encountered, so the day-15 dose of irinotecan was eliminated from the dosing regimen. The recommended phase II dose for heavily pretreated patients is irinotecan at 60 mg/m2 on days 1 and 8 in combination with carboplatin at AUC 4.0 on day 1 with cycles repeated every 28 days. Twenty-seven patients were treated with weekly irinotecan in combination with fixed-dose weekly carboplatin (arm 2). The initial dosing regimen consisted of irinotecan in combination with fixed-dose carboplatin at an AUC of 1.8 on days 1, 8, and 15, with treatment cycles repeated every 28 days. Due to the development of dose-limiting toxicities at the first two dose levels, the dosing regimen was subsequently amended to weekly irinotecan in combination with fixed-dose carboplatin at AUC 2.0 on days 1 and 8 only, and the dosing interval was shortened to every 21 days. With this amended regimen, the recommended phase II doses are irinotecan at 90 mg/m2 in combination with carboplatin at AUC 2.0 on days 1 and 8, with treatment cycles repeated every 21 days.

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.