A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies

Temozolomide (TMZ) is an oral imidazotetrazinone that is spontaneously conv erted to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at physiolo gical pH, MTIC methylates DNA at the O-6 position of guanine, although this lesion may be repaired by the enzyme O-6-alkylguanine-DNA alkyltransferase (AGAT). In this study, TMZ was combined with cisplatin (CDDP), because bot h agents have single-agent activity against melanoma and other tumor types. Additionally, CDDP has been shown to inactivate AGAT, and subtherapeutic c oncentrations of CDDP have been shown to increase the sensitivity of leukem ic blasts to TMZ. This Phase I study sought to determine the toxicities, re commended dose, and pharmacological profile of the TMZ/CDDP combination. Patients were treated with oral TMZ daily for 5 consecutive days together w ith CDDP on day 1 (4 h after TMZ) every 1 weeks at the following TMZ (mg/m( 2)/day)/CDDP (mg/m(2)) dose levels: 100/75, 150/75, 200/75, and 200/100, Pl asma samples were obtained on days 1 and 2 to evaluate the pharmacokinetic parameters of TMZ alone and in combination with CDDP. Fifteen patients rece ived a total of 44 courses of TMZ/CDDP. The principal toxicities of the reg imen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, whic h were intolerable in two of six new patients treated at the 200/100 mg/m(2 ) dose level. Of five patients receiving 17 courses at the next lower dose level (200/75 mg/m(2)), none experienced dose-limiting toxicity. Antitumor activity was observed in patients with non-small cell lung cancer, squamous cell carcinoma of the tongue, and leiomyosarcoma of the uterus. Pharmacoki netic studies of TMZ revealed the following pertinent parameters (mean +/- SD): time to maximum plasma concentration (T-max) = 1.1 +/- 0.6 h (day 1) a nd 1.7 +/- 0.9 h (day 2); elimination half-life t(1/2)) = 1.74 +/- 0.22 h ( day 1) and 2.35 +/- 0.70 h (day 2); and clearance (Cl-s/F) = 115 +/- 27 ml/ min/m(2) (day 1) and 141 +/- 109 ml/min/m(2) (day 2). TMZ drug exposure, de scribed by the area under the plasma concentration-time curve (AUC(infinity )) and the maximum plasma concentration (C-max), was similar on days 1 and 2. On the basis of these results, the recommended doses for Phase II clinical trials are TMZ 200 mg/m(2)/day for 5 days with 75 mg/m(2) CDDP on day 1, ev ery 4 weeks. The addition of CDDP did not affect the tolerable dose of sing le-agent TMZ (200 mg/m(2)/day x 5 days), nor did it substantially alter the pharmacokinetic behavior of TMZ.