A PHASE-I CLINICAL AND PHARMACOLOGICAL PROFILE OF DACARBAZINE WITH AUTOLOGOUS BONE-MARROW TRANSPLANTATION IN PATIENTS WITH SOLID TUMORS

Dacarbazine (DTIC) is a chemotherapy drug which has antitumor activity at standard doses, exhibits a steep dose-response effect in vitro, an d is associated with relatively few non-hematologic toxicities. These characteristics suggest a potential role for this drug in bone marrow transplant preparative regimens. To pursue this hypothesis, 16 patient s with refractory solid tumors were enrolled in a phase I study of sin gle agent DTIC to determine the dose of DTIC requiring bone marrow rei nfusion and to define the dose-limiting toxicity and maximum tolerated dose when given with autologous bone marrow rescue. Pharmacokinetics were evaluated at the 4394 mg/m2 dose level. The marrow requiring dose was 2000 mg/m2 when given as a single intravenous (IV) infusion. The extramyeloid dose-limiting toxicity of DTIC was hypotension, with the maximum tolerated dose of DTIC being 3380 mg/m2 when given with bone m arrow transplantation (BMT). Other toxicities were transient and toler able. At 4394 mg/m2 of DTIC, plasma concentrations declined biexponent ially with a terminal half-life of 3 hours. The mean clearance was 10. 6 L/hr/m2 with a volume of distribution at steady state of 37.5 L/m2 a nd a mean maximum plasma concentration of 150 mcg/ml. One patient with melanoma developed a partial response of short duration after receivi ng 2600 Mg/M2 of DTIC. Dacarbazine can be significantly dose escalated with an acceptable toxicity profile, when given with BMT. Future tria ls should focus on the addition of this drug to current BMT preparativ e regimens used for the treatment of patients with lymphoma.