Clinical trials with etanidazole (SR-2508) by the radiation therapy oncology group (RTOG)

Following the completion of a phase I study of etanidazole (SR 2508), a new hypoxic cell sensitizer, the RTOG, began a phase II/III trial. The objectives of the study were to determine the toxicity and efficacy of SR 2508, combined with conventional radiotherapy for the management of unresectable stage III and IV head and neck squamous carcinomas. During the first step (or the Phase II portion) of the study, 33 patients received radiotherapy plus SR 2508 (RT + SR 2508). The incidence of drug toxicities was modest; including 24% grade I peripheral neuropathy (PN), 6% grade II PN, 27% grade I or II nausea and vomiting, 9% allergy and 15% reversible neutropenia. Because observed toxicities were deemed acceptable, the second step (or phase III portion) was then activated. Patients were randomized to receive either RT or RT + SR 2508. As of November 20, 1989, a total of 242 patients have been entered onto the Phase III portion of the study. One hundred twenty-two patients were randomized to the RT + SR 2508 arm and 120 patients were randomized to the RT alone arm. The analyses presented in this report are based on data available [11]. The incidence of drug toxicities has been low, with 18% grade I or II PN, 26% nausea and vomiting (including one grade III), 14% allergy (including one grade III) and 13% reversible neutropenia. Blood samples were obtained at 0, 15 and 60 min, and 2, 4, and 20-24 hours following the administration of the first or second dose of SR 2508, for the measurement of serum drug concentration, and determination of the area under the curve (AUC). The average single drug dose AUC for 110 patients with data presently available, was 2.55 ± 0.86 mM-hr. The observed incidences of radiotherapy related toxicities in RT + SR 2508 group were not different from those in RT alone group. Preliminary analysis of the treatment results, showed that the 33 patients from the phase II part had achieved an initial complete response rate of 58%. Considering the fact that 61% of the patients had T4 and 49% had N3, this result is encouraging. With an accrual rate of 15 cases per month, this study will meet its patient accrual goal in 1990, and the results concerning the SR 2508 efficacy will be available after another year of follow up.