A phase I study of the combination of two hypoxic cell radiosensitizers, Ro 03-8799 and SR-2508: toxicity and pharmacokinetics.
The hypoxic cell radiosensitizer Ro 03-8799 produces acute central nervous system toxicity which limits repeated doses of the drug to 0.75 g/m2, but peripheral neuropathy does not occur. SR-2508 causes no acute effects at doses greater than 3.0 g/m2, but causes peripheral neuropathy at cumulative doses of 30 g/m2. By combining maximum tolerated doses of each agent, it may be possible to increase efficacy, but not toxicity. Escalating single doses of Ro 03-8799 and SR-2508 were administered to 10 patients. The drugs were infused together in 50 ml of 0.9% saline over 10 min, beginning at 0.5 g/m2 of each agent, and proceeding to a fixed dose of 0.75 g/m2 Ro 03-8799 with 0.5, 1.0, 2.0, and 3.0 g/m2 SR-2508. Four patients experienced the expected acute syndrome related to Ro 03-8799, but the incidence was not increased by escalating doses of SR-2508, and no peripheral neuropathy was seen. Plasma and urine pharmacokinetic studies showed that no drug interaction occurred. Six patients have been given a 9-dose regime over a 3 week period, using 0.75 g/m2 Ro 03-8799 and escalating doses of 0.5, 1.0, and 1.5 g/m2 SR-2508. All exhibited the expected acute side effects related to Ro 03-8799, but with no increase at the higher doses of SR-2508. No other toxicity was seen. Plasma pharmacokinetics performed at the beginning and end of the schedule were similar. Biopsies were taken from six superficial tumors following combined radiosensitizer administration. Mean tumor concentrations over the 30 min following the end of infusion were 30 and 72 micrograms/g for Ro 03-8799 and SR-2508, respectively. These values would be expected to translate into an approximate single dose sensitizer enhancement ratio of 1.5 to 1.6, offering a significant gain over the enhancement possible with the drugs given alone. The overall advantage will be determined by the maximum dose levels and number of doses possible; the escalation of both parameters is now in progress.
D000293:Adolescent; D000328:Adult; D000368:Aged; D003131:Combined Modality Therapy; D004338:Drug Combinations; D004341:Drug Evaluation; D017341:Etanidazole; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*
D004338:Drug Combinations; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; C033815:pimonidazole