Advanced squamous cell carcinoma of the head and neck has shown a 14-30 percent response rate to cisplatin as a single agent and a 40-70 percent response rate to cisplatin + 5-FU. However, the responses to cisplatin and other chemotherapeutic agents are usually of short duration. Ormaplatin (NSC 363812) has demonstrated activity against cisplatin resistant tumors in preclinical studies. Therefore, the applicant plans to evaluate the activity of ormaplatin in recurrent or locally progressive head and neck cancer. The drug will be administered as a 30 min infusion ever 4 weeks at the dosage determined in the ongoing phase I studies. Patients will be evaluated for both toxicity and objective tumor response. He also plans to perform detailed pharmacokinetic and biotransformation studies in conjunction with this phase II study. He plans to obtain the t 1/2- alpha and t 1/2-beta for PtCl2 (dach), identify and determine pharmacokinetic parameters for other active biotransformation products, and determine pharmacokinetic parameters for the inactive biotransformation products. Finally, there has been considerable interest in using levels of Pt-DNA adducts as a prognostic indicator of tumor response, but the theoretical basis for this assay is currently uncertain. The applicant has hypothesized that Pt-DNA adduct levels in peripheral leukocytes are determined by the AUC for active platinum species in the circulation and has proposed studies to test this hypothesis. It has been hypothesized that Pt-DNA adducts in peripheral leukocytes are reflective of Pt-DNA adduct levels in tumor tissue, but this has not been directly tested. He plans to determine Pt-DNA adduct levels in those patients with accessible tumor and correlate it with Pt- DNA adduct levels in peripheral leukocytes. He has hypothesized that adduct levels should be predictive of toxicity. Thus he plans to correlate Pt-DNA adduct levels in peripheral leukocytes with parameters of toxicity. Finally, he has hypothesized that total cellular Pt in peripheral leukocytes should correlate with toxicity and/or tumor response and has proposed to determine both total cellular Pt and Pt-DNA adducts in peripheral leukocytes from this patient population and to correlate these two parameters with each other and with toxicity and efficacy.
