PHASE-I STUDY OF A 5-DAY DOSE SCHEDULE OF 4-IPOMEANOL IN PATIENTS WITH NONSMALL CELL LUNG-CANCER

The mammalian pulmonary toxin 4-ipomeanol (LPO) is activated by the cy tochrome P450 system in bronchial Clara cells in animals. The resultin g metabolites bind rapidly to macromolecules, producing localized cyto toxicity. IPO has irt vitro and in vivo antitumor activity in non-smal l cell lung cancer (NSCLC) and thus was proposed as a lung cancer-spec ific antitumor agent. We have completed a directed Phase I trial in pa tients with NSCLC, Forty-four patients (34 men and 10 women) with NSCL C were treated with IPO, All but two patients had an Eastern Cooperati ve Oncology Group performance status of 0 or 1, They received 91 cours es of therapy with i.v. IPO; 82 courses were administered daily for fi ve days, and 9 were single bolus doses. The dose-limiting toxicity of elevated serum transaminases was observed in three of seven patients a t 922 mg/m(2)/day. The maximum tolerated dose was 693 mg/m(2)/day on 5 consecutive days every 3 weeks. One patient developed grade 4 pulmona ry toxicity at 167 mg/m(2)/day. There was no significant hematological or renal toxicity. No objective antitumor responses were observed. Ph armacokinetic analysis of 39 patients from day 1 of IPO administration showed biexponential elimination with mean half-lives of 8.6 (alpha h alf-life) and 76 min (beta half-life). There was a linear relationship between the area under the plasma drug concentration-time curve and t he dose of IPO, There was no significant difference between the pharma cokinetic parameters measured on day 1 and day 5, Using a 4-day in vit ro cytotoxicity assay, two tumor cell lines established from patients treated at 693 mg/m(2)/day had IC(50)s of similar to 6 mM, a concentra tion more than 75-fold higher than the plasma levels measured in these patients, Thus, although the total amount of drug administered per cy cle on a daily times five dose schedule is more than 2.5-fold higher t han the recommended single daily dose, IPO is unlikely to be a useful drug for patients with lung cancer.