PHASE-I TRIAL OF DIHYDROLENPERONE IN LUNG-CANCER PATIENTS - A NOVEL COMPOUND WITH INVITRO ACTIVITY AGAINST LUNG-CANCER

Antitumor activity of the butyrophenone dihydrolenperone in non-small cell lung cancer was initially suggested by in vitro screening against tumor cells derived from fresh surgical samples using the human tumor colony-forming assay. We have completed a directed phase I trial in p atients with lung cancer. Thirty-two patients with lung cancer have co mpleted 25 courses of therapy at doses of 10 to 60 mg/square meter ora lly on a twice daily schedule. Twenty-three men and 9 women with a med ian age of 55 (range 24-69) were entered. Twenty-four were performance status 0 or 1 and 8 were 2. The maximum tolerated dose was 50 mg/squa re meter orally twice daily and the dose limiting toxicity was somnole nce. Of the 32 patients, 18 developed symptomatic hypotension (grade 1 or 2). There was no significant hematologic, renal, or hepatic toxici ty. In vitro drug testing using the MTT 4,5-dimethylthiazol-2-yl)-2,5- diphenyl-tetrazolium bromide (thiazolyl blue)] assay confirmed 50% inh ibition of non-small cell and small cell lung cancer cell line growth at 70-450 micromolar concentrations. Plasma dihydrolenperone levels we re at least 75-fold less than levels at which in vitro activity was ob served. We conclude: 1) the maximum tolerated dose in our study is 50 mg/square meter orally twice daily, 2) the dose-limiting side effect o f dihydrolenperone is somnolence, and 3) the concentrations of dihydro lenperone observed in plasma are significantly lower than those associ ated with in vitro activity.