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Phase I Trial of Oral 2'-Deoxy-2'-methylidenecytidine: On a Daily x 14-day Schedule¹

Department of Internal Medicine, Osaka Prefectural Habikino Hospital, Osaka 583-8588 [N. M., K. M.]; Department of Internal Medicine, Kinki University School of Medicine, Osaka 589-0014 [N. Y., T. N., K. N., M. F.]; Department of Respiratory Disease, Osaka City General Hospital, Osaka 534-0021 [S. Neg., K. T., N. T.]; 1st Department of Internal Medicine, Osaka City University School of Medicine, Osaka 545-0051 [M. Y., S. K.]; and Pharmaceutical Development Division, Nippon Roche K. K., Tokyo 105-8532, Japan [T. O., S. Nem., K. O., H. M., S. Ni.]

2'-deoxy-2'-methylidenecytidine (DMDC) is a potent deoxycytidine analogue. Preclinical studies of DMDC demonstrated activity against a variety of murine and human tumors in cell cultures and murine models and indicate enhanced antitumor activity of DMDC when it was administered in a manner that provided prolonged systemic exposure. In view of this observation, this study was designed to determine the toxicities, maximum-tolerated dose, and pharmacokinetic profile of DMDC. DMDC was given p.o. under fasting conditions for 14 consecutive days every 4 weeks in patients with advanced solid tumors. The starting dose was 12 mg/m²/day. Pharmacokinetic studies were carried out on days 1 and 14 of the first cycle. Fourteen patients received 22 courses of DMDC. The dose-limiting toxicities were anorexia, leukopenia, thrombocytopenia, and anemia. General fatigue was the common nonhematological toxicity. The maximum-tolerated dose was 18 mg/m²/day, at which two of six patients developed grade 3 toxicities. This dose level could also be considered for Phase II testing with this schedule. At the 18-mg/m²/day dose level, the mean terminal half-life, maximum plasma concentration (C_max), the area under the plasma drug concentration-time curve (AUC_0-) on day 1 were 1.7496 h, 112.9 ng/ml, and 399.8 ng·h/ml, respectively. Forty to 50% of the administered dose was recovered in the urine, indicating a good bioavailability and resulting significant systemic exposure to the drug, which may enable chronic oral treatment.