Phase I trial of oral 2'-deoxy-2'-methylidenecytidine: on a daily x 14-day schedule.


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 (Cmax), the area under the plasma drug concentration-time curve (AUC(0-infinity)) on day 1 were 1.7496 h, 112.9 ng/ml, and 399.8 ng x 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.

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@article{Masuda2000PhaseIT, title={Phase I trial of oral 2'-deoxy-2'-methylidenecytidine: on a daily x 14-day schedule.}, author={Norikazu Masuda and Kazuhiro Matsui and Naoki Yamamoto and Toshiji Nogami and K Nakagawa and S Negoro and Ken Takeda and Nobuhide Takifuji and M Yamada and Shoji Kudoh and Takeshi Okuda and Sohichi Nemoto and K Ogawa and Hiroshi Myobudani and Shinichi Nihira and Masahiro Fukuoka}, journal={Clinical cancer research : an official journal of the American Association for Cancer Research}, year={2000}, volume={6 6}, pages={2288-94} }