Phase I Trial of Oral 2′-Deoxy-2′-methylidenecytidine: On a Daily × 14-day Schedule

• Published in: Clinical cancer research 2000-06, Vol.6 (6), p.2288
• Main Authors: Noriyuki Masuda, Kaoru Matsui, Nobuyuki Yamamoto, Toshiji Nogami, Kazuhiko Nakagawa, Shunichi Negoro, Kouji Takeda, Nobuhide Takifuji, Masaji Yamada, Shinzoh Kudoh, Teruyoshi Okuda, Shinjiroh Nemoto, Kanako Ogawa, Hiroshi Myobudani, Shinichi Nihira, Masahiro Fukuoka
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265

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/m 2 /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/m 2 /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/m 2 /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.