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.
Masuda
N
N
Department of Internal Medicine, Osaka Prefectural Habikino Hospital, Japan.
Matsui
K
K
Yamamoto
N
N
Nogami
T
T
Nakagawa
K
K
Negoro
S
S
Takeda
K
K
Takifuji
N
N
Yamada
M
M
Kudoh
S
S
Okuda
T
T
Nemoto
S
S
Ogawa
K
K
Myobudani
H
H
Nihira
S
S
Fukuoka
M
M
D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D013997:Time Factors
D000970:Antineoplastic Agents; C416375:Ro 09-3431; D003841:Deoxycytidine; C056034:2'-deoxy-2'-methylenecytidine; D003857:Deoxyuridine