title: Phase I study of E7010.
abstract: E7010 is a novel sulfonamide which was discovered using slow-growing colon 38 carcinoma cells as a screening model. E7010 exhibits a broad spectrum of antitumor activity against human tumor xenografts. The mechanism of action is by arresting the progression of cells in M phase of the cell cycle by inhibiting tubulin polymerization. The objective of this phase I study was to determine the maximum allowable dose (MAD), toxicity, and pharmacokinetics of single or 5-day repeated doses of E7010. In the single-dose study, E7010 was administered orally to 16 patients at doses ranging from 80 to 480 mg/m2. The dose-limiting toxicity was peripheral neuropathy at a dose of 480 mg/m2. Hematological and gastrointestinal toxicities were mild. In the 5-day repeated-dose study, 41 patients were given E7010 at doses ranging from 30 to 240 mg/m2 per day. The dose-limiting toxicities were peripheral neuropathy and intestinal paralysis. Gastrointestinal toxicity was dose-dependent but not severe. Hematological toxicity was not dose-dependent. Pharmacokinetic analysis in the single-dose study showed a rapid increase in the plasma levels of the drug after administration, followed by disappearance with a t1/2 of 4.4-16.6 h. The variation in area under the plasma concentration-time curve (AUC) between the patients was small and increased in a dose-dependent manner. Total drug recovery in urine 72 h after administration was 77.8+/-11.4%, indicating that E7010 has favorable absorption and elimination profiles. The changes in the plasma levels of E7010 on day 5 in the 5-day repeated-dose study were almost the same as those on day 1, indicating that the drug did not accumulate. In the single-dose study, spinal cord metastasis exhibited a 74% reduction in a patient with uterine sarcoma and a minor response (MR) was observed in a pulmonary adenocarcinoma patient. In the 5-day repeated-dose study decreases in the tumor markers carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC) were observed in a patient with stomach cancer and in a patient with recurrent uterine cervical carcinoma, respectively. The recommended phase II doses are 320 mg/m2 for a single-dose study and 200 mg/m2 per day for a 5-day repeated-dose study. Since the activity of E7010 is time-dependent, i.e. a certain concentration of E7010 is required for more than 12 h to suppress the growth of P388 leukemia cells, it is recommended that subsequent phase I/II studies be conducted using a divided dose schedule in order to maintain the blood level of E7010.
authors.affiliation: Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Noda
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
authors.forename: M
authors.initials: M
authors.lastname: Fukuoka
authors.forename: K
authors.initials: K
authors.lastname: Furuse
authors.forename: H
authors.initials: H
authors.lastname: Niitani
mesh_terms: D000328:Adult; D000368:Aged; D000627:Aminophenols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000096926:Benzenesulfonamides
chemical_list: D000627:Aminophenols; D000970:Antineoplastic Agents; D013449:Sulfonamides; C079199:E 7010; D000096926:Benzenesulfonamides