st-1481 and Neoplasms

Sigma-Tau Industrie Farmaceutiche Riunite SpA and Novartis AG are developing oral gimatecan, a camptothecin derivative, for the potential treatment of tumors, including glioblastoma.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Camptothecin; Chemistry, Pharmaceutical; Clinical Trials, Phase II as Topic; Humans; Molecular Structure; Neoplasms

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of gimatecan, a lipophilic camptothecin analogue, administered orally once a week for 3 weeks.. Adult patients with advanced solid tumors with good performance status and adequate hematologic, hepatic, and renal function were eligible for the study. The plasma pharmacokinetics of the drug was characterized during the initial 28-day cycle.. A total of 33 patients were evaluated at 7 dose levels ranging from 0.27 to 3.20 mg/m(2)/wk. Anemia, fatigue, neutropenia, nausea, and vomiting were the principal toxicities. DLTs experienced by 3 of 7 patients in dose level 7 (3.20 mg/m(2)) were grade 2 hyperbilirubinemia and grade 3 to 4 fatigue. DLT (anorexia and nausea) occurred in only 1 of 11 patients evaluated at the MTD of 2.40 mg/m(2). There were no objective responses, although disease stabilization was observed in 4 patients. Gimatecan has a very long apparent biological half-life (mean +/- SD, 77 +/- 37 h) and exists in plasma almost entirely as the pharmacologically active intact lactone form. At the MTD, mean peak concentrations of the drug in plasma ranged from 67 to 82 ng/mL for the 3 weekly doses and the mean concentration 7 days after dosing was 15 +/- 18 ng/mL.. Administration of gimatecan orally once a week at doses that are well tolerated provides continuous exposure to potentially effective plasma concentrations of the biologically active form of the drug. This regimen deserves further evaluation to define its antitumor activity in specific tumor types either alone or in combination with other agents.

Topics: Administration, Oral; Adult; Aged; Camptothecin; Drug Administration Schedule; Female; Humans; In Vitro Techniques; Maximum Tolerated Dose; Middle Aged; Neoplasms

Gimatecan is an orally bioavailable camptothecin analogue with preclinical findings of promising antitumor activity. A phase I design of concerted dose escalation and dosing duration was implemented to assess the potential schedule dependency of tolerability that emerged from animal studies.. Gimatecan was given daily for five consecutive days per week for 1, 2 or 3 weeks every 28 days. Plasma levels of total gimatecan were measured on the first and the last day of treatment in each schedule.. Overall, 108 patients were treated with 0.8-7.2 mg/m(2) of gimatecan per cycle. The main toxicity was myelosuppression with dose-limiting thrombocytopenia. In the 1-, 2- and 3-week schedule, the maximum tolerated doses were 4.5, 5.6 and 6.4 mg/m(2). Diarrhea and asthenia were of low grade and of minor clinical relevance, while the higher incidence of nausea and vomiting in the 1-week schedule required the use of antiemetic prophylaxis. Due to the prolonged half-life (approximately 77 h), the plasma concentration of gimatecan increased from the first to the last day of dosing. Six partial responses were observed.. Tolerability of gimatecan was schedule dependent. Further testing with schedules taking into account its long persistence in human plasma is worthwhile.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Camptothecin; Dose-Response Relationship, Drug; Drug Administration Schedule; Europe; Female; Half-Life; Humans; Male; Middle Aged; Neoplasms; Treatment Outcome