Phase I and pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Zhu
Andrew X
AX
Massachusetts General Hospital, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA. azhu@partners.org
Ready
Neal
N
Clark
Jeffrey W
JW
Safran
Howard
H
Amato
Antonino
A
Salem
Nadia
N
Pace
Silvia
S
He
Xiaoying
X
Zvereva
Nela
N
Lynch
Thomas J
TJ
Ryan
David P
DP
Supko
Jeffrey G
JG
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
C433984:ST 1481; D002166:Camptothecin