Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study.
OBJECTIVE
Cantuzumab mertansine (SB-408075; huC242-DM1) is a conjugate of the maytansinoid drug DM1 to the antibody huC242, which targets CanAg antigen. In previous studies, cantuzumab mertansine was considered safe and tolerable, but transaminitis precluded tolerance of higher doses. Based on those studies, it was suggested that treatment at intervals of the half-life of the intact immunoconjugate may allow a higher dose density. This provided the rationale for the three-times weekly treatment explored in this protocol.


METHODS
Patients with advanced solid tumors and documented CanAg expression were treated with escalating doses of cantuzumab mertansine IV administered three-times a week in a 3 out of 4 weeks schedule. Plasma samples were assayed to determine pharmacokinetic parameters.


RESULTS
Twenty patients (pts) with colon (11/20), rectal carcinomas (2/20), or other malignancies (7/20) were treated with doses ranging from 30 to 60 mg/m2 per day of cantuzumab mertansine IV three-times a week. The maximum tolerated dose (MTD) was 45 mg/m2, and the dose-limiting toxicity was grade 3 transaminitis. Hepatic, hematologic, and neurosensory effects occurred, but were rarely severe with repetitive treatment at doses of 45 mg/m2.


CONCLUSIONS
Treatment with cantuzumab mertansine at 45 mg/m2 per day three-times weekly x 3-every-4-week schedule proved that a dose-intense treatment with an immunoconjugate can be safely administered. The pharmacokinetic profile of the intact immunoconjugate indicates that the linker is cleaved with a half-life of about 2 days, resulting in faster clearance of the maytansinoid relative to the antibody. Therefore, with the development of second-generation immunoconjugates, there is a need for improvement of the immunoconjugate linker to take full advantage of the slow clearance of full-length antibody molecules.
Rodon
Jordi
J
Institute for Drug Development, Cancer Therapy and Research Center, 7979 Wurzbach, Suite #414, San Antonio, TX 78229, USA. jrodon@idd.org
Garrison
Mitchell
M
Hammond
Lisa A
LA
de Bono
Johann
J
Smith
Lon
L
Forero
Leonardo
L
Hao
Desirée
D
Takimoto
Chris
C
Lambert
John M
JM
Pandite
Lini
L
Howard
Maria
M
Xie
Hongsheng
H
Tolcher
Anthony W
AW
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006207:Half-Life; D006402:Hematologic Diseases / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D008453:Maytansine; C483240:cantuzumab mertansine