Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study
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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.
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.
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.
Treatment with cantuzumab mertansine at 45 mg/m2 per day three-times weekly × 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.
KeywordsCantuzumab mertansine SB-408075 huC242–DM1 CanAg Immunoconjugates Pharmacokinetics Phase I
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