A phase I study of a CanAg-targeted immunoconjugate, huC242-DM4, in patients with Can Ag-expressing solid tumors

Abstract

3062 Background: HuC242-DM4 is a novel, targeted anti-cancer agent in development for the treatment of CanAg-expressing tumors such as carcinomas of the colon and pancreas. The compound is formed by the conjugation of the potent cytotoxic maytansinoid drug, DM4, to the humanized monoclonal antibody, huC242. This agent was highly active across a broad spectrum of CanAg-expressing human tumor xenograft models. Methods: Patients were enrolled with metastatic or inoperable colorectal, pancreatic, and other CanAg-expressing tumors who have failed standard therapy (about 95% of pts. had received = 4 prior chemotherapy regimens). Results: Thirty patients were treated with huC242-DM4, receiving a single intravenous (IV) infusion once every three weeks. Cohorts of 3 patients initially were enrolled on each dose level. Patients have received huC242-DM4 at 18, 36, 60, 90, 126, 168, 223, and 297 mg/m2. To date, dose limiting toxicity (DLT) was experienced by two of six patients treated at the 223 mg/m2 dose level during their second cycle of treatment. The patients experienced decreased visual acuity, corneal deposits and keratitis. Both patients were subsequently treated with lubricating eye drops. At present, these adverse events have markedly improved in one patient, while the other patient has completely returned to baseline. Of 10 patients treated at the168 mg/m2 dose level (including two patients who were dose reduced to 168 mg/m2), seven patients have received at least two cycles of treatment. One patient had grade 3 diarrhea and dehydration during his second cycle at 168 mg/m2. The latter improved with intravenous fluids. Preliminary pharmacokinetic data reveal a half-life of huC242-DM4 of about 5 days in patients with low plasma CanAg levels. In patients with high plasma CanAg levels (>900 units/mL), clearance of huC242-DM4 is increased. There has been no clinically significant myelosuppression and no formation of antibody to humanized antibody (HAHA) or drug (HADA). One patient had a 36% decline in CEA (not associated with tumor shrinkage). Conclusions: HuC242-DM4 was well tolerated at the 168 mg/m2 dose level. The MTD is not yet defined and approaches to prevent /ameliorate ocular toxicity are planned. No significant financial relationships to disclose.