A phase I study of CS-1008 (humanized monoclonal antibody targeting death receptor 5 or DR5), administered weekly to patients with advanced solid tumors or lymphomas

Document Type

Article

Department

Haematology and Oncology, East Africa

Abstract

Background: CS-1008 is an IgG1 agonistic humanized monoclonal antibody targeting the human death receptor 5 (DR5). CS- 1008 triggers apoptosis after binding to DR5 resulting in death of targeted cells; it has demonstrated cytotoxic activity against DR5-positive human tumor cell lines in vitro, and in vivo it has shown significant anti-tumor activity against human tumor xenografts in nude mice.

Methods: A phase I trial in patients with relapsed/refractory solid tumors and lymphomas was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety profile of CS-1008 administered intravenously every week (a cycle was defined as 3 consecutive weeks). Three to six patients were enrolled in successive dose escalating cohorts at doses from 1 to 8 mg/kg weekly (1, 2, 4 and 8). The MTD was defined as the highest dose at which 0/3 or 1/6 patients experience dose limiting toxicities (DLT).

Results: Seventeen patients were enrolled, with a median age of 57 years (range, 31–88 years). Nine patients were enrolled in the 1, 2, and 4 mg/kg dose cohorts (3 in each one) and 8 patients in the 8m/kg dose cohort. CS-1008 was well tolerated, with no DLTs observed and the MTD was not reached. There were no infusion related toxicities, grade 3 or 4 toxicities related with CS-1008, or renal/ hepatic/hematological toxicities. Nine non-related severe adverse events were reported, all of them related to the primary tumor or disease progression. PK results demonstrated a half-life of 8 to 16 days. Seven patients had stable disease: 2 in the 1 mg/kg dose cohort (hepatocellular carcinoma 497+ days, head and neck cancer 225 days), 1 in the 2 mg/kg cohort (colon cancer 77 days), 2 in the 4 mg/kg dose cohort (colon cancer 78 days, cholangiocarcinoma 155 days), and 2 in the 8 mg/kg dose cohort (colon cancer 79 days, hepatocellular carcinoma 78 days).

Conclusions: CS-1008 is well tolerated, and the MTD was not reached. The high number of patients with stable disease in this phase I trial suggests anti-tumor activity. Clinical trials of CS-1008 in combination with chemotherapy for the treatment of DR5 positive epithelial tumors have been initiated.

Comments

This work was published before the author joined Aga Khan University.

Publication (Name of Journal)

Journal of Clinical Oncology

DOI

https://doi.org/10.1200/jco.2008.26.15_suppl.3537

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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