Phase I Study of huN901-DM1 (BB-10901) in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma.

Abstract Background: huN901-DM1 (BB-10901) is a humanized monoclonal antibody that binds with high affinity to CD56 and is covalently linked to a novel cytotoxic maytansinoid DM1. Once bound to CD56, the conjugate is internalized and releases DM1. CD56 is expressed on a variety of tumor types including small cell lung carcinoma, neuroendocrine tumors and hematological malignancies. About 70% of MM patients have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of huN901-DM1. Objectives: To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and pharmacokinetics (PK) of huN901-DM1 given on a weekly schedule. Methods: Relapsed or relapsed/refractory MM patients who have failed at least one prior therapy and have CD56-expressing myeloma received a single IV infusion of huN901-DM1 on 2 consecutive weeks every 3 weeks. Subjects are enrolled in cohorts of 3 at each dose level. The starting dose was 40 mg/m2/week based on experience from a prior phase I trial in solid tumors. Results: Twelve patients have received huN901-DM1, 3 patients each on 40 mg/m2/week, 60 mg/m2/week, 75 mg/m2/week, and 90 mg/m2/week cohorts. No patients have experienced DLTs and no serious adverse events related to study drug were observed. In addition, no patients have experienced serious hypersensitivity reactions or evidence of HAHA or HADA formation. Our preliminary PK findings demonstrate a terminal half life of huN901-DM1 of about 20 hours. Immunohistochemistry performed on marrow aspirates 24 hours after huN901-DM1 infusion at 40 mg/m2 confirmed the presence of huN901-DM1 on myeloma cells in the marrow. To date one patient treated at 60 mg/m2/week had a minimal response (European Bone Marrow Transplant criteria) and has received 15 cycles of therapy. Conclusions: This phase I study provides preliminary evidence of safety and clinical activity of huN901-DM1 in patients with CD56-positive MM who have failed established MM treatments. Targeting of huN901-DM1 to myeloma cells in the marrow was confirmed. Toxicity is manageable. The MTD is not yet defined and enrollment is ongoing.