Phase I study of lorvotuzumab mertansine (IMGN901) in patients with CD56-positive solid tumours

Background: Lorvotuzumab mertansine is a conjugate of the cytotoxic maytansinoid DM1 and the CD56-binding antibody, huN901, and is designed to bind to and kill CD56-expressing cancer cells. Tumours expressing CD56 include small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), non-pulmonary small cell cancers, neuroendocrine tumours, ovarian cancer and multiple myeloma. Methods: Patients with relapsed or refractory SCLC or other CD56+ solid tumours were eligible to participate in the dose-escalation phase of this study. The expansion phase of this study is limited to patients with SCLC, MCC, and ovarian cancer. The study incorporated fairly standard eligibility criteria, but patients with neurological toxicity >grade 2 or recent history of pancreatitis were excluded. Cohorts of 4 patients were enrolled at each dose level, with evidence of dose-limiting toxicity triggering cohort expansion. Lorvotuzumab mertansine is administered by IV infusion on 3 consecutive days every 21 days. Results: Sixty patients have been enrolled in the study at dose levels of 4 - 94mg/m²day. The maximum tolerated dose (MTD) was established to be 75 mg/m²/day. The doselimiting toxicities noted over the course of the dose-escalation phase were headache with aseptic meningitis-like symptoms, neuropathy, fatigue, and myalgia, as previously reported. Headache and aseptic meningitis-like symptoms were addressed by a slowed infusion rate and steroid prophylaxis. Since instituting these precautionary measures, no meningitis-like symptoms or grade 3/4 headache have been seen at the MTD in this trial. After safety assessment of the first seven patients treated in the expansion cohort and at a dose of 75 mg/m²/day, a decision was made to explore a dose of 60 mg/m²/day in subsequent patients. Evidence of clinical activity has been observed: 2 complete responses in MCC, 1 objective response in SCLC, and clinically relevant stable disease in a number of patients. Conclusions: Lorvotuzumab mertansine has shown preliminary evidence of safety and clinical activity. The expansion cohort of this study is open to enrollment at a dose of 60 mg/m2/day for patients with SCLC, MCC, and ovarian cancer.