ADVL1522: A phase 2 study of lorvotuzumab mertansine (IMGN901) in children with relapsed or refractory wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor, or synovial sarcoma-A Children's Oncology Group study.

Abstract

Lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate linking an antimitotic agent (DM1) to an anti-CD56 antibody (lorvotuzumab). Preclinical efficacy has been noted in Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), and pleuropulmonary blastoma also express CD56. A phase 2 trial of lorvotuzumab mertansine was conducted to assess its efficacy, recommended phase 2 dose, and toxicities. Eligible patients had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine (110 mg/m2 per dose) was administered at the adult recommended phase 2 dose intravenously on days 1 and 8 of 21-day cycles. Dexamethasone premedication was used. Pharmacokinetic samples, peripheral blood CD56-positive cell counts, and tumor CD56 expression were assessed. Sixty-two patients enrolled. The median age was 14.3 years (range, 2.8-29.9 years); 35 were male. Diagnoses included Wilms tumor (n=17), rhabdomyosarcoma (n=17), neuroblastoma (n=12), synovial sarcoma (n=10), MPNST (n=5), and pleuropulmonary blastoma (n=1). Five patients experienced 9 dose-limiting toxicities: hyperglycemia (n=1), colonic fistula (n=1) with perforation (n=1), nausea (n=1) with vomiting (n=1), increased alanine aminotransferase in cycle 1 (n=2), and increased alanine aminotransferase in cycle 2 (n=1) with increased aspartate aminotransferase (n=1). Non-dose-limiting toxicities (grade 3 or higher) attributed to lorvotuzumab mertansine were rare. The median values of the maximum concentration, half-life, and area under the curve from zero to infinity for DM1 were 0.87 µg/mL, 35 hours, and 27.9 µg/mL h, respectively. Peripheral blood CD56+ leukocytes decreased by 71.9% on day 8. One patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response. Lorvotuzumab mertansine (110 mg/m2 ) is tolerated in children at the adult recommended phase 2 dose; clinical activity is limited.