enoblituzumab (mga271) in children with b7-h3-expressing solid tumors

Conditions: Neuroblastoma; Rhabdomyosarcoma; Osteosarcoma; Ewing Sarcoma; Wilms Tumor; Desmoplastic Small Round Cell Tumor

Summary: this study is a phase 1, open-label, dose escalation and cohort expansion trial designed to characterize the safety, tolerability, pk, pd, immunogenicity and preliminary antitumor activity of enoblituzumab administered iv on a weekly schedule for up to 96 doses (approximately 2 years) in children and young adults with b7-h3-expressing relapsed or refractory malignant solid tumors.

this study is a phase 1, open-label, dose escalation and cohort expansion trial designed to characterize the safety, tolerability, pk, pd, immunogenicity and preliminary antitumor activity of enoblituzumab administered iv on a weekly schedule for up to 96 doses (approximately 2 years) in children and young adults with b7-h3-expressing relapsed or refractory malignant solid tumors. the study consists of a dose escalation phase to determine the mtd (or mad) of enoblituzumab followed by a cohort expansion phase to further define the safety and initial antitumor activity of enoblituzumab. in the cohort expansion phase, 5 cohorts of 10 patients each will be enrolled to further evaluate the safety and potential efficacy of enoblituzumab administered at the mtd/mad in patients with:1) neuroblastoma - measurable disease, 2) neuroblastoma - non-measurable disease, 3) rhabdomyosarcoma, 4) osteosarcoma, and 5) ewing's sarcoma, wilms' tumor, desmoplastic small round cell tumors, or malignant solid tumors of any other histology that test positive for b7-h3. all tumor evaluations will be carried out by both response evaluation criteria in solid tumors (recist) and immune-related response criteria (irrc). disease assessment in patients with neuroblastoma will use neuroblastoma overall response criteria.

Eligibility criteria:
general inclusion criteria: * age at treatment 1 to 35 years. * relapsed or refractory malignant solid tumors of any histology for which no standard curative therapy is available (escalation phase). * histologically proven: neuroblastoma, rhabdomyosarcoma, osteosarcoma, ewing's sarcoma/ primitive neuroectodermal tumor, wilms tumor, desmoplastic small round cell tumor or malignant solid tumors of any other histology that test positive for b7-h3 . * must have malignant solid tumors that demonstrate b7-h3 expression at 2+ or greater levels on the membranous surface of at least 10% of tumor cells or ≥ 25% of tumor vasculature by ihc. * with the exception of patients with non-measurable neuroblastoma patients must have measurable disease as per recist 1.1 * karnofsky (patients ≥ 16 years)/lansky (patients \< 16 years) index ≥ 70. * acceptable laboratory parameters and adequate organ reserve. exclusion criteria: * patients are to be excluded from the study if they have any of the following: * patients with a history of symptomatic central nervous system (cns) unless they have been treated and are asymptomatic. * patients with any history of known or suspected autoimmune disease with the specific exceptions of vitiligo, resolved childhood atopic dermatitis, psoriasis not requiring systemic treatment within the past 2 years, and patients with a history of grave's disease that are now euthyroid clinically and by laboratory testing. * history of prior allogeneic bone marrow/stem-cell or solid organ transplantation. * patients receiving autologous stem cell transplantation must wait 8 weeks before initiation of study drug administration. * treatment with systemic chemotherapy or investigational therapy within 4 weeks of first study drug administration; other agents (e.g., biologics) within 2 weeks; radiation within 2 weeks; patients receiving 131i-mibg therapy must wait 6 weeks prior to the initiation of study drug administration; corticosteroids (≥ 0.2 mg/kg/day prednisone or equivalent) or other immune suppressive drugs within the 2 weeks prior to the initiation of study drug administration. * history of clinically significant cardiovascular disease * active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days prior to the initiation of study drug. * known positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome. * known history of hepatitis b or hepatitis c infection or known positive test for hepatitis b surface antigen, hepatitis b core antigen, or hepatitis c polymerase chain reaction. * second primary invasive malignancy that has not been in remission for greater than 2 years. * history of severe trauma or major surgery within 4 weeks prior to the initiation of study drug administration. * known hypersensitivity to recombinant proteins, polysorbate 80 or any excipient contained in the drug formulation for enoblituzumab * patients in canada may not have a history or evidence of latent or active tuberculosis infection.

Keywords: neuroblastoma rhabdomyosarcoma osteosarcoma ewing sarcoma wilms tumor desmoplastic small round cell tumor pediatric