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 and desmoplastic small round cell tumors.
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.
General Inclusion Criteria:
- Age ≥ 1 to 21 years at diagnosis of primary tumor (treatment up to the age of 30 years old).
- 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 (cohort expansion phase).
- 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.
- 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
|Maximum Eligible Age:||30 Years|
|Minimum Eligible Age:||1 Year|