Modified Immune Cells (Autologous iC9.GD2.CAR.IL-15 T cells) for Treating Patients with Relapsed or Refractory High Risk Neuroblastoma, Ganglioneuroblastoma, or Osteosarcoma

Summary

Objectives

PRIMARY OBJECTIVE:
I. To determine the safety and tolerability of autologous iC9-GD2CAR-CD28-CD3zeta-IL-15-expressing T-lymphocytes (autologous iC9.GD2.CAR.IL-15 T cells) administered to adult and pediatric subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma.

SECONDARY OBJECTIVES:
I. To identify the maximum tolerated dose (MTD) of iC9.GD2.CAR.IL-15 T cells in pediatric subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma.
II. To identify the maximum tolerated dose (MTD) of iC9.GD2.CAR.IL-15 T cells in adult subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma.
III. To assess expansion and persistence of iC9.GD2.CAR.IL-15 T cells in vivo.
III. To evaluate the anti-tumor response rate to iC9.GD2.CAR.IL-15 T cell administration in subjects with relapsed/refractory neuroblastoma per Revised International Neuroblastoma Response Criteria (INRC) or subjects with relapsed/refractory osteosarcoma by RECIST version (v) 1.1.
IV. To determine overall survival (OS) in pediatric subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma treated with iC9.GD2.CAR.IL-15 T cells.
V. To evaluate the anti-tumor response rate to iC9.GD2.CAR.IL-15 T cell administration in subjects with relapsed/refractory neuroblastoma per Revised International Neuroblastoma Response Criteria (INRC).
VI. To determine overall survival (OS) in subjects relapsed/refractory osteosarcoma treated with iC9.GD2.CAR.IL-15 T cells.
VII. To determine overall survival (OS) in subjects with relapsed/refractory neuroblastoma treated with iC9.GD2.CAR.IL-15 T cells.
VIII. To determine progression free survival (PFS) in subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma treated with iC9.GD2.CAR.IL-15 T cells.
IX. To determine progression free survival (PFS) in subjects with relapsed/refractory neuroblastoma treated with iC9.GD2.CAR.IL-15 T cells.

EXPLORATORY OBJECTIVES:
I. To measure proxy-reported symptoms in pediatric subjects at baseline and over time in osteosarcoma subjects treated with iC9.GD2.CAR.IL-15 T cells.
II. To measure proxy-reported symptoms in pediatric subjects at baseline and over time in neuroblastoma subjects treated with iC9.GD2.CAR.IL-15 T cells.
III. To evaluate utility of metaiodobenzylguanidine (mIBG) semiquantitative scoring (Curie scoring system) in predicting response to iC9.GD2.CAR.IL-15 T cells in subjects with neuroblastoma.
IV. To retrospectively analyze GD2 expression in neuroblastoma subjects' samples.
V. To retrospectively analyze GD2 expression in osteosarcoma subjects’ samples.
VI. To determine the utility of the safety switch in iC9.GD2.CAR.IL-15 T cells in subjects with relapsed/refractory neuroblastoma by allowing for administration of rimiducid (0.4 mg/kg/dose) to subjects with severe pain despite appropriate medical interventions (such as gabapentin for neuropathic pain or narcotics) or grade >= 3 immune effector cell-associated neurotoxicity syndrome (ICANS) that does not improve to grade =< 1 within 72 hours with standard of care (SOC) interventions and grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus following infusion of iC9.GD2.CAR.IL-15 T cells.
VII. To determine the utility of the safety switch in iC9.GD2.CAR.IL-15 T cells in subjects with relapsed/refractory osteosarcoma by allowing for administration of rimiducid (0.4 mg/kg/dose) to subjects with severe pain despite appropriate medical interventions (such as gabapentin for neuropathic pain or narcotics) or grade >= 3 ICANS that does not improve to grade =< 1 within 72 hours with SOC interventions and grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus following infusion of iC9.GD2.CAR.IL-15 T cells.
VIII. To measure changes in IL-15 levels at baseline and over time in subjects treated with iC9.GD2.CAR.IL-15 T cells.
IX. To determine whether there are correlations between CAR T cell behavior and the integration locations of iC9.GD2.CAR.IL-15.

OUTLINE: This is a dose-escalation study of autologous iC9-GD2CAR-CD28-CD3zeta-IL-15-expressing T-lymphocytes.

Patients receive lymphodepletion chemotherapy consisting of cyclophosphamide intravenously (IV) over 1 hour on days 1-2 and fludarabine phosphate IV over 30 minutes on days 1-4 in the absence of disease progression or unacceptable toxicity. Lymphodepletion may be repeated if necessary per physician discretion. Within 2-14 days after completion of lymphodepletion chemotherapy, patients receive autologous iC9-GD2CAR-CD28-CD3zeta-IL-15-expressing T-lymphocytes IV over 5-10 minutes. Patients who experience clinical benefit and meet certain criteria have the option to receive a second infusion of autologous iC9-GD2CAR-CD28-CD3zeta-IL-15-expressing T-lymphocytes IV at the discretion of treating physician. Patients undergo echocardiography during screening and bone marrow biopsy, tumor biopsy, computed tomography (CT) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study.

After completion of study treatment, patients are followed up on days 2 and 4, weeks 1, 2, 3, 4, and 6, and months 3, 6, 9, and 12. Subsequently, patients with iC9.GD2.CAR.IL-15 T cells detected are followed every 6 months for 4 years, then yearly for up to 15 years. All other patients are followed up yearly for 15 years.