Immunotherapy for Malignant Pediatric Brain Tumors Employing Adoptive Cellular Therapy (IMPACT)

Overview

This is an open-label phase 1 safety and feasibility study that will employ multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA) derived from a patient's primary brain tumor tissues. Young patients with embryonal central nervous system (CNS) malignancies typically are unable to receive irradiation due to significant adverse effects and are treated with intensive chemotherapy followed by autologous stem cell rescue; however, despite intensive therapy, many of these patients relapse. In this study, individualized TSA-T cells will be generated against proteogenomically determined tumor-specific antigens after standard of care treatment in children less than 5 years of age with embryonal brain tumors. Correlative biological studies will measure clinical anti-tumor, immunological and biomarker effects.

This study will be conducted at Children's National Hospital (CNH) in Washington, DC. TSA-T products will be manufactured at the cell therapy Good Manufacturing Practice (GMP) facility at CNH. Patients enrolled in the study will receive their infusions at CNH. This is a phase 1 study treating children with embryonal brain tumors after definitive resection. Residual tumor may be present at the primary site or metastatic deposits but is not required. Patients will be treated with standard of care therapy as required, which may include up to 3 induction chemotherapy cycles (vincristine, cyclophosphamide, cisplatin, etoposide with or without methotrexate) and up to 3 consolidation cycles (carboplatin and thiotepa, each followed by an infusion of autologous peripheral blood stem cells (PBSCs)). Please note: Methotrexate will be part of the induction chemotherapy as per treating physician's discretion. The first TSA-T dose will be infused via a Codman Holter Rickham reservoir and catheter (intraventricular access device) on day 0, which will ideally be within 10 days following the patient's blood count recovery (ANC\>1000, ALC\>500) after the final consolidation cycle. Patients will receive the TSA-T product as per the table below until the recommended phase 2 dose (RP2D) is reached. Three patients will be enrolled at dose level 1 (2.5x107 cell) and monitored for at least 42 days during the safety monitoring period. If 2 DLTs are observed, the dose will be de-escalated to dose level -1 (1x107 cells). If no DLT is observed, 3 more patients will be enrolled at dose level 2 (5x107 cells). If 1 DLT is observed, an additional 3 patients will be enrolled at dose level 1 (2.5x107 cell) to complete the 42-day safety monitoring period. After these first 6 patients, an interim analysis to evaluate adverse events (AE) will occur. If there are ≤1 DLT in these first 6 patients and no other serious safety concerns, the remainder of the planned enrollment of 12 patients will be enrolled at dose level 2 (5x107 cells). If \>1 DLT is observed in the first 6 patients, the dose will be reduced to 1x107 cells, and another 3 patients will be enrolled and monitored for the 42-day safety monitoring period. If no further DLTs are encountered, the remainder of the planned enrollment of 12 will be enrolled at 1x107 cells. If any DLTs are observed at 1x107 cells, enrollment will be suspended, and the Data Review Committee (DRC) will meet to determine the feasibility of a further dose reduction. For the 3 patients treated at dose level 2 (5x107 cells), similarly if 1 DLT is observed, additional 3 patients will be enrolled at this dose level. If \>1 DLT is observed out of the 6 patients, the dose will be de-escalated to dose level 1, and the remainder of the patients will be enrolled at 2.5x107 cells. Each patient will receive at least one TSA-T infusion and may receive a maximum of 8 total infusions if sufficient TSA-T cells are available. For any infusion following the first infusion, if a patient's TSA-T supply is insufficient to meet the dose at the enrollment dose level, the final infusion may be administered at a lower dose level at the treating physician's discretion. The first and second infusions will be administered at least 42 days apart and additional infusions will be spaced at least 28 days apart. If patients have a response of stable disease or better by iRANO criteria at the evaluation after the second infusion OR if they have clinical stability and a clinical assessment of possible pseudoprogression on MRI despite the appearance of radiographic progression (see below), they are eligible to receive up to 6 additional infusions of TSA-T at a minimum of 28-day intervals as long as TSA-T cells are available. Each additional infusion will be the same as the enrollment dose level (i.e., no subsequent dose escalation). Prior to the first infusion, if a patient's TSA-T supply is insufficient for the dose level that the patient is assigned to, the patient may receive TSA-Ts at a lower dose with a minimum of 1x107 cells. These patients will not count towards the overall safety objective and will be replaced for that objective, although they will count towards the feasibility objective of identifying and producing adequate TSA-T products. If patients who are clinically stable are deemed to have possible pseudoprogression, then these patients may still be eligible for infusion if serial imaging and clinical assessments demonstrate stability most consistent with pseudoprogression. In these patients, disease assessment after the imaging that first raises the concern for pseudoprogression (potential progressive disease versus pseudoprogression) must be at least stable compared with the initial scan demonstrating enlarging tumor size.