This is a Phase 1 study evaluating the safety and feasibility of CART-EGFR-IL13Ra2 cells in a 3+3 dose escalation design as described below.~• Cohort 1 (N = 3-6): will receive a single fixed dose of 1x107 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0. This dose level will be evaluated as follows:~If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.~If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Cohort 2.~In the event that 2 or more DLTs occur in Cohort 1, then enrollment into Cohort 1 will be stopped and the dose will be de-escalated to 5x106 CART-EGFR-IL13Ra2 cells. This de-escalated cohort will be identified as Cohort -1.~• Cohort -1 (N = 3-6): will receive a single fixed dose of 5x106 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0. This dose level will be evaluated as follows:~If 0 DLT/3 or 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.~If ≥ 2 DLTs occur at any time, enrollment onto this cohort will be stopped.~In the event of 0 DLT/3 subjects or 1 DLT/6 subjects in Cohort 1, then the study will advance to Cohort 2.~Cohort 2 (N = 3-6): will receive a single fixed dose of 2.5x107 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0. This dose level will be evaluated as follows:~If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.~If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Cohort 3.~If 2 DLTs occur at any time, enrollment in this Cohort will be stopped. If less than 6 subjects were treated at the previous dose level (Cohort 1), additional subjects will be enrolled in that Cohort to reach a minimum of 6 evaluable subjects.~Cohort 3 (N = 3-6): will receive a single fixed dose of 1x108 CART-EGFR-IL13Ra2 cells via intrathecal administration on Day 0. This dose level will be evaluated as follows:~If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.~If 0 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.~If 2 DLTs occur at any time, enrollment in this Cohort will be stopped. If less than 6 subjects were treated at the previous dose level (Cohort 2), additional subjects will be enrolled in that Cohort to reach a minimum of 6 evaluable subjects.~The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 DLT occurs in 6 evaluable subjects.~The DLT observation period is 28 days post-initial treatment with CART-EGFR-IL13Ra2 cells (Day 0). In order to allow for appropriate monitoring/assessment of toxicities, the CART-EGFR-IL13Ra2 injections in the 1st and 2nd subjects in each cohort must be staggered by at least 28 days. If there are no emergent safety concerns identified in the first subject treated, subsequent subject injections within that same cohort do not need to be staggered and may occur sequentially (e.g. CART-EGFR-IL13Ra2 injections in the 2nd and 3rd subjects may occur in parallel without additional staggering requirements). Formal DLT evaluations will be performed after the 3rd subject in each cohort reaches the Day 28 safety follow-up visit, and will allow for a formal decision regarding cohort progression, expansion, or dose de-escalation. Formal DLT evaluations will be determined by the Clinical PI and Sponsor Medical Director in accordance with the definition in Section 8.1.7.~Subjects must receive the target dose of CART-EGFR-IL13Ra2 cells as per their cohort assignment in order to be considered evaluable for dose escalation decisions and MTD determination. Subjects who do not receive the dose of CART-EGFR-IL13Ra2 cells as per their cohort assignment will not be considered evaluable for this purpose and will be replaced in this cohort. However, these subjects will still be included in the overall safety analysis, as well as the analyses of secondary and exploratory objectives.
This is an open-label phase 1 study to assess the safety and feasibility of autologous T cells co-expressing two CARs targeting the cryptic EGFR epitope 806 and IL13Ra2 (referred to as CART-EGFR-IL13Ra2 cells) in patients with EGFR-amplified glioblastoma, IDH-wildtype that has recurred following prior radiotherapy.