CART-EGFR-IL13Ra2 in EGFR Amplified Recurrent GBM
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Detailed Description
This is a Phase 1 study evaluating the safety and feasibility of CART-EGFR-IL13Ra2 cells following lymphodepletion with fludarabine and cyclophosphamide in a 3+3 dose escalation design.
• Cohort 1 (N = 3-6): will receive a single fixed dose of 5x107 CART-EGFR-IL13Ra2 cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide and fludarabine given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day is 3 days (+/- 1 day) prior to the infusion of CART-EGFR-IL13Ra2 cells. This dose level will be evaluated as follows:
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If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
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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 1x107 CART-EGFR-IL13Ra2 cells. This de-escalated cohort will be designated Cohort -1.
- Cohort -1 (N = 3-6): will receive a single fixed dose of 1x107 CART-EGFR-IL13Ra2 cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide and fludarabine given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day is 3 days (+/- 1 day) prior to the infusion of
CART-EGFR-IL13Ra2 cells. This dose level will be evaluated as follows:
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If 0 DLT/3 or 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level to confirm MTD.
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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.
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Cohort 2 (N = 3-6): will receive a single fixed dose of 1x108 CART-EGFR-IL13Ra2 cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide and fludarabine given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day is 3 days (+/- 1 day) prior to the infusion of CART-EGFR-IL13Ra2 cells. This dose level will be evaluated as follows:o If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
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If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Cohort 3.
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If 2 DLTs occur at any time, enrollment in this Cohort will be stopped and Cohort 1 will be identified as the maximum tolerated dose (MTD). If less than 6 subjects were infused in Cohort 1, at least 6 evaluable subjects will be infused at this dose level to further demonstrate safety and to confirm the MTD.
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Cohort 3 (N = 3-6): will receive a single fixed dose of 5x108 CART-EGFR-IL13Ra2 cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide and fludarabine given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day is 3 days (+/- 1 day) prior to the infusion of
CART-EGFR-IL13Ra2 cells. 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, this dose will be identified as the maximum tolerated dose (MTD). If less than 6 subjects were infused in Cohort 3, at least 6 evaluable subjects will be infused at this dose level to further demonstrate safety and to confirm the MTD.
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If 2 DLTs occur at any time, enrollment in this Cohort will be stopped and Cohort 2 will be identified as the maximum tolerated dose (MTD). If less than 6 subjects were infused in Cohort 2, at least 6 evaluable subjects will be infused at this dose level to further demonstrate safety and to confirm the MTD.
The DLT observation period is 28 days post CART-EGFR-IL13Ra2 infusion (Day 0). The first two infusions in each cohort will be staggered by at least 28 days to allow for the assessment of DLTs and a formal decision regarding cohort progression, expansion, or dose de-escalation. Formal DLT assessments will be performed by the Clinical PI and Sponsor Medical Director in accordance with the definition in the protocol 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 MTD determination at that dose level. Subjects who do not receive CART-EGFR-IL13Ra2 cells as per their cohort assignment will not be evaluable for MTD determination and will be replaced in this cohort. However, the subject will still be followed for safety and included in the analysis of secondary and exploratory objectives.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Cohort 1 Cohort 1 (N = 3-6): will receive a single fixed dose of 5x107 CART-EGFR-IL13Ra2 cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide and fludarabine given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day is 3 days (+/- 1 day) prior to the infusion of CART-EGFR-IL13Ra2 cells. |
Drug: 5x10(7) CART-EGFR-IL13Ra2
5x10(7) CART-EGFR-IL13Ra2 cells via intravenous infusion
Drug: Cyclophosphamide
Lymphodepleting chemotherapy
Drug: Fludarabine
Lymphodepleting chemotherapy
|
Experimental: Cohort -1 Cohort -1 (N = 3-6): will receive a single fixed dose of 1x107 CART-EGFR-IL13Ra2 cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide and fludarabine given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day is 3 days (+/- 1 day) prior to the infusion of CART-EGFR-IL13Ra2 cells. |
Drug: 1x107 CART-EGFR-IL13Ra2
1x10(7) CART-EGFR-IL13Ra2 cells via intravenous infusion
Drug: Cyclophosphamide
Lymphodepleting chemotherapy
Drug: Fludarabine
Lymphodepleting chemotherapy
|
Experimental: Cohort 2 Cohort 2 (N = 3-6): will receive a single fixed dose of 1x108 CART-EGFR-IL13Ra2 cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide and fludarabine given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day is 3 days (+/- 1 day) prior to the infusion of CART-EGFR-IL13Ra2 cells. |
Drug: 1x10(8) CART-EGFR-IL13Ra2
1x10(8) CART-EGFR-IL13Ra2 cells via intravenous infusion
Drug: Cyclophosphamide
Lymphodepleting chemotherapy
Drug: Fludarabine
Lymphodepleting chemotherapy
|
Experimental: Cohort 3 Cohort 3 (N = 3-6): will receive a single fixed dose of 5x108 CART-EGFR-IL13Ra2 cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide and fludarabine given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day is 3 days (+/- 1 day) prior to the infusion of CART-EGFR-IL13Ra2 cells. |
Drug: 5x108 CART-EGFR-IL13Ra2
5x10(8) CART-EGFR-IL13Ra2 cells via intravenous infusion
Drug: Cyclophosphamide
Lymphodepleting chemotherapy
Drug: Fludarabine
Lymphodepleting chemotherapy
|
Outcome Measures
Primary Outcome Measures
- Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V5.0 [15 years]
- Number of subjects with dose-limiting toxicities [12 months]
- Determination of maximum tolerated dose assessed by collection of adverse events as graded by CTCAE. [12 months]
Secondary Outcome Measures
- Progression-Free Survival (PFS) [15 years post]
- Objective Response Rate (ORR) [15 years]
- Proportion of subjects who enroll on the study who receive study treatment [12 months]
- Frequency of manufacturing failures as determined by production of study treatment that meets protocol defined targeted dose [12 months]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Signed, written informed consent
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Male or female age ≥ 18 years
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Patients with glioblastoma, IDH-wildtype (as defined by WHO 2021 Classification of CNS Tumors) that has recurred following prior radiotherapy1. For patients with tumors harboring methylation of the MGMT promoter, at least 12 weeks must have elapsed since completion of first-line radiotherapy.
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Tumor tissue positive for wild-type EGFR amplification by NeoGenomics Laboratories. Archival tumor from patient's initial surgery at time of original diagnosis or recently collected tumor from time of recurrence are acceptable.
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Adequate organ function defined as:
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Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 30 ml/min and not on dialysis.
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ALT/AST ≤ 3 x upper limit of normal range and total bilirubin ≤ 2.0 mg/dl, except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome (≤ 3.0 mg/dl).
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Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA
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Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
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Karnofsky Performance Status ≥ 60%.
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Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.
Exclusion Criteria:
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Active hepatitis B or hepatitis C infection.
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Any other active, uncontrolled infection.
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Class III/IV cardiovascular disability according to the New York Heart Association Classification
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Tumors primarily localized to the brain stem or spinal cord.
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Severe, active co-morbidity in the opinion of the physician-investigator that would preclude participation in this study.
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Receipt of bevacizumab within 3 months prior to enrollment.
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Dependence on systemic steroids for management of symptoms associated with GBM and associated cerebral edema. Patients must not have an ongoing requirement for dexamethasone.
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Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10 mg daily of prednisone. Patients with autoimmune neurological diseases (such as MS or Parkinson's) will be excluded.
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Pregnant or nursing (lactating) women.
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History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- University of Pennsylvania
- Tmunity Therapeutics
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 16321