Recurrent Glioblastoma
Conditions
Brief summary
This is an open-label, phase 1b study to evaluate different approaches for CART-EGFR-IL13Ra2 dosing and further characterize the safety, feasibility, preliminary efficacy, and pharmacokinetics of CART-EGFR-IL13Ra2 cells in patients with EGFR-amplified glioblastoma that has recurred following prior radiotherapy.
Interventions
BIOLOGICALCART-EGFR-IL13Ra2 T cells
CART-EGFR-IL13Ra2 cells are autologous T cells co-expressing two CARs targeting the cryptic EGFR epitope 806 and IL13Ra2.
Sponsors
University of Pennsylvania
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study will evaluate three different approaches for administering CART-EGFR-IL13Ra2 cells in the setting of recurrent glioblastoma. Each dosing approach will be evaluated as a separate treatment arm as outlined below: * Arm A: Single Fixed-Dose Administration Following Lymphodepletion * Arm B: Repeat Dose Administration Following Lymphodepletion * Arm C: Single Fixed-Dose Administration in the Pre-Operative Setting Subjects will be assigned to each treatment arm sequentially according to their planned treatment date, starting with Arm C. Once Arm C is fully enrolled, enrollment into Arm A may commence. Once Arm A is fully enrolled and all required safety evaluations have been completed, an interim review of the Arm A data will be performed and evaluated in combination with cumulative CART-EGFR-IL13Ra2 experience from other studies. The results of this interim data review will be evaluated by the Clinical PI and Sponsor Medical Director and used to determine whether Treatment Arm
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed, written informed consent 2. Male or female age ≥ 18 years 3. 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, a t l east 1 2 w eeks must have elapsed since completion of first-line radiotherapy. 4. 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. 5. Surgical tumor resection for disease control/management (Arms A, B, C) or tumor biopsy to confirm tumor recurrence (Arms A and B only) is clinically indicated in the opinion of the physician-investigator. 6. Adequate organ function defined as: 1. Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 30 ml/min and not on dialysis. 2. ALT/AST ≤ 3 x ULN 3. Total bilirubin ≤ 2.0 mg/dL, except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome (≤ 3.0 mg/dL) 4. Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA 5. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen \> 92% on room air 7. Karnofsky Performance Status ≥ 60%. 8. Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.
Exclusion criteria
1. Active hepatitis B or hepatitis C infection. 2. Any other active, uncontrolled infection. 3. Class III/IV cardiovascular disability according to the New York Heart Association Classification 4. Tumors primarily localized to the brain stem or spinal cord. 5. Severe, active co-morbidity in the opinion of the physician-investigator that would preclude participation in this study. 6. Receipt of bevacizumab within 3 months prior to physician-investigator confirmation of eligibility. 7. 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. 8. Patients who are pregnant or nursing (lactating). 9. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V5.0 | Up to 15 years following CART-EGFR-IL13Ra2 administration | Type, frequency, severity, and attribution of adverse events |
| Occurrence of treatment-limiting toxicities (Arms A and B only) | Up to 28 days following CART-EGFR-IL13Ra2 administration | Type, frequency, severity, and attribution of treatment limiting adverse events as defined in protocol section 8.1.7 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the feasibility of different approaches for CART-EGFR-IL13Ra2 dosing | Up to 2 years | Proportion of eligible subjects who receive study treatment. Proportion of eligible subjects assigned to arm B who receive all planned doses of CART-EGFR-IL13Ra2 cells |
| Progression-free Survival (PFS) | Up to 15 years following CART-EGFR-IL13Ra2 administration | Per RANO 2.0 criteria |
| Overall Survival (OS) | Up to 15 years following CART-EGFR-IL13Ra2 administration | Per RANO 2.0 criteria |
| Objective Response Rate (ORR) | Up to 15 years following CART-EGFR-IL13Ra2 administration | Per RANO 2.0 criteria in participants with measurable disease at the time of study treatment (Treatment Arms A and B) or Post-Surgical Resection (Treatment Arm C) |
| Duration of response (DOR) | Up to 15 years following CART-EGFR-IL13Ra2 administration | Per RANO 2.0 criteria in participants with measurable disease at the time of study treatment (Treatment Arms A and B) or Post-Surgical Resection (Treatment Arm C) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORStephen Bagley, MD, MSCE
University of Pennsylvania
Outcome results
None listed