Glioblastoma
Conditions
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.
Interventions
autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR and a humanized scFv targeting IL13Ra2
Sponsors
University of Pennsylvania
Kite Pharma (a Gilead Company)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3+3 Dose escalation design
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 radiotherapy. For patients with tumors harboring methylation of the MGMT promoter, at least 12 weeks 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 or tumor biopsy to confirm tumor recurrence 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 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). 3. Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO/MUGA 4. 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.
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 |
| Number of subjects with dose-limiting toxicities (DLTs) | 28 days following initial treatment with CART-EGFR-IL13Ra2 cells | Dose Escalation Phase only; Unacceptable toxicity as defined by the protocol |
| Determination of maximum tolerated dose (MTD). | 28 days following initial treatment with CART-EGFR-IL13Ra2 cellsnths | Dose Escalation Phase only: The maximum tolerated dose (MTD) is defined as the highest dose explored at which 0 or 1 DLT occurs in 6 evaluable subjects. |
| Determine the recommended dose for expansion (RDE). | Up to 12 months following initial treatment with CART-EGFR-IL13Ra2 cells | — |
| Proportion of eligible subjects who receive all planned doses of CART-EGFR-IL13Ra2 cells. | 28 days following initial treatment with CART-EGFR-IL13Ra2 cells | Cohort 4 only |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of subjects who enroll on this study who received study treatment. | 12 months | Evaluated based on the proportion of subjects who screen fail and those who receive any dose of CART-EGFR-IL13Ra2 cells. |
| Frequency of manufacturing failures | 3 months | Proportion of subjects with CART-EGFR-IL13Ra2 products that fail to meet the product release criteria, out of the number of subjects in whom manufacturing was attempted. Proportion of subjects with CART-EGFR-IL13Ra2 products that fail to meet the assigned dose, out of the number of subjects in whom manufacturing was attempted. |
| Progression-Free Survival (PFS) | Up to 15 years following CART-EGFR-IL13Ra2 administration | Per modified RANO criteria |
| Objective Response Rate (ORR) | Up to 12 months following CART-EGFR-IL13Ra2 administration | Per modified RANO criteria (in subjects with measurable disease at the time of study treatment); Proportion of subjects with confirmed CR and PR. |
| Duration of response (DOR) | Up to 15 years following initial CART-EGFR-IL13Ra2 administration | Per modified RANO criteria (in subjects with measurable disease at the time of study treatment); Time from the date when a response of confirmed CR/PR is first met to the date of confirmed disease progression, death or receipt of alternative treatment other than CART-EGFR-IL13Ra2 retreatment. |
| Overall Survival (OS) | Up to 15 years following initial CART-EGFR-IL13Ra2 administration | Time from initial study treatment to the date of death from any cause. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORStephen Bagley, MD, MSCE
University of Pennsylvania
Outcome results
None listed