Glioblastoma
Conditions
Brief summary
This is an open-label phase 1 study to assess the safety, feasibility, pharmacokinetics and preliminary efficacy 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 newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma, without evidence of disease recurrence/progression following completion of initial radiotherapy.
Interventions
autologous T cells transduced with a bicistronic lentiviral vector containing a murine scFv targeting EGFR epitope 806 and a humanized scFv targeting IL13Ra2; both scFvs are fused to the 4-1BB and CD3ζ signaling domains.
BIOLOGICALRituximab or Rituximab biosimilar
375 mg/m2/day x 1 day
Fludarabine: 30mg/m2/day x 3 days; Cyclophosphamide: 300mg/m2/day x 3 days
Sponsors
University of Pennsylvania
Kite Pharma (a Gilead Company)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Step #1 Inclusion Criteria: 1. Signed informed consent form 2. Male or females age ≥ 18 years. 3. Patients with newly diagnosed, EGFR-amplified, MGMT-unmethylated glioblastoma (as defined by WHO 2021 Classification for CNS Tumors, including that the tumor must be IDH wildtype). The tumor must also have histopathologic evidence of glioblastoma (i.e., presence of microvascular proliferation and/or necrosis). 4. Patients must have undergone maximal safe resection of the tumor as per routine cancer care. Patients who have had a biopsy only are not eligible. 5. Tumor tissue positive for wild-type EGFR amplification by Neogenomics Laboratories 6. Karnofsky Performance Status ≥ 60% 7. Patient scheduled to receive 60 Gy of radiotherapy. Either photon or proton therapy is acceptable. Step #1
Exclusion criteria
1. Active hepatitis B or hepatitis C infection 2. Class III/IV cardiovascular disability according to the New York Heart Association Classification. 3. Tumors with enhancing disease involving the thalamus, brain stem or spinal cord. 4. Tumors with an MGMT promoter methylation result of hypermethylated, methylated, low positive methylated, or indeterminate. 5. Multifocal disease if ≥ 1 focus of tumor has not undergone maximal safe resection 6. Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study. 7. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40). 8. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded. 9. Anticipated treatment plan that involves bevacizumab, any other systemic anti-neoplastic therapy, and/or tumor-treating fields as part of 1st line therapy. Step #2 Inclusion Criteria: 1. Patient completed full course of radiotherapy to 60 Gy. 2. No overt evidence of disease recurrence/progression post-radiotherapy confirmed by RANO 2.0 criteria. 3. Karnofsky Performance Status ≥ 60% 4. Adequate organ function defined as: 1. Serum creatinine ≤ 1.5x ULN or estimated creatinine clearance ≥ 30 mL/min and not on dialysis 2. ALT/AST ≤ 3 x ILN 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 minimum level of pulmonary reserve defined as \> 92% on room air Step #2
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 (TLTs) | 28 days post-CAR T cell administration | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of response (DOR) | Up to 15 years following initial CART-EGFR-IL13Ra2 administration | Per RANO 2.0 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. |
| Proportion of enrolled subjects who receive study treatment as planned | 28 days following initial treatment with CART-EGFR-IL13Ra2 cells | Evaluated based on the proportion of subjects who screen fail and those who receive any dose of CART-EGFR-IL13Ra2 cells. |
| Proportion of eligible subjects who receive study treatment as planned | 28 days following initial treatment with 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. |
| 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. |
| Progression-free Survival (PFS) | Up to 15 years following CART-EGFR-IL13Ra2 administration | Per RANO 2.0 criteria |
| Objective Response Rate (ORR) | Up to 12 months following CART-EGFR-IL13Ra2 administration | Per RANO 2.0 criteria (in subjects with measurable disease at the time of study treatment); Proportion of subjects with confirmed CR and PR. |
Countries
United States
Contacts
CONTACTAbramson Cancer Center Clinical Trials Service
PRINCIPAL_INVESTIGATORStephen Bagley, MD, MSCE
University of Pennsylvania
Outcome results
None listed