Clinical trial NCT05168423: CART-EGFR-IL13Ra2 in EGFR Amplified Recurrent GBM
Official title: Phase 1, Open-label Study Evaluating the Safety and Feasibility of CART-EGFR-IL13Ra2 Cells in Patients With EGFR-Amplified Recurrent Glioblastoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Glioblastoma
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Kite Pharma (a Gilead Company)
First posted: 2021-12-23
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 3+3 Dose escalation design
Primary purpose: TREATMENT

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. This study will take place in two parts: an initial dose escalation phase followed by a dose exploration phase. In the dose expansion phase, the maximum tolerated dose (MTD) of CART-EGFR-IL13Ra2 cells will be determined using a standard 3+3 design. Once the MTD has been determined, the dose exploration phase will allow for further identification of a recommended dose for expansion (RDE) as well as the safety and feasibility of alternative dosing schedules.


Eligibility criteria: 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).

Primary outcomes:
measure: Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V5.0
timeFrame: Up to 15 years following CART-EGFR-IL13Ra2 administration
measure: Number of subjects with dose-limiting toxicities (DLTs)
timeFrame: 28 days following initial treatment with CART-EGFR-IL13Ra2 cells
measure: Determination of maximum tolerated dose (MTD).
timeFrame: 28 days following initial treatment with CART-EGFR-IL13Ra2 cellsnths
measure: Determine the recommended dose for expansion (RDE).
timeFrame: Up to 12 months following initial treatment with CART-EGFR-IL13Ra2 cells
measure: Proportion of eligible subjects who receive all planned doses of CART-EGFR-IL13Ra2 cells.
timeFrame: 28 days following initial treatment with CART-EGFR-IL13Ra2 cells
Secondary outcomes:
measure: Proportion of subjects who enroll on this study who received study treatment.
timeFrame: 12 months
measure: Frequency of manufacturing failures
timeFrame: 3 months
measure: Progression-Free Survival (PFS)
timeFrame: Up to 15 years following CART-EGFR-IL13Ra2 administration
measure: Objective Response Rate (ORR)
timeFrame: Up to 12 months following CART-EGFR-IL13Ra2 administration
measure: Duration of response (DOR)
timeFrame: Up to 15 years following initial CART-EGFR-IL13Ra2 administration
measure: Overall Survival (OS)
timeFrame: Up to 15 years following initial CART-EGFR-IL13Ra2 administration
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Stephen Bagley, MD, MSCE
role: PRINCIPAL_INVESTIGATOR
References: