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CART-EGFR-IL13Ra2 in EGFR Amplified Recurrent GBM

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05168423
Recruitment Status : Not yet recruiting
First Posted : December 23, 2021
Last Update Posted : January 11, 2022
Sponsor:
Collaborator:
Tmunity Therapeutics
Information provided by (Responsible Party):
University of Pennsylvania

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
Glioblastoma Drug: 5x10(7) CART-EGFR-IL13Ra2 Drug: 1x107 CART-EGFR-IL13Ra2 Drug: 1x10(8) CART-EGFR-IL13Ra2 Drug: 5x108 CART-EGFR-IL13Ra2 Drug: Cyclophosphamide Drug: Fludarabine Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: 3+3 Dose escalation design
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Open-label Study Evaluating the Safety of CART-EGFR-IL13Ra2 Cells Following Lymphodepleting Chemotherapy in Patients With EGFR-Amplified Recurrent Glioblastoma
Estimated Study Start Date : June 19, 2022
Estimated Primary Completion Date : December 19, 2024
Estimated Study Completion Date : December 19, 2039

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V5.0 [ Time Frame: 15 years ]
  2. Number of subjects with dose-limiting toxicities [ Time Frame: 12 months ]
  3. Determination of maximum tolerated dose assessed by collection of adverse events as graded by CTCAE. [ Time Frame: 12 months ]

Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: 15 years post ]
  2. Objective Response Rate (ORR) [ Time Frame: 15 years ]
  3. Proportion of subjects who enroll on the study who receive study treatment [ Time Frame: 12 months ]
  4. Frequency of manufacturing failures as determined by production of study treatment that meets protocol defined targeted dose [ Time Frame: 12 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 radiotherapy1. 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. 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
  6. Karnofsky Performance Status ≥ 60%.
  7. 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 enrollment.
  7. Dependence on systemic steroids for management of symptoms associated with GBM and associated cerebral edema. Patients must not have an ongoing requirement for dexamethasone.
  8. 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.
  9. Pregnant or nursing (lactating) women.
  10. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT05168423    
Other Study ID Numbers: 16321
First Posted: December 23, 2021    Key Record Dates
Last Update Posted: January 11, 2022
Last Verified: January 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
Fludarabine
Isotretinoin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Dermatologic Agents