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A Phase I/II Study of the Safety and Feasibility of Administering T Cells Expressing Anti-EGFRvIII Chimeric Antigen Receptor to Patients With Malignant Gliomas Expressing EGFRvIII


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Malignant Glioma, Glioblastoma, Brain Cancer

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Trial Information

A Phase I/II Study of the Safety and Feasibility of Administering T Cells Expressing Anti-EGFRvIII Chimeric Antigen Receptor to Patients With Malignant Gliomas Expressing EGFRvIII


BACKGROUND:

- Patients with recurrent gliomas have very limited treatment options. EGFR variant III

(EGFRvIII) is the most common mutant variant of EGFR and is present in 24-67% of patients
with glioblastoma.

- EGFRvIII expression promotes oncogenesis and is associated with poor prognosis.

- EGFRvIII is not expressed in normal tissue and is an attractive target for
immunotherapy.

- We have constructed a retroviral vector that contains a chimeric antigen receptor (CAR)
that recognizes the EGFRvIII tumor antigen, which can be used to mediate genetic
transfer of this CAR with high efficiency without the need to perform any selection.

OBJECTIVES:

Primary Objectives

- To evaluate the safety of the administration of anti-EGFRvIII CAR engineered peripheral
blood lymphocytes in patients receiving the non-myeloablative conditioning regimen, and
aldesleukin

- Determine the six month progression free survival of patients receiving anti-EGFRvIII
CAR-engineered peripheral blood lymphocytes and aldesleukin following a
nonmyeloablative but lymphoid depleting preparative regimen.

Secondary objectives

- Determine the in vivo survival of CAR gene-engineered cells.

- Evaluate radiographic changes after treatment

ELIGIBILITY:

- Histologically proven glioblastoma or glisarcoma expressing EGFRvIII as determined by
IHC or RT-PCR

- Failed prior standard treatment with radiotherapy with or without chemotherapy

- Karnofsky score greater than or equal to 60%

- Cardiac, pulmonary and laboratory parameters within acceptable limits

DESIGN:

- The study will be conducted using a Phase I/II design.

- Patients will be accrued to both the phase I and phase II portion of the trial in two
groups:

- patients with recurrent malignant glioma requiring steroid use at the start of
treatment

- patients with recurrent malignant glioma not requiring steroids at the start of
treatment.

- Patients will receive a non-myeloablative but lymphocyte depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex
vivo tumor reactive, CAR gene-transduced PBMC, plus IV aldesleukin.

- Once the MTD has been determined for each individual group in the phase I portion of
the trial, the study will proceed to the phase II portion.

- Patients will again be accrued to the same two groups. For each of the 2 groups
evaluated, the study will be conducted using a single stage phase II design.

- A total of 160 patients may be enrolled over a period of 7 years.

Inclusion Criteria


-INCLUSION CRITERIA:

1. Patients with histologically proven glioblastomas or gliosarcomas that express
EGFRvIII as assessed by IHC or PCR.

2. Patients must have progression of disease after radiotherapy (including patients that
undergo surgery for recurrent disease and are rendered NED). This includes recurrent
GBM after receiving all standard first-line treatment, including surgery (if feasible
due to neurosurgical and neuro-anatomical considerations) and adjuvant radiotherapy
+/- chemotherapy.

3. Patients must either not be receiving steroids, or be on a stable dose of steroids
for at least five days prior to registration.

4. Patients must be > 18 years old, and must have a life expectancy > 8 weeks

5. Patients must be able to understand and sign the Informed Consent Document

6. Must be willing to sign a durable power of attorney.

7. Patients must have a Karnofsky performance status of greater than or equal to 60

8. Patients of both genders must be willing to practice birth control for four months
following the preparative regimen.

9. Serology:

- Seronegative for HIV antibody. (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV
seropositive can have decreased immune-competence and thus be less responsive to
the experimental treatment and more susceptible to its toxicities.)

- Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody
unless antigen negative.

10. Hematology

- WBC greater than or equal to 3000/mm(3)

- ANC greater than or equal to 1000/mm(3) without the support of filgrastim

- Platelet count greater than or equal to 100,000/mm(3)

- Hemoglobin greater than or equal to 8.0 g/dl (eligibility level for hemoglobin
may be reached by transfusion)

11. Chemistry:

- ALT/AST less than or equal to to 2.5 times the upper limit of normal

- Creatinine less than or equal to to 1.6 mg/dl

- Total bilirubin less than or equal to to 1.5 mg/dl, except in patients with
Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

12. Patients must be at least 4 weeks from radiation therapy. Additionally, patients must
be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from
procarbazine, 2 weeks from vincristine and 4 weeks from last bevacizumab
administration. Patients must be at least 4 weeks from other cytotoxic therapies not
listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen)
including investigative agents. All toxicities from prior therapies should be
resolved to CTCAE less than or equal to grade 1 (except for toxicities such as
alopecia, or vitiligo).

EXCLUSION CRITERIA:

1. A prior history of gliadel implantation in the past six months..

2. Women who are currently pregnant or breast feeding because of the potentially
dangerous effects of the preparative regimen on the fetus or infant.

3. Active systemic infections, coagulation disorders or other major medical illnesses
including those of the cardiovascular, respiratory or immune system, myocardial
infarction, cardiac arrhythmias, obstructive/restrictive pulmonary disease.

4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

5. Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who have decreased immune
competence may be less responsive to the experimental treatment and more susceptible
to its toxicities).

6. History of severe immediate hypersensitivity to any of the agents including

cyclophosphamide, fludarabine, or aldesleukin.

7. History of coronary revascularization or ischemic symptoms.

8. Clinically significant hemorrhagic or ischemic stroke, including transient ischemic
attacks and other central nervous system bleeding in the preceding 6 months that were
not related to glioma surgery. History of prior intratumoral bleeding is not an
exclusion criteria; patients who with history of prior intratumoral bleeding,
however, need to undergo a non-contrast head CT to exclude acute bleeding.

9. Other concomitant anti-cancer therapy except corticosteroids.

10. Any patient known to have an LVEF less than or equal to 45%.

11. Documented FEV1 less than or equal to 60% predicted tested in patients with:

- A prolonged history of cigarette smoking (20 pk/year of smoking within thepast 2
years).

- Symptoms of respiratory dysfunction

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the safety and the six month progression free survival in patients administered anti-EGFRlll CAR engineered peripheral blood lymphocytes, the non-myeloablative conditioning regimen, and aldesleukin.

Outcome Time Frame:

7 years

Safety Issue:

Yes

Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110266

NCT ID:

NCT01454596

Start Date:

September 2011

Completion Date:

September 2018

Related Keywords:

  • Malignant Glioma
  • Glioblastoma
  • Brain Cancer
  • Cell Therapy
  • Gene Therapy
  • Immunotherapy
  • Brain Cancer
  • Glioma
  • Glioblastoma
  • Brain Neoplasms
  • Glioblastoma
  • Glioma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892