CAR T Cell Receptor Immunotherapy Targeting EGFRvIII for Patients With Malignant Gliomas Expressing EGFRvIII
| Status: | Completed |
|---|---|
| Conditions: | Cancer, Brain Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 1/27/2019 |
| Start Date: | May 16, 2012 |
| End Date: | January 17, 2019 |
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:
The NCI Surgery Branch has developed an experimental therapy for treating patients with
gliomas that involves taking white blood cells from the patient, growing them in the
laboratory in large numbers, genetically modifying these specific cells with a type of virus
(retrovirus) to attack only the tumor cells, and then giving the cells back to the patient.
This type of therapy is called gene transfer. In this protocol, we are modifying the patient
s white blood cells with a retrovirus that has the gene for anti-EGFRvIII incorporated in the
retrovirus.
Objective:
The purpose of this study is to determine a safe number of these cells to infuse and to see
if these particular tumor-fighting cells (anti-EGFRvIII cells) are a safe and effective
treatment for advanced gliomas.
Eligibility:
- Adults age 18-70 with malignant glioma expressing the EGFRvIII molecule.
Design:
Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo
a history and physical examination, scans, x-rays, lab tests, and other tests as needed
Leukapheresis: If the patients meet all of the requirements for the study they will undergo
leukapheresis to obtain white blood cells to make the anti-EGFRvIII cells. {Leukapheresis is
a common procedure, which removes only the white blood cells from the patient.}
Treatment: Once their cells have grown, the patients will be admitted to the hospital for the
conditioning chemotherapy, the anti-EGFRvIII cells, and aldesleukin. They will stay in the
hospital for about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects,
lab tests, and scans every month for the first year, and then every 1-2 months as long as
their tumors are shrinking. Follow up visits will take up to 2 days.
The NCI Surgery Branch has developed an experimental therapy for treating patients with
gliomas that involves taking white blood cells from the patient, growing them in the
laboratory in large numbers, genetically modifying these specific cells with a type of virus
(retrovirus) to attack only the tumor cells, and then giving the cells back to the patient.
This type of therapy is called gene transfer. In this protocol, we are modifying the patient
s white blood cells with a retrovirus that has the gene for anti-EGFRvIII incorporated in the
retrovirus.
Objective:
The purpose of this study is to determine a safe number of these cells to infuse and to see
if these particular tumor-fighting cells (anti-EGFRvIII cells) are a safe and effective
treatment for advanced gliomas.
Eligibility:
- Adults age 18-70 with malignant glioma expressing the EGFRvIII molecule.
Design:
Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo
a history and physical examination, scans, x-rays, lab tests, and other tests as needed
Leukapheresis: If the patients meet all of the requirements for the study they will undergo
leukapheresis to obtain white blood cells to make the anti-EGFRvIII cells. {Leukapheresis is
a common procedure, which removes only the white blood cells from the patient.}
Treatment: Once their cells have grown, the patients will be admitted to the hospital for the
conditioning chemotherapy, the anti-EGFRvIII cells, and aldesleukin. They will stay in the
hospital for about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects,
lab tests, and scans every month for the first year, and then every 1-2 months as long as
their tumors are shrinking. Follow up visits will take up to 2 days.
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, lymphodepleting
preparative 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, lymphodepleting preparative regimen.
ELIGIBILITY:
- Histologically proven glioblastoma or gliosarcoma expressing EGFRvIII as determined by
IHC or RT-PCR
- Failed prior standard treatment with radiotherapy with or without chemotherapy
- Karnofsky performance score (KPS) 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 receive a non-myeloablative, lymphodepleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex
vivo tumorreactive, CAR gene-transduced PBMC, plus IV aldesleukin.
- Once the maximum tolerated cell dose (MTD) has been determined, the study will proceed
to the phase II portion.
- In the phase II portion of the trial, patients will be accrued to two cohorts:
- Patients with recurrent malignant glioma receiving steroids at the time of
treatment.
- Patients with recurrent malignant glioma not receiving steroids at the time of
treatment.
- A total of 107 patients may be enrolled over a period of 7 years.
- 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, lymphodepleting
preparative 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, lymphodepleting preparative regimen.
ELIGIBILITY:
- Histologically proven glioblastoma or gliosarcoma expressing EGFRvIII as determined by
IHC or RT-PCR
- Failed prior standard treatment with radiotherapy with or without chemotherapy
- Karnofsky performance score (KPS) 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 receive a non-myeloablative, lymphodepleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex
vivo tumorreactive, CAR gene-transduced PBMC, plus IV aldesleukin.
- Once the maximum tolerated cell dose (MTD) has been determined, the study will proceed
to the phase II portion.
- In the phase II portion of the trial, patients will be accrued to two cohorts:
- Patients with recurrent malignant glioma receiving steroids at the time of
treatment.
- Patients with recurrent malignant glioma not receiving steroids at the time of
treatment.
- A total of 107 patients may be enrolled over a period of 7 years.
-INCLUSION CRITERIA:
1. Patients with histologically proven glioblastomas or gliosarcomas that express
EGFRvIII as assessed by IHC or PCR confirmed by the NCI Laboratory of Pathology.
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. Age greater than or equal to 18 years and less than or equal to age 70 years.
5. Ability of subject to understand and the willingness to sign a written informed
consent document.
6. Willing to sign a durable power of attorney.
7. KPS greater than or equal to 60
8. Patients of both genders must be willing to practice birth control from the time of
enrollment on this study and for four months after treatment.
9. Women of child-bearing potential must have a negative pregnancy test because of the
potentially dangerous effects of the treatment on the fetus.
10. Serology
- Seronegative for HIV antibody. (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV
seropositive may 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.
If hepatitis C antibody test is positive, then patients must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative.
11. 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. Subjects may be transfused to reach
this cut-off.
12. Chemistry
- Serum ALT/AST less than or equal to 2.5 x ULN
- Serum creatinine less than or equal to 1.6 mg/dl
- Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert
s Syndrome, who must have a total bilirubin equal to or less than 3.0 mg/dl.
13. 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).
14. Subject s must be co-enrolled on protocol 03-C-0277
EXCLUSION CRITERIA:
1. A prior history of gliadel implantation in the past six months..
2. Women of child-bearing potential who are pregnant or breast feeding because of the
potentially dangerous effects of the treatment on the fetus or infant.
3. Active systemic infections, requiring anti-infective treatment, coagulation disorders,
or any other active or uncompensated major medical illnesses
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 reaction to 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 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 (greater than or equal to 20 pack-year
smoking history, with cessation within the past two years).
- Symptoms of respiratory dysfunction
12. Patients who are receiving any other investigational agents.
13. Documented LVEF less than or equal to 45% tested in patients:
- Age greater than or equal to 65 years
- With clinically significant atrial and/or ventricular arrhythmias including but
not limited to: atrial fibrillation, ventricular tachycardia, second or third
degree heart block or have a history of ischemic heart disease and/or chest pain.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 866-820-4505
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