White Blood Cells With Anti-EGFR-III for Malignant Gliomas

This study is currently recruiting participants.
Verified January 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01454596
First received: October 6, 2011
Last updated: March 14, 2014
Last verified: January 2014

October 6, 2011
March 14, 2014
September 2011
September 2018   (final data collection date for primary 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. [ Time Frame: 7 years ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT01454596 on ClinicalTrials.gov Archive Site
  • Determine the in vivo survival of CAR gene-engineered cells. [ Time Frame: 7 years ] [ Designated as safety issue: No ]
  • Evaluate radiographic changes after treatment. [ Time Frame: 7 years ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
White Blood Cells With Anti-EGFR-III for Malignant Gliomas
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:

- A new cancer treatment involves collecting white blood cells from a patient, modifying them to act against the cancer, and returning them to the body. The white blood cells may then be able to identify and destroy the cancer cells. Some kinds of advanced gliomas contain a protein called EGFR, which is not present in normal tissues. Doctors want to modify white blood cells to have an anti-EGFR effect, and use them to treat the glioma.

Objectives:

- To see if anti-EGFR white blood cells are a safe and effective treatment for advanced gliomas.

Eligibility:

- Individuals greater than or equal to 18 years of age and less than or equal to 66 years of age who have a malignant glioma that has not responded to standard treatments.

Design:

  • Participants will be screened with a medical history and physical exam. They will also have blood tests and imaging studies.
  • Participants will have leukapheresis about a month before the treatment to collect white blood cells.
  • They will have chemotherapy 1 week before the treatment to prepare the body for the anti-EGFR cells.
  • The anti-EGFR cells will be given as an infusion. Interleukin-2 will be given along with the cells to help boost the immune system s response. It will be given every 8 hours for up to 15 doses.
  • Participants will be monitored in the hospital with blood tests and other studies during their recovery from treatment.
  • Participants will have regular followup exams with blood tests, imaging studies, and other exams every 1 to 6 months.

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 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, the study will proceed to the phase II portion.
  • In the phase 2 portion of the trial, patients will be accrued to 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
  • A total of 160 patients may be enrolled over a period of 7 years.
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Malignant Glioma
  • Glioblastoma
  • Brain Cancer
  • Genetic: Anti-EGFRvIII CAR (PG13-139-CD8-CD28BBZ (F10) transduced PBL
    N/A
  • Drug: Aldesleukin
    N/A
  • Drug: Fludarabine
    N/A
  • Drug: Cyclophosphamide
    N/A
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
160
September 2018
September 2018   (final data collection date for primary outcome measure)

-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 greater than or equal to 18 years of age and less than or equal to age 66, 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. 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 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. 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 (eligibility level for hemoglobin may be reached by transfusion)
  12. 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.
  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).

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 treatment 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
Both
18 Years to 66 Years
No
Contact: June Kryk, R.N. (301) 451-1929 ncisbirc@mail.nih.gov
United States
 
NCT01454596
110266, 11-C-0266
Not Provided
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP