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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 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: July 25, 2014
Last verified: June 2014
  Purpose

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.

Condition Intervention Phase
Malignant Glioma
Glioblastoma
Brain Cancer
Biological: Anti-EGFRvIII CAR transduced PBL
Drug: Aldesleukin
Drug: Fludarabine
Drug: Cyclophosphamide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 and todetermine the six month progression free surviv... [ Time Frame: approximately 7 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 160
Study Start Date: September 2011
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: September 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
Patients will receive a non-myeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of anti- EGFRvIII CAR transduced PBL, plus IV aldesleukin.
Biological: Anti-EGFRvIII CAR transduced PBL
On day 0 (one to four days after the last dose of fludarabine),cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
Drug: Aldesleukin
Aldesleukin(based on total body weight) 72,000 IU/kg IV over 15 minute approximately every eight hours (+/- one hour) beginning within 24 hours of cell infusion and continuing for up to 5 days maximum of 15 doses).
Drug: Fludarabine
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Drug: Cyclophosphamide
Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.

Detailed Description:

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.
  Eligibility

Ages Eligible for Study:   18 Years to 66 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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 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 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%.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01454596

Contacts
Contact: June Kryk, R.N. (301) 451-1929 ncisbirc@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01454596     History of Changes
Other Study ID Numbers: 110266, 11-C-0266
Study First Received: October 6, 2011
Last Updated: July 25, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Cell Therapy
Gene Therapy
Immunotherapy
Brain Cancer
Glioma
Glioblastoma

Additional relevant MeSH terms:
Glioblastoma
Glioma
Brain Neoplasms
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cyclophosphamide
Fludarabine phosphate
Aldesleukin
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014