CAR T Cell Receptor Immunotherapy Targeting EGFRvIII for Patients With Malignant Gliomas Expressing EGFRvIII

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Malignant Glioma; Glioblastoma; Brain Cancer; Gliosarcoma	Biological: Anti-EGFRvIII CAR transduced PBL; Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide	Phase 1; Phase 2

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, 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	107 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Masking:	None (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
Actual Study Start Date :	May 16, 2012
Estimated Primary Completion Date :	December 29, 2028
Estimated Study Completion Date :	December 28, 2029

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1/Phase I Arm; Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-EGFRvIII CAR transduced PBL + aldesleukin	Biological: Anti-EGFRvIII CAR transduced PBL; Day 0: Cells will be infused intravenously over 20-30 minutes. Patients enrolled in dose level 9 will receive two cell doses, 2 hours apart.; Drug: Aldesleukin; Aldeskeukin 72,000 IU /kg IV or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).; Drug: Fludarabine; Days -7 to -3: Fludarabine 25 mg /m2/day IVPB daily over 30 minutes for 5 days.; Drug: Cyclophosphamide; Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg /day X 2 days over 1 hr.
Experimental: 2/Phase II Arm; Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-EGFRvIII CAR transduced PBL + aldesleukin	Biological: Anti-EGFRvIII CAR transduced PBL; Day 0: Cells will be infused intravenously over 20-30 minutes. Patients enrolled in dose level 9 will receive two cell doses, 2 hours apart.; Drug: Aldesleukin; Aldeskeukin 72,000 IU /kg IV or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).; Drug: Fludarabine; Days -7 to -3: Fludarabine 25 mg /m2/day IVPB daily over 30 minutes for 5 days.; Drug: Cyclophosphamide; Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg /day X 2 days over 1 hr.

Outcome Measures

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Primary Outcome Measures :

1. Frequency of treatment related adverse events [ Time Frame: 30 days after end of treatment, and then annually for 5 years following cell infusion ]
   Aggregate of all adverse events and their frequency
2. Progression-free survival [ Time Frame: 6 months after end of treatment ]
   Number of patients whose disease has not progressed 6 months following treatment

Secondary Outcome Measures :

1. Radiographic changes [ Time Frame: 4 weeks after cell infusion, monthly as feasible for 12 months, and then every 1-2 months as feasible ]
   Response and progression using RECIST v1.0 criteria
2. Engineered cell survival [ Time Frame: conclusion of the study ]
   CAR and vector presence will be quantitated in PBMC samples using established PCR techniques

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 70 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

-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.

Contacts and Locations

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Contacts

Contact: Mary E. Link, R.N.	(866) 820-4505	IRC@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 irc@nih.gov

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Steven A Rosenberg, M.D.	National Cancer Institute (NCI)

More Information

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Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

FRANKEL SA, GERMAN WJ. Glioblastoma multiforme; review of 219 cases with regard to natural history, pathology, diagnostic methods, and treatment. J Neurosurg. 1958 Sep;15(5):489-503.

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96.

Bloom HJ. Combined modality therapy for intracranial tumors. Cancer. 1975 Jan;35(1):111-20. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Badhiwala J, Decker WK, Berens ME, Bhardwaj RD. Clinical trials in cellular immunotherapy for brain/CNS tumors. Expert Rev Neurother. 2013 Apr;13(4):405-24. doi: 10.1586/ern.13.23. Review.

Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, Feldman SA, Chinnasamy N, Kuan CT, Song H, Zhang W, Fine HA, Rosenberg SA. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther. 2012 Oct;23(10):1043-53. doi: 10.1089/hum.2012.041. Epub 2012 Sep 24.

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT01454596 History of Changes
Other Study ID Numbers:	110266; 11-C-0266
First Posted:	October 19, 2011
Last Update Posted:	August 6, 2018
Last Verified:	August 1, 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Cell Therapy; Gene Therapy; Immunotherapy	Brain Cancer; Glioma; Glioblastoma

Additional relevant MeSH terms:

Glioblastoma; Glioma; Gliosarcoma; 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; Fludarabine; Aldesleukin; Vidarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action