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

NCT01454596 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 11026611-C-0266
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The National Cancer Institute (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 epidermal growth factor receptor (EGFR) vIII 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 National Institutes of Health (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.

Conditions

Malignant Glioma; Glioblastoma; Brain Cancer; Gliosarcoma

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Number of Treatment Related Adverse Events

  Aggregate of all adverse events ≥Grade 3 that are possibly, probably, and definitely related to treatment. Adverse events were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). Per CTCAE, Grade 3 adverse events are severe, Grade 4 is life threatening, and Grade 5 is death.

  From 4 weeks after cell infusion up to 77 days

• Progression Free Survival

  Progression was assessed by the Response Assessment in Neuro-Oncology (RANO) criteria and is defined as the circumstance when the magnetic resonance imaging (MRI) scan is ranked -2 (definitely worse) or -3 (development of a new lesion).

  Time from the date of registration to the date of first observation of progressive disease up to 6 months after end of treatment

Secondary Outcomes (3)

• Number of Patients With an Objective Response

  4 weeks after cell infusion and monthly as feasible up to 12 months

• Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment

  1 month post transplant

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

  51 dys Grp A, Cohort 1; Cohort 2:68 dys; Cohort 3:40 dys; Grp B, Cohort 1:67 dys; Cohort 2:48 dys; Cohort 3:55 dys; Cohort 4: 46 dys; Cohort 5:147 dys; C. Ster/No Ster Grp, Cohort 6:12 mos, 26 dys; Cohort 7:11 mos, 18 dys; Cohort 8:7 dys; Cohort 9:70 dys.

Study Arms (2)

1/Phase I Arm

EXPERIMENTAL

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of epidermal growth factor receptor (EGFRv)III Chimeric antigen receptor (CAR) transduced peripheral blood lymphocytes (PBL) + aldesleukin

Biological: Epidermal growth factor receptor(EGFRv)III Chimeric antigen receptor (CAR) transduced PBL; Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide

2/Phase II Arm

EXPERIMENTAL

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + maximum tolerated dose (MTD) of anti-EGFRvIII CAR transduced PBL established in Phase I + aldesleukin

Biological: Epidermal growth factor receptor(EGFRv)III Chimeric antigen receptor (CAR) transduced PBL; Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

Epidermal growth factor receptor(EGFRv)III Chimeric antigen receptor (CAR) transduced PBL BIOLOGICAL

Day 0: Cells will be infused intravenously over 20-30 minutes. Patients will receive two cell doses, 2 hours apart.

1/Phase I Arm; 2/Phase II Arm

Aldesleukin DRUG

Aldeskeukin 72,000 IU /kg intravenous (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).

Also known as: Proleukin

1/Phase I Arm; 2/Phase II Arm

Fludarabine DRUG

Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Also known as: Fludara

1/Phase I Arm; 2/Phase II Arm

Cyclophosphamide DRUG

Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr.

Also known as: Cytoxan

1/Phase I Arm; 2/Phase II Arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with histologically proven glioblastomas or gliosarcomas that express epidermal growth factor receptor(EGFRv)III as assessed by immunohistochemistry (IHC) or polymerase chain reaction (PCR) confirmed by the National Cancer Institute (NCI) Laboratory of Pathology.
• Patients must have progression of disease after radiotherapy (including patients that undergo surgery for recurrent disease and are rendered no evidence of disease (NED)). This includes recurrent glioblastoma (GBM) after receiving all standard first-line treatment, including surgery (if feasible due to neurosurgical and neuro-anatomical considerations) and adjuvant radiotherapy +/- chemotherapy.
• Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.
• Age greater than or equal to 18 years and less than or equal to age 70 years.
• Ability of subject to understand and the willingness to sign a written informed consent document.
• Willing to sign a durable power of attorney.
• Karnofsky Performance Status (KPS) greater than or equal to 60
• 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.
• Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
• Serology
• Seronegative for human immunodeficiency virus (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 Reverse transcription polymerase chain reaction (RT-PCR) and be Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) negative.
• Hematology
• White blood cell (WBC) greater than or equal to 3000/mm(3)
• Absolute neutrophil count (ANC) greater than or equal to 1000/mm(3) without the support of filgrastim

You may not qualify if:

• A prior history of gliadel implantation in the past six months..
• 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.
• Active systemic infections, requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• 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).
• History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
• History of coronary revascularization or ischemic symptoms.
• Other concomitant anti-cancer therapy except corticosteroids.
• Any patient known to have left ventricular ejection fraction (LVEF) less than or equal to 45%.
• Documented forced expiratory volume 1 (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
• Patients who are receiving any other investigational agents.
• Documented LVEF less than or equal to 45% tested in patients:
• Age greater than or equal to 65 years

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• 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. doi: 10.3171/jns.1958.15.5.0489. No abstract available.

  PMID: 13576192 BACKGROUND

• 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. doi: 10.1056/NEJMoa043330.

  PMID: 15758009 BACKGROUND

• Bloom HJ. Combined modality therapy for intracranial tumors. Cancer. 1975 Jan;35(1):111-20. doi: 10.1002/1097-0142(197501)35:13.0.co;2-#.

  PMID: 162849 BACKGROUND

• 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.

  PMID: 23545055 DERIVED

• 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.

  PMID: 22780919 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Glioma; Glioblastoma; Brain Neoplasms; Gliosarcoma

Interventions

Automobiles; aldesleukin; fludarabine; fludarabine phosphate; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Motor Vehicles; Transportation; Technology, Industry, and Agriculture; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Dr. Steven A. Rosenberg
• Organization: National Cancer Institute

sar@nci.nih.gov

240-858-3080

Study Officials

• Steven A Rosenberg, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 6, 2011
• First Posted: October 19, 2011
• Study Start: May 16, 2012
• Primary Completion: November 1, 2018
• Study Completion: January 17, 2019
• Last Updated: August 21, 2019
• Results First Posted: August 21, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)