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NCT01454596

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

Completed Phase 1, PHASE2 Results posted Last updated 21 August 2019
What this trial tests

Phase 1, PHASE2 trial testing Epidermal growth factor receptor(EGFRv)III Chimeric antigen receptor (CAR) transduced PBL in Malignant Glioma in 18 participants. Completed in 17 January 2019.

Timeline
16 May 2012
Primary endpoint
1 November 2018
17 January 2019

Quick facts

Lead sponsorNational Cancer Institute (NCI)
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designsequential
Maskingnone
Primary purposetreatment
Enrollment18
Start date16 May 2012
Primary completion1 November 2018
Estimated completion17 January 2019
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

National Cancer Institute (NCI)

Who can join

Adults 18 to 70, any sex, with Malignant Glioma or Glioblastoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Treatment Related Adverse Events Primary · From 4 weeks after cell infusion up to 77 days

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.

GroupValue95% CI
Group A (Steroids) - Cohort 1: 1x10(7)0
Group A (Steroids) - Cohort 2: 3x10(7)0
Group A (Steroids) - Cohort 3: 1x10(8)0
Group B (No Steroids) - Cohort 1: 1x10(7)0
Group B (No Steroids) - Cohort 2: 3x10(7)0
Group B (No Steroids) - Cohort 3: 1x10(8)0
Group B (No Steroids) - Cohort 4: 3x10(8)0
Group B (No Steroids) - Cohort 5: 1x10(9)0
Combined Steroids/no Steroids) - Cohort 6: 3x10(9)0
Combined Steroids/no Steroids) - Cohort 7: 1x10(10)0
Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10)1
Combined Steroids/no Steroids) - Cohort 9: 3x10(10)1
Progression Free Survival Primary · Time from the date of registration to the date of first observation of progressive disease up to 6 months after end of treatment

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).

GroupValue95% CI
Group A (Steroids) - Cohort 1: 1x10(7)1.1
Group A (Steroids) - Cohort 2: 3x10(7)1.1
Group A (Steroids) - Cohort 3: 1x10(8)1.3
Group B (No Steroids) - Cohort 1: 1x10(7)1.9
Group B (No Steroids) - Cohort 2: 3x10(7)2.0
Group B (No Steroids) - Cohort 3: 1x10(8)1.5
Group B (No Steroids) - Cohort 4: 3x10(8)1.2
Group B (No Steroids) - Cohort 5: 1x10(9)1.10.9 – 1.3
Combined Steroids/no Steroids) - Cohort 6: 3x10(9)2.70.9 – 12.5
Combined Steroids/no Steroids) - Cohort 7: 1x10(10)1.11.1 – 1.6
Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10)0
Combined Steroids/no Steroids) - Cohort 9: 3x10(10)2.0
Number of Patients With an Objective Response Secondary · 4 weeks after cell infusion and monthly as feasible up to 12 months

Objective response was assessed by comparison with baseline dynamic contrast enhanced magnetic resonance imaging with perfusion using Neuro-oncology Working Group proposed guidelines. Complete Response is disappearance of all measurable and non-measurable disease for at least 4 weeks. Partial Response is \>/= 50% decrease in lesions for at least 4 weeks. Stable Disease does not meet the criteria for complete response, partial response or progression and requires stable lesions compared with baseline. Progression is \>/= 25% increase in lesions.

GroupValue95% CI
Group A (Steroids) - Cohort 1: 1x10(7)0
Group A (Steroids) - Cohort 2: 3x10(7)0
Group A (Steroids) - Cohort 3: 1x10(8)0
Group B (No Steroids) - Cohort 1: 1x10(7)0
Group B (No Steroids) - Cohort 2: 3x10(7)0
Group B (No Steroids) - Cohort 3: 1x10(8)0
Group B (No Steroids) - Cohort 4: 3x10(8)0
Group B (No Steroids) - Cohort 5: 1x10(9)0
Combined Steroids/no Steroids) - Cohort 6: 3x10(9)0
Combined Steroids/no Steroids) - Cohort 7: 1x10(10)0
Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10)0
Combined Steroids/no Steroids) - Cohort 9: 3x10(10)0
Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment Secondary · 1 month post transplant

CAR and vector presence were quantitated in peripheral blood mononuclear cell (PBMC) samples using established polymerase chain reaction (PCR) techniques

GroupValue95% CI
Group A (Steroids) - Cohort 1: 1x10(7)2323 – 23
Group A (Steroids) - Cohort 2: 3x10(7)7070 – 70
Group A (Steroids) - Cohort 3: 1x10(8)3636 – 36
Group B (No Steroids) - Cohort 1: 1x10(7)6767 – 67
Group B (No Steroids) - Cohort 2: 3x10(7)77 – 7
Group B (No Steroids) - Cohort 3: 1x10(8)4343 – 43
Group B (No Steroids) - Cohort 4: 3x10(8)2828 – 28
Group B (No Steroids) - Cohort 5: 1x10(9)2510 – 219
Combined Steroids/no Steroids) - Cohort 6: 3x10(9)1212 – 12
Combined Steroids/no Steroids) - Cohort 7: 1x10(10)67.526 – 109
Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10)NANA – NA
Combined Steroids/no Steroids) - Cohort 9: 3x10(10)88 – 8
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) Secondary · 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.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one o

GroupValue95% CI
Group A (Steroids) - Cohort 1: 1x10(7)1
Group A (Steroids) - Cohort 2: 3x10(7)1
Group A (Steroids) - Cohort 3: 1x10(8)1
Group B (No Steroids) - Cohort 1: 1x10(7)1
Group B (No Steroids) - Cohort 2: 3x10(7)1
Group B (No Steroids) - Cohort 3: 1x10(8)1
Group B (No Steroids) - Cohort 4: 3x10(8)1
Group B (No Steroids) - Cohort 5: 1x10(9)3
Combined Steroids/no Steroids) - Cohort 6: 3x10(9)3
Combined Steroids/no Steroids) - Cohort 7: 1x10(10)3
Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10)1
Combined Steroids/no Steroids) - Cohort 9: 3x10(10)1

Adverse events — posted to ClinicalTrials.gov

Time frame: Date treatment consent signed to date off study, approximately 51 days for Group A, Cohort 1; Cohort 2: 68 days; Cohort 3: 40 days; Group B, Cohort 1: 67 days; Cohort 2: 48 days; Cohort 3: 55 days; Cohort 4: 46 days; Cohort 5: 147 days; and Combined Steroids/No Steroids Group, Cohort 6: 12 months and 26 days; Cohort 7: 11 months and 18 days; Cohort 8: 7 days; Cohort 9: 70 days.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Group A (Steroids) - Cohort 1: 1x10(7)
Serious: 0/1 (0%)
Deaths: 0/1
Group A (Steroids) - Cohort 2: 3x10(7)
Serious: 0/1 (0%)
Deaths: 0/1
Group A (Steroids) - Cohort 3: 1x10(8)
Serious: 0/1 (0%)
Deaths: 0/1
Group B (No Steroids) - Cohort 1: 1x10(7)
Serious: 0/1 (0%)
Deaths: 0/1
Group B (No Steroids) - Cohort 2: 3x10(7)
Serious: 0/1 (0%)
Deaths: 0/1
Group B (No Steroids) - Cohort 3: 1x10(8)
Serious: 0/1 (0%)
Deaths: 0/1
Group B (No Steroids) - Cohort 4: 3x10(8)
Serious: 0/1 (0%)
Deaths: 0/1
Group B (No Steroids) - Cohort 5: 1x10(9)
Serious: 0/3 (0%)
Deaths: 0/3
Combined Steroids/no Steroids) - Cohort 6: 3x10(9)
Serious: 0/3 (0%)
Deaths: 0/3
Combined Steroids/no Steroids) - Cohort 7: 1x10(10)
Serious: 0/3 (0%)
Deaths: 0/3
Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10)
Serious: 1/1 (100%)
Deaths: 1/1
Combined Steroids/no Steroids) - Cohort 9: 3x10(10)
Serious: 1/1 (100%)
Deaths: 0/1

Serious adverse events (3 terms)

ReactionSystemGroup A (Steroids) - Cohor…Group A (Steroids) - Cohor…Group A (Steroids) - Cohor…Group B (No Steroids) - Co…Group B (No Steroids) - Co…Group B (No Steroids) - Co…Group B (No Steroids) - Co…Group B (No Steroids) - Co…Combined Steroids/no Stero…Combined Steroids/no Stero…Combined Steroids/no Stero…Combined Steroids/no Stero…
Death not associated with CTCAE term: Multi-organ failureGeneral disorders
Dyspnea (shortness of breath)Respiratory, thoracic and mediastinal disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
Other adverse events (27 terms — click to expand)

ReactionSystemGroup A (Steroids) - Cohor…Group A (Steroids) - Cohor…Group A (Steroids) - Cohor…Group B (No Steroids) - Co…Group B (No Steroids) - Co…Group B (No Steroids) - Co…Group B (No Steroids) - Co…Group B (No Steroids) - Co…Combined Steroids/no Stero…Combined Steroids/no Stero…Combined Steroids/no Stero…Combined Steroids/no Stero…
PlateletsInvestigations
Leukocytes (total WBC)Investigations
LymphopeniaInvestigations
Neutrophils/granulocytes (ANC/AGC)Investigations
HemoglobinInvestigations
InfectionInfections and infestations
Thrombosis/thrombus/embolismVascular disorders
PTT (Partial Thromboplastin Time)Investigations
Potassium, serum-high (hyperkalemia)Metabolism and nutrition disorders
Potassium, serum-low (hypokalemia)Metabolism and nutrition disorders
ConfusionPsychiatric disorders
Fatigue (asthenia, lethargy, malaise)General disorders
Phosphate, serum-low (hypophosphatemia)Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)Investigations
AST, SGOT(serum glutamic oxaloacetic transaminase)Investigations
CreatinineInvestigations
DiarrheaGastrointestinal disorders
DizzinessNervous system disorders
Pain::Head/headacheNervous system disorders
Acute vascular leak syndromeVascular disorders
Neuropathy: motorNervous system disorders
Incontinence, urinaryRenal and urinary disorders
Pulmonary/Upper Respiratory - Other (pulmonary edema)Respiratory, thoracic and mediastinal disorders
Supraventricular and nodal arrhythmia::Atrial fibrillationCardiac disorders
Febrile NeutropeniaBlood and lymphatic system disorders
HypotensionVascular disorders
Sodium, serum-low (hyponatremia)Metabolism and nutrition disorders

Most-reported serious reactions: Death not associated with CTCAE term: Multi-organ failure, Dyspnea (shortness of breath), Hypoxia.

Data from ClinicalTrials.gov NCT01454596 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. The basic principles of chimeric antigen receptor design.
    Sadelain M, Brentjens R, Rivière I. · · 2013 · cited 1144× · PMID 23550147 · DOI 10.1158/2159-8290.cd-12-0548
  2. Engineered T cells: the promise and challenges of cancer immunotherapy.
    Fesnak AD, June CH, Levine BL. · · 2016 · cited 812× · PMID 27550819 · DOI 10.1038/nrc.2016.97
  3. CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment.
    Martinez M, Moon EK. · · 2019 · cited 653× · PMID 30804938 · DOI 10.3389/fimmu.2019.00128
  4. Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma.
    Brown CE, Badie B, Barish ME, Weng L, et al · · 2015 · cited 624× · PMID 26059190 · DOI 10.1158/1078-0432.ccr-15-0428
  5. Driving CAR T-cells forward.
    Jackson HJ, Rafiq S, Brentjens RJ. · · 2016 · cited 457× · PMID 27000958 · DOI 10.1038/nrclinonc.2016.36
  6. T cell receptor (TCR) signaling in health and disease.
    Shah K, Al-Haidari A, Sun J, Kazi JU. · · 2021 · cited 414× · PMID 34897277 · DOI 10.1038/s41392-021-00823-w
  7. CAR T cells in solid tumors: challenges and opportunities.
    Marofi F, Motavalli R, Safonov VA, Thangavelu L, et al · · 2021 · cited 394× · PMID 33494834 · DOI 10.1186/s13287-020-02128-1
  8. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma.
    Johnson LA, Scholler J, Ohkuri T, Kosaka A, et al · · 2015 · cited 356× · PMID 25696001 · DOI 10.1126/scitranslmed.aaa4963

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