Recurrent GlioblastomaPhase 1INTERCEPTNCT03283631
Intracerebral EGFR-vIII CAR-T Cells for Recurrent GBM
A Phase 1 study testing EGFRvIII-CARs in people with Recurrent Glioblastoma and Recurrent Gliosarcoma, run by Gary Archer Ph.D. at 1 site in United States.
Trial summary
The goal of this protocol is to transfer autologous peripheral blood mononuclear cells (PBMCs) transduced with genes encoding a chimeric antigen receptor (CAR) that recognizes epidermal growth factor receptor variant III (EGFRvIII) tumor-specific antigen into patients with recurrent glioblastoma (GBM) following… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Recurrent Glioblastoma, Recurrent Gliosarcoma
- What is being tested?
- EGFRvIII-CARs
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteUnited States
- Study dates
- 30 May 2018to 30 Jun 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Disease progression or recurrence of a supratentorial World Health Organization (WHO) grade IV malignant glioma (GBM or gliosarcoma) based on imaging studies with measurable disease. At the time of biopsy, prior to stereotactic radiosurgery (SRS) and administration of the EGFRvIII-CARS, the presence of recurrent tumor must be confirmed by histopathological analysis.
- Adults ≥ 18 years old.
- Karnofsky Performance Status (KPS) score ≥ 70.
- EGFRvIII, the target antigen, must be identified on tumor tissue by immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR), i.e. EGFRvIII positive via pathology report.
- Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,000 cells/µl, platelets ≥ 125,000 cells/µl (prior to biopsy).
- Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT), and bilirubin ≤ 1.5 times upper limit of normal (prior to biopsy).
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- Signed informed consent approved by the Institutional Review Board.
- Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as < 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, [i.e. with a failure rate of < 1% per year] are implants, injectables, combined oral contraceptives, intra-uterine device [IUD; only hormonal], sexual abstinence or vasectomized partner) during the trial and for a period of > 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy test within 48 hours prior to starting SRS.
- Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control [i.e. with a failure rate of < 1% per year] include a female partner using implants, injectables, combined oral contraceptives, IUDs [only hormonal], sexual abstinence or prior vasectomy) during the trial and for a period of > 6 months following the last administration of trial drugs.
- Meet eligibility requirements for SRS: able to get MRI; the patient must have a lesion that, in the opinion of the study radiation oncologist, can safely receive SRS to the entire tumor; must not be abutting optic apparatus or brainstem and catheter tip will be at least 5mm away from the ventricle; and must be able to be secured and positioned in a stereotactic U-frame mask.
Who cannot join
- Pregnant or breast-feeding.
- Patients with known potentially anaphylactic allergic reactions to gadolinium-DTPA.
- Patients who cannot undergo MRI with contrast or SPECT/CT.
- Patients with evidence of tumor in the brainstem, cerebellum, optic apparatus, or spinal cord, radiological evidence of actively growing multifocal disease, or leptomeningeal disease.
- Patients < 12 weeks from the end of radiation therapy, unless they have two progressive scans at least 4 weeks apart, have progression outside of the radiation field, or have histologic confirmation of progression.
- Severe, active comorbidity, including any of the following:
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- Unstable angina and/or congestive heart failure requiring hospitalization;
- Transmural myocardial infarction within the last 6 months;
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study initiation;
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy;
- Known hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
- Known autoimmune disorder, such as HIV;
- Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy;
- Active connective tissue disorders, such as lupus or scleroderma that, in the opinion of the treating physician, may put the patient at high risk for radiation toxicity.
- Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids.
- Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin;
- Current, recent (within 4 weeks of the administration of this study agent), or planned participation in another experimental therapeutic drug study.
- Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except for nitrosourea (6 weeks) or metronomic dosed chemotherapy such as daily etoposide or cyclophosphamide (1 week)] prior to biopsy unless patients have recovered from side effects of such therapy.
- Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax > 99.5 F, 37.5 C).
- Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to CAR T Cell infusion.
- Prior therapy targeted to EGFRvIII.
- Prior history of brain SRS, (patients who have received external beam radiation per standard of care are allowed).
Trial locations and contacts
1 site in 1 country.
United States1 site
Duke University Medical Center
Durham, North Carolina, 27710
About this study
Official title: INTERCEPT: INTracerebral EGFR-vIII Chimeric Antigen Receptor Gene-Modified T CElls for PaTients With Recurrent GBM
The goal of this protocol is to transfer autologous peripheral blood mononuclear cells (PBMCs) transduced with genes encoding a chimeric antigen receptor (CAR) that recognizes epidermal growth factor receptor variant III (EGFRvIII) tumor-specific antigen into patients with recurrent glioblastoma (GBM) following stereotactic radiosurgery (SRS). The CAR used is targeted to a tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, which is expressed on a subset of patients. Normal PBMCs derived from patients with GBM are genetically engineered with a viral vector encoding the CAR and infused directly into the patient's tumor with the aim of mediating regression of their tumors. Despite our CAR being targeted to a tumor specific antigen, given the prior toxicity using CARs that were not targeted to tumor-specific antigens, the investigators elected to begin with very low doses of cells. Enrollment on this study was suspended in April 2020 while an amendment to reduce the anticipated number of participants was under review and approved. The decision to terminate the study was made in January, 2021 to shift toward the next iteration of a related CAR T cell trial.
Read the detailed description
Patients with evidence of radiographic recurrence who expressed EGFRvIII on their original tumor diagnosis had autologous PBMCs harvested by leukapheresis. These autologous PBMCs were transduced with a retrovirus containing the sequences for the EGFRvIII CAR and sent to the Duke Radiopharmacy for radiolabeling with 111Indium (111In). Within 2-3 weeks of leukapheresis, on Day -4 to -2, patients had a BrainLab MRI to prepare for biopsy and catheter placement. On Day -1, the patient underwent standard of care (SOC) stereotactic biopsy under local anesthesia to confirm tumor recurrence. At the time of biopsy, prior to catheter insertion and administration of study drug, the presence of recurrent tumor was confirmed by histopathology. If tumor recurrence was confirmed, a catheter was placed intratumorally for delivery of EGFRvIII-CARs by Convection Enhanced Delivery (CED).
SRS will took place on Day 0 (+1 day) and 111In-labeled EGFRvIII-CARs were infused on the same day over a 6 to 6.5 hour period immediately after SRS.
On days 1 and 2 after 111In-labeled EGFRvIII-CAR infusion, whole planar imaging followed by Single-Photon Emission Computed Tomography (SPECT) Computed Tomography (CT) imaging assessed the intracerebral and systemic localization of the 111In-labeled EGFRvIII-CARs that described the distribution of EGFRvIII-CARs within the brain and systemically.
This protocol was designed to determine the maximum tolerated dose (MTD) of a novel, tumor-specific treatment with autologous EGFRvIII-CARs. The proposed starting dose was 2.5 x 10^8 of 111In-labeled cells in 3 milliliters (mL). The infusion flow rate was fixed at 0.5 mL/hr.
Enrollment on this study was suspended in April 2020 while an amendment to reduce the anticipated number of participants was under review and approved. Upon approval of this amendment, the enrollment suspension remained due to a change in access to necessary equipment for CAR manufacturing. The decision to terminate the study was made in January, 2021 to shift toward the next iteration of a related CAR T cell trial. The knowledge gained from this study experience is directing our next CAR T-cell platform and will be used to secure additional funding.
- Conditions
- Recurrent Glioblastoma, Recurrent Gliosarcoma
- Being tested
- EGFRvIII-CARs
- Keywords
- Malignant Glioma, INTERCEPT, Pro00083828, Adult, Chimeric Antigen Receptor, CAR T cell, EGFRvIII
- Medical subject headings
- Glioblastoma, Gliosarcoma, Glioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EGFRvIII-CARsBiological
Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells
| Study group | Role | What they receive |
|---|---|---|
| EGFRvIII-CARs | Experimental | Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells Receives: Biological: EGFRvIII-CARs |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of Maximum Tolerated Dose (MTD)
MTD of EGFRvIII-CAR gene-modified T cells when administered intracerebrally by CED after SRS in patients with recurrent GBM
Measured: 4 weeks
Secondary outcomes (4)
Assessment of T Cell trafficking within the brain tumor
Change in volume of distribution and maximal percentage of enhanced tumor volume covered
Measured: 2 days
Assessment of T cell trafficking systemically
Change in the volume of distribution of 111In-labeled EGFRvIII-CARs present in each body area (neck, chest, abdomen, pelvis, and extremities)
Measured: 2 days
Median survival
The time between SRS / CAR treatment and death or last follow-up
Measured: 1 year
Median progression-free survival
The time between SRS / CAR treatment and first failure (death or disease progression)
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Sep 2017
- Study start30 May 2018
- Primary completion19 Sep 2019
- Study completion30 Jun 2020
Why it stopped: We are halting enrollment of this study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Recurrent GlioblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gary Archer Ph.D.
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI), Duke Cancer Institute
- Responsible party
- Sponsor-investigator, Gary Archer Ph.D., Duke University
- Investigators
- Daniel Landi, MD, Principal investigator, Duke UniversityDavid Ashley, MBBS, FRACP, PhD, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03283631
- Sponsor's protocol ID
- Pro00083828
- Other IDs
- 5P50CA190991-03
- Acronym
- INTERCEPT
- Status last verified
- Apr 2021
- First submitted
- 13 Sep 2017
- Last updated
- 5 Apr 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- INTERCEPT: INTracerebral EGFR-vIII Chimeric Antigen Receptor Gene-Modified T CElls for PaTients With Recurrent GBM
- ClinicalTrials.gov ID
- NCT03283631
- Acronym / sponsor ID
- INTERCEPT / Pro00083828
- Conditions
- Recurrent Glioblastoma, Recurrent Gliosarcoma
- Keywords
- Malignant Glioma, INTERCEPT, Pro00083828, Adult, Chimeric Antigen Receptor, CAR T cell, EGFRvIII
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: We are halting enrollment of this study.
- Enrolment
- 2 participants (actual)
- Lead sponsor
- Gary Archer Ph.D.University, hospital or other
- Collaborators
- National Cancer Institute (NCI), Duke Cancer Institute
- Study start
- 30 May 2018 (actual)
- Primary completion
- 19 Sep 2019 (actual)
- Study completion
- 30 Jun 2020 (actual)
- First posted
- 14 Sep 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this protocol is to transfer autologous peripheral blood mononuclear cells (PBMCs) transduced with genes encoding a chimeric antigen receptor (CAR) that recognizes epidermal growth factor receptor variant III (EGFRvIII) tumor-specific antigen into patients with recurrent glioblastoma (GBM) following stereotactic radiosurgery (SRS). The CAR used is targeted to a tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, which is expressed on a subset of patients. Normal PBMCs derived from patients with GBM are genetically engineered with a viral vector encoding the CAR and infused directly into the patient's tumor with the aim of mediating regression of their tumors. Despite our CAR being targeted to a tumor specific antigen, given the prior toxicity using CARs that were not targeted to tumor-specific antigens, the investigators elected to begin with very low doses of cells. Enrollment on this study was suspended in April 2020 while an amendment to reduce the anticipated number of participants was under review and approved. The decision to terminate the study was made in January, 2021 to shift toward the next iteration of a related CAR T cell trial.
Detailed description
Patients with evidence of radiographic recurrence who expressed EGFRvIII on their original tumor diagnosis had autologous PBMCs harvested by leukapheresis. These autologous PBMCs were transduced with a retrovirus containing the sequences for the EGFRvIII CAR and sent to the Duke Radiopharmacy for radiolabeling with 111Indium (111In). Within 2-3 weeks of leukapheresis, on Day -4 to -2, patients had a BrainLab MRI to prepare for biopsy and catheter placement. On Day -1, the patient underwent standard of care (SOC) stereotactic biopsy under local anesthesia to confirm tumor recurrence. At the time of biopsy, prior to catheter insertion and administration of study drug, the presence of recurrent tumor was confirmed by histopathology. If tumor recurrence was confirmed, a catheter was placed intratumorally for delivery of EGFRvIII-CARs by Convection Enhanced Delivery (CED).
SRS will took place on Day 0 (+1 day) and 111In-labeled EGFRvIII-CARs were infused on the same day over a 6 to 6.5 hour period immediately after SRS.
On days 1 and 2 after 111In-labeled EGFRvIII-CAR infusion, whole planar imaging followed by Single-Photon Emission Computed Tomography (SPECT) Computed Tomography (CT) imaging assessed the intracerebral and systemic localization of the 111In-labeled EGFRvIII-CARs that described the distribution of EGFRvIII-CARs within the brain and systemically.
This protocol was designed to determine the maximum tolerated dose (MTD) of a novel, tumor-specific treatment with autologous EGFRvIII-CARs. The proposed starting dose was 2.5 x 10^8 of 111In-labeled cells in 3 milliliters (mL). The infusion flow rate was fixed at 0.5 mL/hr.
Enrollment on this study was suspended in April 2020 while an amendment to reduce the anticipated number of participants was under review and approved. Upon approval of this amendment, the enrollment suspension remained due to a change in access to necessary equipment for CAR manufacturing. The decision to terminate the study was made in January, 2021 to shift toward the next iteration of a related CAR T cell trial. The knowledge gained from this study experience is directing our next CAR T-cell platform and will be used to secure additional funding.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| EGFRvIII-CARs | Experimental | Biological: EGFRvIII-CARsGamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Disease progression or recurrence of a supratentorial World Health Organization (WHO) grade IV malignant glioma (GBM or gliosarcoma) based on imaging studies with measurable disease. At the time of biopsy, prior to stereotactic radiosurgery (SRS) and administration of the EGFRvIII-CARS, the presence of recurrent tumor must be confirmed by histopathological analysis.
- Adults ≥ 18 years old.
- Karnofsky Performance Status (KPS) score ≥ 70.
- EGFRvIII, the target antigen, must be identified on tumor tissue by immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR), i.e. EGFRvIII positive via pathology report.
- Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,000 cells/µl, platelets ≥ 125,000 cells/µl (prior to biopsy).
Key exclusion criteria (22 listed)
- Pregnant or breast-feeding.
- Patients with known potentially anaphylactic allergic reactions to gadolinium-DTPA.
- Patients who cannot undergo MRI with contrast or SPECT/CT.
- Patients with evidence of tumor in the brainstem, cerebellum, optic apparatus, or spinal cord, radiological evidence of actively growing multifocal disease, or leptomeningeal disease.
- Patients < 12 weeks from the end of radiation therapy, unless they have two progressive scans at least 4 weeks apart, have progression outside of the radiation field, or have histologic confirmation of progression.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EGFRvIII-CARsGamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells | Biological | EGFRvIII-CARs |
Primary outcome
Determination of Maximum Tolerated Dose (MTD)
Time frame: 4 weeks
MTD of EGFRvIII-CAR gene-modified T cells when administered intracerebrally by CED after SRS in patients with recurrent GBM
4 secondary outcomes
Assessment of T Cell trafficking within the brain tumor
Time frame: 2 days
Assessment of T cell trafficking systemically
Time frame: 2 days
Median survival
Time frame: 1 year
Median progression-free survival
Time frame: 1 year
Results and safety
The study was stopped early (reason given: We are halting enrollment of this study.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2021.
- The Preston Robert Tisch Brain Tumor CenterLink provided by the sponsor.
- Duke Cancer InstituteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Daniel Landi, MD principal investigator
Duke University
David Ashley, MBBS, FRACP, PhD principal investigator
Duke University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing EGFRvIII-CARs in people with Recurrent Glioblastoma and Recurrent Gliosarcoma, run by Gary Archer Ph.D. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 5 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: We are halting enrollment of this study.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of Maximum Tolerated Dose (MTD) (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2021.