EGFRvIII CAR T Cells for Newly-Diagnosed WHO Grade IV Malignant Glioma
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Brain Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 2/1/2019 |
| Start Date: | February 1, 2017 |
| End Date: | September 25, 2019 |
EGFRvIII Chimeric Antigen Receptor (CAR) Gene-modified T Cells for Patients With Newly-Diagnosed GBM During Lymphopenia
Newly diagnosed WHO grade IV malignant glioma subjects who are eligible will be enrolled
following surgery to remove the brain tumor. They will then undergo a leukapheresis to
harvest cells for the generation of the study drug, Epidermal Growth Factor variant III
Chimeric Antigen Receptor (EGFRvIII CAR) T cells prior to beginning standard of care (SOC)
radiation therapy (RT) with temozolomide (TMZ). Once SOC RT with TMZ is completed, subjects
will return for the post-RT brain imaging assessment, and if stable will start post-RT TMZ
cycles. Patients will receive up to 3 cycles of dose intensified TMZ prior to receiving the
EGFRvIII CAR T cells, which will be infused in dose escalation cohorts. Following a one month
delay between cycles, the subject will resume post-RT cycles of TMZ and be monitored with
blood work and brain imaging as per SOC. Once the maximally tolerated dose (MTD) is reached
in the dose escalation cohorts, an expanded cohort of 12 subjects will be enrolled to obtain
a more precise estimate of the probability of unacceptable toxicity and to track the EGFRvIII
CAR T cells using 111 Indium (111In) labeling. Computed Tomography (CT) will be done on days
1, 2, and 3 post-infusion to determine intracerebral (IC) localization.
following surgery to remove the brain tumor. They will then undergo a leukapheresis to
harvest cells for the generation of the study drug, Epidermal Growth Factor variant III
Chimeric Antigen Receptor (EGFRvIII CAR) T cells prior to beginning standard of care (SOC)
radiation therapy (RT) with temozolomide (TMZ). Once SOC RT with TMZ is completed, subjects
will return for the post-RT brain imaging assessment, and if stable will start post-RT TMZ
cycles. Patients will receive up to 3 cycles of dose intensified TMZ prior to receiving the
EGFRvIII CAR T cells, which will be infused in dose escalation cohorts. Following a one month
delay between cycles, the subject will resume post-RT cycles of TMZ and be monitored with
blood work and brain imaging as per SOC. Once the maximally tolerated dose (MTD) is reached
in the dose escalation cohorts, an expanded cohort of 12 subjects will be enrolled to obtain
a more precise estimate of the probability of unacceptable toxicity and to track the EGFRvIII
CAR T cells using 111 Indium (111In) labeling. Computed Tomography (CT) will be done on days
1, 2, and 3 post-infusion to determine intracerebral (IC) localization.
Following consent, subjects will be enrolled onto dose-escalation cohorts. Patients will
undergo leukapheresis to harvest Peripheral Blood Mononuclear Cells (PBMCs) for the
generation of EGFRvIII CAR T cells prior to beginning RT and concurrent TMZ. T cells will be
isolated from the patient's PBMCs and transduced to express the CRA. Briefly, PBMC will be
stimulated with Muromonab-cluster of differentiation 3 (CD3) (OKT3), an anti-CD3 monoclonal
antibody (mAb) and transduced on RetroNectin® coated plates. Transduced cells will be
expanded in interleukin-2 (IL-2) for 14 days.
Patients will then complete standard of care RT and concurrent TMZ. Patients who remain
eligible after standard of care radiation and TMZ will receive up to 3 cycles of TMZ at
50-100 mg/m^2/day for 21 days of 28 day cycles, which is the standard dose-intensified (DI)
TMZ regimen. If the CAR-specific T cells do not meet release criteria, the patient will be
withdrawn before CAR treatment and replaced.
At least 48 hours after the last dose of DI TMZ, the total dose of EGFRvIII CAR T cells will
be delivered intravenously. If sufficient CAR-specific T cells cannot be generated to meet
the targeted assigned dose within the dose-escalation portion of the study, the patient will
be treated at a lower pre-defined dose level using available CAR-specific T cells and
replaced in the assigned higher dose. The administered dose will be the highest defined dose
level for which there are sufficient CAR-specific T cells available. Within the expanded
cohort, if sufficient CAR-specific T cells can't be generated to meet the MTD dose, all
available T cells will be administered.
Following the infusion of EGFRvIII CARs, blood samples for immune monitoring will be drawn 1,
5, and 10 days after the infusion, then 1, 3, and 6 months, then yearly until progression (or
death or lost to contact). The return visits for immune monitoring at 3 months, 6 months, and
yearly will coincide with standard of care clinic visits. Blood will also be taken for
Replication Competent Retrovirus (RCR) Polymerase Chain Reaction (PCR) per the Food and Drug
Administration (FDA) at 3, 6 and 12 months during standard of care clinic visits. Lastly,
blood for evaluation of cytokine release syndrome (CRS) will be drawn prior to cell infusion,
1 and 4 hours after infusion, and on days 1, 2, 5, 10, and at one month. Measurements for CRS
include IL-2, IL-6, Tumor Necrosis Factor alpha (TNFα), interferon (IFN) gamma,
Granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein (CRP).
Patients will return to clinic one month following the EGFRvIII CAR T cell infusion to be
evaluated for cycles of standard of care 5-day TMZ at 150-200 mg/m^2/day for the first 5-day
cycle, followed by 200 mg/m^2/day for 5-days every 28 days per the treating oncologist. This
will result in a >30 day delay between the last cycle of DI TMZ and the first cycle of 5-day
TMZ.
Tumor progression will be documented histologically, unless there are clinical
contraindications, to exclude inflammatory responses presenting as radiographic or clinical
changes, which could indicate a potentially toxic or therapeutic responses and not tumor
progression. If tissue is obtained through Tissue Bank Consent Institutional Review Board
(IRB) # 2635, it will be used to confirm tumor progression histologically, and to assess
immunologic cell infiltration and EGFRvIII antigen escape at the tumor site. Patients will be
eligible for additional adjuvant therapy at the time of tumor progression.
A classical "3+3" study design will be used to estimate the MTD for CAR-specific T cells
treatment among patients with newly-diagnosed GBM. Four dose levels will be considered: #1:
4.5 x 10^6/kg, #2: 1.5 x 10^7/kg, #3: 4.5 x 10^7/kg, and #4: 1.5 x 10^8/kg. Starting with the
lowest dose level, cohorts of 3-6 subjects will be accrued at each dose level. If a patient
is lost to follow-up during the first 4 weeks after CAR treatment without experiencing a
dose-limiting toxicity (DLT), then the patient will not be evaluable for the determination of
DLT and will be replaced. The MTD is the highest dose level at which ≤1 of 6 patients
experiences DLT during the 4 week observation period after CAR treatment.
An expanded cohort of 12 patients will be enrolled at the MTD of EGFRvIII CAR T cells in
order to obtain a more precise estimate of the probability of unacceptable toxicity. This
cohort will also have the cells radiolabeled with 111In to track their distribution. Briefly,
CARs will be counted and re-suspended in phosphate buffered saline (PBS). 4-6x10^8 cells will
be labeled with a total of 500 microCi of 111In. The cells will be washed and mixed with cold
CARs to achieve the desired cell dose. The labeled CARs will be infused into the patient
through an intravenous catheter within the Ambulatory Bone Marrow Transplant (BMT) Unit.
Distribution of 111In-labeled EGFRvIII CARs will be evaluated at 1, 2, and 3 days
post-infusion using scintigraphy.
undergo leukapheresis to harvest Peripheral Blood Mononuclear Cells (PBMCs) for the
generation of EGFRvIII CAR T cells prior to beginning RT and concurrent TMZ. T cells will be
isolated from the patient's PBMCs and transduced to express the CRA. Briefly, PBMC will be
stimulated with Muromonab-cluster of differentiation 3 (CD3) (OKT3), an anti-CD3 monoclonal
antibody (mAb) and transduced on RetroNectin® coated plates. Transduced cells will be
expanded in interleukin-2 (IL-2) for 14 days.
Patients will then complete standard of care RT and concurrent TMZ. Patients who remain
eligible after standard of care radiation and TMZ will receive up to 3 cycles of TMZ at
50-100 mg/m^2/day for 21 days of 28 day cycles, which is the standard dose-intensified (DI)
TMZ regimen. If the CAR-specific T cells do not meet release criteria, the patient will be
withdrawn before CAR treatment and replaced.
At least 48 hours after the last dose of DI TMZ, the total dose of EGFRvIII CAR T cells will
be delivered intravenously. If sufficient CAR-specific T cells cannot be generated to meet
the targeted assigned dose within the dose-escalation portion of the study, the patient will
be treated at a lower pre-defined dose level using available CAR-specific T cells and
replaced in the assigned higher dose. The administered dose will be the highest defined dose
level for which there are sufficient CAR-specific T cells available. Within the expanded
cohort, if sufficient CAR-specific T cells can't be generated to meet the MTD dose, all
available T cells will be administered.
Following the infusion of EGFRvIII CARs, blood samples for immune monitoring will be drawn 1,
5, and 10 days after the infusion, then 1, 3, and 6 months, then yearly until progression (or
death or lost to contact). The return visits for immune monitoring at 3 months, 6 months, and
yearly will coincide with standard of care clinic visits. Blood will also be taken for
Replication Competent Retrovirus (RCR) Polymerase Chain Reaction (PCR) per the Food and Drug
Administration (FDA) at 3, 6 and 12 months during standard of care clinic visits. Lastly,
blood for evaluation of cytokine release syndrome (CRS) will be drawn prior to cell infusion,
1 and 4 hours after infusion, and on days 1, 2, 5, 10, and at one month. Measurements for CRS
include IL-2, IL-6, Tumor Necrosis Factor alpha (TNFα), interferon (IFN) gamma,
Granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein (CRP).
Patients will return to clinic one month following the EGFRvIII CAR T cell infusion to be
evaluated for cycles of standard of care 5-day TMZ at 150-200 mg/m^2/day for the first 5-day
cycle, followed by 200 mg/m^2/day for 5-days every 28 days per the treating oncologist. This
will result in a >30 day delay between the last cycle of DI TMZ and the first cycle of 5-day
TMZ.
Tumor progression will be documented histologically, unless there are clinical
contraindications, to exclude inflammatory responses presenting as radiographic or clinical
changes, which could indicate a potentially toxic or therapeutic responses and not tumor
progression. If tissue is obtained through Tissue Bank Consent Institutional Review Board
(IRB) # 2635, it will be used to confirm tumor progression histologically, and to assess
immunologic cell infiltration and EGFRvIII antigen escape at the tumor site. Patients will be
eligible for additional adjuvant therapy at the time of tumor progression.
A classical "3+3" study design will be used to estimate the MTD for CAR-specific T cells
treatment among patients with newly-diagnosed GBM. Four dose levels will be considered: #1:
4.5 x 10^6/kg, #2: 1.5 x 10^7/kg, #3: 4.5 x 10^7/kg, and #4: 1.5 x 10^8/kg. Starting with the
lowest dose level, cohorts of 3-6 subjects will be accrued at each dose level. If a patient
is lost to follow-up during the first 4 weeks after CAR treatment without experiencing a
dose-limiting toxicity (DLT), then the patient will not be evaluable for the determination of
DLT and will be replaced. The MTD is the highest dose level at which ≤1 of 6 patients
experiences DLT during the 4 week observation period after CAR treatment.
An expanded cohort of 12 patients will be enrolled at the MTD of EGFRvIII CAR T cells in
order to obtain a more precise estimate of the probability of unacceptable toxicity. This
cohort will also have the cells radiolabeled with 111In to track their distribution. Briefly,
CARs will be counted and re-suspended in phosphate buffered saline (PBS). 4-6x10^8 cells will
be labeled with a total of 500 microCi of 111In. The cells will be washed and mixed with cold
CARs to achieve the desired cell dose. The labeled CARs will be infused into the patient
through an intravenous catheter within the Ambulatory Bone Marrow Transplant (BMT) Unit.
Distribution of 111In-labeled EGFRvIII CARs will be evaluated at 1, 2, and 3 days
post-infusion using scintigraphy.
Inclusion Criteria:
1. Age 18-80 years of age
2. Histopathologically proven newly-diagnosed, supratentorial malignant primary brain
tumor (World Health Organization (WHO) Grade IV GBM).
3. Karnofsky Performance Status (KPS) score ≥ 70.
4. The presence of the target antigen, EGFRvIII, must be identified on tumor tissue by
immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR).
5. Hematology:
- Absolute Neutrophil Count (ANC) ≥ 1000/mm^3 without the support of filgrastim
- Platelet count ≥ 100,000/mm^3
- Hemoglobin ≥ 8.0 g/dl (eligibility level for hemoglobin may be reached with
transfusion).
6. Chemistry:
- Alanine Amino Transferase (ALT)/Aspartate Amino Transferase (AST) ≤ 2.5 times the
upper limit of normal
- Creatinine ≤ 1.6 mg/dl
- Total bilirubin ≤ 1.5 mg/dl.
Exclusion Criteria:
1. Patients who are pregnant, breast-feeding, or unwilling to practice an effective
method of birth control.
2. Patients with known potentially anaphylactic allergic reactions to
Gadolinium-Diethylene Triamine Pentaacetic Acid (gd-DTPA).
3. Patients who cannot undergo Magnetic Resonance Imaging (MRI) or Single Photon
Emission-Computed Tomography (SPECT) due to obesity or to having certain metal in
their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal
prostheses, joints, rods, or plates).
4. Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord, or with
evidence of leptomeningeal disease.
5. Active infection requiring treatment or an unexplained febrile (> 101.5 F) illness.
6. Known autoimmune disease, immunosuppressive disease or human immunodeficiency virus
(HIV) infection (i.e., known HIV or Hepatitis C).
7. Patients with unstable or severe intercurrent medical conditions such as severe heart
or lung disease.
8. Patients with previous history of radiosurgery, brachytherapy, gliadel implantation,
or radiolabeled monoclonal antibodies.
9. Prior antitumor therapy for glioma (other than steroids).
10. Allergic to TMZ.
We found this trial at
1
site
Durham, North Carolina 27710
Phone: 919-684-5301
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