Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02664363 |
| Other study ID # |
Pro00069444 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2017 |
| Est. completion date |
September 12, 2019 |
Study information
| Verified date |
February 2023 |
| Source |
Duke University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Please note that enrollment on this study terminated early due to the end of grant funding.
Newly diagnosed WHO grade IV malignant glioma subjects who are eligible were enrolled
following surgery to remove their brain tumor. They then underwent 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 was completed, subjects returned
for the post-RT brain imaging assessment, and, if stable, started post-RT TMZ cycles.
Patients received up to 3 cycles of dose-intensified TMZ prior to receiving the EGFRvIII CAR
T cells, which was infused in dose escalation cohorts. Following a one-month delay between
cycles, the subject resumed post-RT cycles of TMZ and were monitored with blood work and
brain imaging as per SOC.
An expanded cohort of 12 subjects was originally planned for once the maximally tolerated
dose (MTD) was reached in the dose escalation cohorts, in order 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) was planned on days 1, 2, and 3
post-infusion to determine intracerebral (IC) localization.
Description:
Please note that enrollment on this study terminated early due to the end of grant funding.
Following consent, subjects were enrolled onto dose-escalation cohorts. Patients will
underwent 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 were
isolated from the patient's PBMCs and transduced to express the CAR. Briefly, PBMCs were
stimulated with Muromonab-cluster of differentiation 3 (CD3) (OKT3), an anti-CD3 monoclonal
antibody (mAb), and transduced on RetroNectin® coated plates. Transduced cells were expanded
in interleukin-2 (IL-2) for 14 days.
Patients then completed standard of care RT and concurrent TMZ. Patients who remained
eligible after standard of care radiation and TMZ received 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 did not meet release criteria, the patient was 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 were
delivered intravenously. If sufficient CAR-specific T cells could not be generated to meet
the targeted assigned dose within the dose-escalation portion of the study, the patient was
have been treated at a lower pre-defined dose level using available CAR-specific T cells and
replaced in the assigned higher dose. The administered dose would have been 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 could not be generated to meet the MTD
dose, all available T cells would be administered.
Following the infusion of EGFRvIII CARs, blood samples for immune monitoring were 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 coincided with SOC clinic visits. Blood was also taken for Replication Competent
Retrovirus (RCR) Polymerase Chain Reaction (PCR) per the Food and Drug Administration (FDA)
at 3, 6, and 12 months during SOC clinic visits. Lastly, blood for evaluation of cytokine
release syndrome (CRS) was 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 included 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 returned to clinic one month following the EGFRvIII CAR T cell infusion to be
evaluated for cycles of SOC 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
resulted in a >30 day delay between the last cycle of DI TMZ and the first cycle of 5-day
TMZ.
Tumor progression was documented histologically, unless there were 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 was obtained through Duke Brain Tumor Center Biorepository, it was
used to confirm tumor progression histologically, and to assess immunologic cell infiltration
and EGFRvIII antigen escape at the tumor site. Patients would be eligible for additional
adjuvant therapy at the time of tumor progression.
A classical "3+3" study design was planned to estimate the MTD for CAR-specific T cells
treatment among patients with newly-diagnosed GBM. Four dose levels were to 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 would be accrued at each dose level. If a
patient was lost to follow-up during the first 4 weeks after CAR treatment without
experiencing a dose-limiting toxicity (DLT), then the patient was not considered evaluable
for the determination of DLT and would be replaced. The MTD was considered to be the highest
dose level at which ≤1 of 6 patients experienced DLT during the 4-week observation period
after CAR treatment. Only 3-patient cohort was enrolled at the the first dose level due to
grant funding ending.
An expanded cohort of 12 patients was planned at the MTD of EGFRvIII CAR T cells, in order to
obtain a more precise estimate of the probability of unacceptable toxicity. This cohort would
have the cells radiolabeled with 111In to track their distribution. Briefly, CARs would have
been counted and re-suspended in phosphate buffered saline (PBS). 4-6x10^8 cells would be
labeled with a total of 500 microCi of 111In. The cells would be washed and mixed with cold
CARs to achieve the desired cell dose. The labeled CARs would be infused into the patient
through an intravenous catheter within the Ambulatory Bone Marrow Transplant (BMT) Unit.
Distribution of 111In-labeled EGFRvIII CARs would be evaluated at 1, 2, and 3 days
post-infusion using scintigraphy. There was no enrollment on the expanded cohort due to grant
funding ending.
