Phase I Study of Intraventricular Infusion of T Cells Expressing B7-H3 Specific Chimeric Antigen Receptors (CAR) in Subjects With Recurrent or Refractory Glioblastoma
Summary
The purpose of this study is to test the safety of using T lymphocyte chimeric antigen receptor cells against the B7-H3 antigen (CAR.B7-H3T cells) in patients with glioblastoma. CAR.B7-H3T cells treatment has not been tested in humans and is not an approved treatment by the Food and Drug Administration for glioblastoma.
Detailed description
This is a phase 1, single center, open-label study aims to determine the safety of escalating doses of chimeric antigen receptor T cells (CAR-T) cells targeting the B7-H3 antigen administered via intraventricular infusion to adult subjects with relapsed or refractory glioblastoma (GBM). Subjects with GBM who meet procurement eligibility criteria will have cells collected following their initial surgical resection to manufacture CAR.B7-H3T cells, preferably prior to initiation of adjuvant chemoradiation. At the time that the subjects have confirmed refractory or recurrent GBM, CAR.B7-H3T cells will be manufactured for subjects who likely to be eligible for cell infusion. Eligible subjects will receive up to 3 weekly infusions of CAR.B7-H3 cells. To receive the additional cycles of CAR.B7-H3 cells, all treatment-related toxicities must have resolved to grade \< 3, the subject must not have experienced a dose limiting toxicity (DLT) and the subject must not have progressive disease that has been confirmed by magnetic resonance imaging per Immunotherapy response assessment in neuro-oncology criteria. The data from the dose escalation will be used to determine a recommended phase 2 dose (RP2D), which will be decided on based on the maximum tolerated dose (MTD) and additional factors such as the feasibility of administering infusions.
Arms & interventions
- DrugCAR.B7-H3T cells infusion
The Chimeric Antigen Receptors (CAR).B7-H3T cells will be administered via intraventricular infusion up to 3 weekly infusions. A suspension of T cells infusion is given, over 5-10 minutes, via a Rickham catheter and will be followed by a normal-saline flush. Dose escalation will be performed considering the dose limiting toxicities (DLTs) listed in the protocol. Six doses will be explored. The starting dose will be 2 × 10\^6 transduced cells/infusion (Dose Level (DL) 1) and will enroll at least 3 subjects. If there are no dose DLTs within 4 weeks of the third cellular product administration in the first 3 subjects, then the next cohort will evaluate 5 × 10\^6 transduced cells/infusion (DL2).
Outcome measures
Primary
Number of participants with adverse event
Number of participants with adverse event (AE)s as a measure of safety and tolerability of intraventricular administration CAR.B7-H3 T cells in subjects with progressive recurrent or refractory glioblastoma multiforme. AEs will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Dose Limiting Toxicities (DLTs) are defined as at least possibly related to CAR.B7-H3T cell product administration.
Time frame: Up to 10 weeks
Cytokine Release Syndrome
Cytokine Release Syndrome (CRS) will be graded according to American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading. Grade 1 - Mild (Symptomatic Management): Fever ≥38\^ o C, No hypotension, No hypoxia, Grade 2 - Moderate (Moderate Intervention): Fever ≥38\^ o C, Hypotension not requiring vasopressors, Hypoxia requiring low-flow nasal cannula (≤6 L/minute) or blow-by, Grade 3 - Severe (Aggressive Intervention): Fever ≥ 38\^ o C , Hypotension requiring a vasopressor with or without vasopressin, Hypoxia requiring high-flow nasal cannula (\>6 L/minute), facemask, nonrebreather mask, or Venturi mask, Grade 4 - Life-threatening (Life-sustaining intervention): Fever ≥38\^oC, Hypotension requiring multiple vasopressors (excluding vasopressin),Hypoxia requiring positive pressure (e.g. Continuous positive airway pressure, BiPAP, intubation, mechanical ventilation), Grade 5 - Death: Death.
Time frame: Up to 10 weeks
Neurotoxicity
Neurotoxicity will be graded according to the Central Nervous System (CNS) Toxicity criteria. Grade 0: Normal or no change from baseline exam at start of therapy, Grade 1: Mild lethargy and/or irritability or visual, motor, or sensory symptoms without change in neurological exam, Grade 2: Moderate lethargy, disorientation, or psychosis lasting \< 48 hours or mild increase in pre-existing neurological deficit, Grade 3: \>48hours of severe lethargy, but responsive to verbal stimuli or disorientation or psychosis lasting \>48 hours, Grade 4: Coma, unresponsive to verbal stimuli, increasing neurological deficit above grade 3, evidence of herniation, development of uncontrolled seizures, intracerebral hemorrhage.
Time frame: Up to 10 weeks
Secondary
Identification of Recommended phase 2 dose (RP2D)
Time frame: Up to 4 weeks
Objective Response Rate (ORR)
Time frame: Up to 4 weeks
Progression Free Survival (PFS)
Time frame: Up to 12 months
Overall Survival (OS)
Time frame: Up to 5 years
Duration of Response (DOR)
Time frame: Up to 12 months
Eligibility criteria
Study locations (1)
Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599