A Phase I Study of Autologous CAR-T Cells Targeting the B7-H3 Antigen and Containing the Inducible Caspase 9 Safety Switch in Subjects With Refractory Pancreatic Ductal Adenocarcinoma (PDAC)
Summary
The purpose of this gene therapy research study is to test the safety and tolerability of using a new treatment called autologous T lymphocyte chimeric antigen receptor cells against the B7-H3 antigen (iC9.CAR.B7-H3 T cells) in patients with pancreatic ductal adenocarcinoma that came back after receiving standard therapy for this cancer. The iC9.CAR.B7-H3 treatment is experimental and has not been approved by the Food and Drug Administration.
Detailed description
This is a phase 1, single-center, open-label study to determine the safety of escalating doses of chimeric antigen receptor T cells (CAR-T) cells targeting the B7-H3 antigen and containing the inducible caspase 9 safety switch (iC9-CAR.B7-H3 T cells) administered to adult subjects with refractory pancreatic ductal adenocarcinoma. The safety of iC9-CAR.B7-H3 T cells will be investigated using a modified 3+3 design with a starting dose of 1 × 106 transduced cells/kg. The data from the dose escalation will be used to determine a recommended phase 2 dose, which will be decided based on the maximum tolerated dose and additional factors such as the ability to manufacture sufficient cells for infusion. The body has different ways of fighting cancer and other diseases; however, no single way seems perfect. The experimental treatment in this study combines two different ways the body fights cancer, and they are antibodies and T cells. Antibodies are proteins that protect the body from foreign invaders like bacteria. Antibodies work by attaching to these bacteria or substances, which stops them from growing and causing bad effects. T cells are special infection-fighting blood cells that can kill viruses and other cells, including tumor cells. Antibodies and T cells have been used to treat patients with cancer. They both have shown promise, but neither alone has been able to cure most patients. The treatment that is being studied in this study is called autologous T lymphocyte chimeric antigen receptor cells targeted against the B7-H3 antigen and containing inducible caspase 9 safety switch (iC9). The short name for this treatment is iC9.CAR.B7-H3 T cells. For the rest of this consent, we will refer to the iC9.CAR.B7-H3 T cells as the modified CAR-T cells for ease of reading this consent.
Arms & interventions
- BiologicaliC9-CAR.B7-H3 T cell infusion
iC9-CAR.B7-H3 T cell product will be administered via intravenous injection over 5 - 10 minutes.
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 iC9-CAR.B7-H3 T cells in subjects with progressive recurrent or refractory pancreatic cancer. 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 iC9-CAR.B7-H3 T cell product administration.
Time frame: Up to 4 weeks
Cytokine Release Syndrome
Cytokine Release Syndrome (CRS) will be graded according to the 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 4 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 4 weeks
Secondary
Definition of Dose Limiting Toxicity
Time frame: Up to 4 weeks
Progression Free Survival (PFS)
Time frame: Up to 2 years
Overall Survival (OS)
Time frame: Up to 2 years
The disease control rate (DCR)
Time frame: Up to 2 years
B7-H3 expression
Time frame: Up to 18 months
The proportion of subjects who were able to receive CAR-T cell infusion
Time frame: Up to 18 months
Objective response rate (ORR)- bridging therapy
Time frame: Up to 2 years
Objective response rate- no bridging therapy
Time frame: Up to 2 years
Eligibility criteria
Study locations (1)
University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599