The purpose of this 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 ovarian cancer 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. The study team wants to know how much (dose) of the iC9-CAR.B7-H3 T cells are safe to use in patients without causing too many side effects and what is the maximum dose could be tolerated. There are two parts to this study. In part 1, approximately blood will be collected from subjects to prepare the iC9.CAR.B7-H3 T cells. The study team will collect disease-fighting T cells from the blood and modify them to prepare the iC9.CAR.B7-H3 T cells. In part 2, the iC9.CAR.B7-H3 T cells will be given to eligible subjects by infusion three days after completion of lymphodepletion chemotherapy.
This phase 1, single-center, open-label study to determine the safety of escalating dosing of chimeric antigen receptor T (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 relapsed or refractory platinum-resistant epithelial ovarian cancer. The safety of iC9-CAR.B7-H3 T cells administered intraperitoneally via a port/catheter will be investigated using a modified 3+3 design with a starting dose of 1 ×106. 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 ability to manufacture sufficient cells for infusion. Additional subjects will be enrolled in an expansion cohort at the recommended phase 2 dose. Subjects will receive standard-of-care therapy e.g., chemotherapy or radiation therapy to stabilize their disease if the treating physician feels it is in the subject's best interests before the cell therapy. Subjects with ≥ grade 4 Cytokine Release Syndrome (CRS) or Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) or grade 3 CRS or ICANS that do not improve to grade 0-1 within 72 hours will be given a 0.4mg/kg of rimiducid. Furthermore, subjects who experience a ≥ Grade 3 non-hematologic or hematologic toxicity (Excluding Grade 3 electrolyte abnormalities, hyperglycemia, diarrhea, or nausea and vomiting and Grade 3-4 hematologic toxicity without functional sequelae that do not persist at Grade 3-5 for \> 7 days) felt to be secondary to iC9-CAR.B7-H3 may be given rimiducid (0.4 mg/kg).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
iC9-CAR.B7-H3 T cells will then be administered intraperitoneally
cyclophosphamide 300 mg/m2 IV will be given.
fludarabine 30 mg/m2 IV will be given.
Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States
RECRUITINGToxicity: NCI-CTCAE
Toxicity will be graded as the Number of participants with adverse events (AE)s 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) is defined as at least possibly related to CAR.B7-H3T cell product administration.
Time frame: Up to 4 weeks
Toxicity: Cytokine Release Syndrome (CRS)
CRS will be graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading. Grade 1 - Mild: Fever ≥38\^ o C, No hypotension, No hypoxia, Grade 2 - Moderate: Fever ≥38\^ o C, Hypotension not requiring vasopressors, Hypoxia requiring low-flow nasal cannula (≤6 L/minute) or blow-by, Grade 3 - Severe: 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: 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
Time frame: Up to 4 weeks
Toxicity: Immune effector cell-associated neurotoxicity syndrome (ICANS)
Neurotoxicity will be graded according to the Immune effector cell-associated neurotoxicity syndrome (ICANS) criteria between Grades 1-5. immune Effector Cell-Associated Encephalopathy (ICE) Score is a neurological assessment score that quantifies the severity of neurologic impairment. Each item in the assessment is associated with the point value indicated. The higher ICE scores are the better = lower the ICAN grade. An ICE score of 10 indicates a normal neurological assessment while an ICE score of 0-2 ICE Score indicates a severe neurological impairment.
Time frame: Up to 4 weeks
The recommended phase 2 dose (RP2D)
The RP2D of iC9-CAR.B7-H3 T cells will be determined based on modified 3+3 dose finding rules and the tolerability of iC9-CAR.B7-H3 T cells will be assessed by NCI-CTCAE v5, ASTCT Consensus CRS Grading Criteria. ICANS will be graded according to the ASTCT Consensus ICANS Grading Criteria
Time frame: Up to 4 weeks
Progression Free Survival (PFS)
PFS will be measured from the first day of lymphodepletion chemotherapy prior to iC9-CAR.B7-H3 T cell infusion to progression per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1 or death. Radiographic response will be measured by RECIST 1.1 indicating if the subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Up to 2 years
Overall Survival (OS)
OS will be measured from the first day of lymphodepleting chemotherapy prior to iC9-CAR.B7-H3 T cell infusion to the date of death for any cause.
Time frame: Up to 2 years
The disease control rate (DCR)
DCR will be defined based on response evaluation criteria in solid tumors (RECIST1.1) and immune response evaluation criteria in solid tumors ( irRECIST) or death. RECIST1.1: Complete Response, the disappearance of all target lesions; Partial Response, \>=30% decrease in the sum of the longest diameter; Stable Disease, no response or less response than Partial or Progressive; or Progressive Disease, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. irRECIST: Complete Response ( irCR) disappearance of all lesions, no new lesions, lymph nodes \< 10 mm in short axis; Partial Response (irPR), ≥30% decrease in the sum of lesions; Stable response, not meeting criteria for irCR, irPR, or Progressive Disease (irPD); Progressive Disease(irPD), ≥20% increase in tumor burden and minimum 5 mm absolute increase in compared to nadir.
Time frame: Up to 6 months
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