This phase 1, single-center, open-label study explores the safety of escalating doses of chimeric antigen receptor T cells (CAR-T) cells in subjects with relapsed/refractory triple-negative breast cancer (TNBC).
T lymphocyte chimeric antigen receptor cells against the B7-H3 antigen (iC9-CAR.B7-H3 T cells) treatment is experimental and has not been approved by the Food and Drug Administration. The safety of iC9-CAR.B7-H3 T cells will be investigated using a modified 3+3 design. The data from the dose escalation will be used to determine a recommended phase 2 dose (RP2D), which will be decided based on the maximum tolerated dose (MTD) and additional factors such as the ability to manufacture sufficient cells for infusion. Subjects with TNBC who meet procurement eligibility criteria will have cells collected to manufacture iC9-CAR.B7-H3 T cells. Eligible subjects will receive lymphodepletion with cyclophosphamide and fludarabine.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
42
iC9-CAR.B7-H3 T cells will then be administered intravenously
cyclophosphamide 300 mg/m2 IV will be given.
fludarabine 30 mg/m2 IV will be given.
University of North Carolina
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.
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 8 weeks after infusion of Biological/Vaccine
Toxicity: Immune effector cell-associated neurotoxicity syndrome (ICANS)
Neurotoxicity will be graded according to the Immune effector cell-associated neurotoxicity syndrome (ICANS) criteria. Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).
Time frame: Up to 4 weeks
The recommended phase 2 dose (RP2D) NCI-CTCAE v5.
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 criteria.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: Up to 4 weeks
The recommended phase 2 dose (RP2D) CRS Grading
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 byASTCT Consensus CRS Grading Criteria.
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 ASTCT Consensus ICANS Grading Criteria.
Time frame: Up to 4 weeks
Objective response rate
Objective response rate is defined as the percentage of subjects achieving a confirmed partial response (PR) or better (≥ PR) based on RECIST 1.1 criteria. Complete response - Disappearance of all target lesions. Any pathological lymph node (LN) must be \<10mm. Partial response: At least a 30% decrease in the sum of the largest distance (LD) of the target lesions. Progressive Disease (PD): At least a 20% increase in the sum of the LD of the target lesions taking as reference the smallest sum LD recorded since the treatment started including baseline if that is the smallest in the study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. The appearance of one or more new lesions also constitutes PD. Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD since the treatment started.
Time frame: Up to 2 years
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 RECIST 1.1 or death.
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
Duration of Response (DOR)
DOR is defined as the time from documentation of PR or better to progressive disease (PD) based on RECIST 1.1 and/or irRECIST. Per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) for target and/or non-target lesions and assessed by imaging: 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 target lesions and non-target lesions are irNN; Stable response (irSD), not meeting criteria for irCR, irPR, or irPD; Progressive Disease (irPD), ≥20% increase in tumor burden and minimum 5 mm absolute increase in compared to nadir; for no new non-target or (irNN) and where irPR or irPD are confirmed by a repeat, consecutive assessment no less than 4 weeks later.
Time frame: Up to 2 years