Breast Cancer, Relapse, Resistant Cancer, Triple Negative Breast Cancer
Conditions
Keywords
cellular therapy, biologic therapy
Brief summary
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).
Detailed description
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.
Interventions
BIOLOGICALiC9-CAR.B7-H3 T Cell Therapy
iC9-CAR.B7-H3 T cells will then be administered intravenously
DRUGcyclophosphamide
cyclophosphamide 300 mg/m2 IV will be given.
DRUGfludarabine
fludarabine 30 mg/m2 IV will be given.
Sponsors
UNC Lineberger Comprehensive Cancer Center
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Unless otherwise noted, subjects must meet all of the following criteria to participate in in all phases of the study: 1. Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information explained to, understood by and signed by the subject or legally authorized representative. 2. Age ≥ 18 years at the time of consent. 3. Karnofsky score of \> 60% (see APPENDIX VI- Karnofsky Scale)) 4. Histologically confirmed TNBC (ER-, PR-, HER2-negative) 1. ER- and PR-negative: defined as \< 1% staining by immunohistochemistry (IHC) 2. HER2-negative: defined as IHC 0-1+ or fluorescence in situ hybridization (FISH) ratio \< 2.0
Exclusion criteria
1. Patients with a history of symptomatic CNS involvement or multiple metastases requiring whole-brain radiation. 2. Subjects with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. 3. Subject does not have a measurable and or evaluable disease as defined by RECIST 1.1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity: NCI-CTCAE | Up to 4 weeks | 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. |
| Toxicity: Cytokine Release Syndrome (CRS) | Up to 8 weeks after infusion of Biological/Vaccine | 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 |
| Toxicity: Immune effector cell-associated neurotoxicity syndrome (ICANS) | Up to 4 weeks | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The recommended phase 2 dose (RP2D) NCI-CTCAE v5. | Up to 4 weeks | 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. |
| The recommended phase 2 dose (RP2D) CRS Grading | Up to 4 weeks | 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. |
| The recommended phase 2 dose (RP2D) | Up to 4 weeks | 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. |
| Objective response rate | Up to 2 years | 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. |
| Progression Free Survival (PFS) | Up to 2 years | 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. |
| Overall Survival (OS) | Up to 2 years | 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. |
| Duration of Response (DOR) | Up to 2 years | DOR is time from the first immune Complete Response (iCR) or immune Partial Response (iPR) until progressive disease (iCPD) per immune Response Evaluation Criteria in Solid Tumors (iRECIST), criteria or death, whichever occurs first. Per iRECIST) responses are assessed by imaging as follows: iCR: Disappearance of all lesions, with pathological lymph nodes \<10 mm. iPR: ≥30% decrease in target lesions from baseline. Immune Stable Disease (iSD): Neither sufficient shrinkage for iPR nor sufficient increase. Immune Unconfirmed Progressive Disease (iUPD): Initial evidence of progression based on RECIST 1.1, including growth of existing lesions and/or new lesions; requires confirmation. Immune Confirmed Progressive Disease (iCPD): Progression confirmed at a subsequent assessment following iUPD per iRECIST. New lesions are recorded separately and do not automatically constitute treatment failure. Progression must be confirmed after iUPD to establish iCPD. |
Countries
United States
Contacts
CONTACTCaroline Babinec
CONTACTCatherine Cheng
PRINCIPAL_INVESTIGATORYara Abdou, MD
UNC Lineberger Comprehensive Cancer Center
Outcome results
None listed