Chimeric Antigen Receptor (CAR) T-cell Therapy with iC9-CAR.B7-H3 T-cells for the Treatment of Refractory Pancreatic Ductal Adenocarcinoma
This phase I trial studies the safety, side effects, and best dose of autologous T lymphocyte chimeric antigen receptor (CAR) cells targeted against the B7-H3 antigen and containing inducible caspase 9 safety switch (iC9-CAR.B7-H3 T-cells) for the treatment of pancreatic ductal adenocarcinoma (PDAC) that does not respond to treatment (refractory). PDAC tumor cells carry a substance on their surface called B7-H3. Normal (healthy) cells very rarely carry the B7-H3 substance on their surface. CAR T-cell therapy is a type of treatment in which a patient's own T-cells are taken from their blood and genetically modified to create a special receptor so they can recognize and attack pancreatic tumor cells. This special receptor is called the anti-B7-H3 antibody. This antibody attaches to tumor cells that carry the B7-H3 substance on their surface. Once the anti-B7-H3 antibody attaches to the cancerous cells, it is hoped that the modified T-cells will attack and destroy them. Because modified CAR T-cells are different from normal T-cells, it is possible that a person's own immune system may attack and destroy them, so they may not stay very long in the body. To prevent this from happening, lymphodepletion therapy with cyclophosphamide and fludarabine is used before receiving iC9-CAR.B7-H3 T-cells. Chemotherapy drugs, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lymphodepletion is a type of chemotherapy that been shown to increase the amount of time that the modified CAR T-cells survive in the body and have been associated with improved cancer-free survival. The iC9-CAR.B7-H3 T-cells also have an extra component called the iC9 switch. The body may react when the modified CAR-T-cells are given, and patients may experience unpleasant side effects such as fever and pain. Sometimes these side effects do not go away with normal treatments. If these side effects do occur and there is no other way to adequately treat them, it is possible to shut down the modified CAR-T-cells and stop their activity inside the patient's body. If that is needed, the iC9 switch is activated by giving an investigational drug called rimiducid. Once the modified CAR-T-cells are turned off, they will no longer have any effect in fighting cancerous cells in the body. Giving iC9-CAR.B7-H3 T-cells following lymphodepleting chemotherapy with cyclophosphamide and fludarabine may be safe, tolerable, and/or effective for the treatment of refractory PDAC.
Inclusion Criteria
- PRIOR TO PROCUREMENT: 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
- PRIOR TO PROCUREMENT: Age ≥ 18 years at the time of consent
- PRIOR TO PROCUREMENT: Eastern Cooperative Oncology Group (ECOG) of 0-1
- PRIOR TO PROCUREMENT: Histological or cytological evidence/confirmation of pancreatic ductal adenocarcinoma
- PRIOR TO PROCUREMENT: Subject must have a life expectancy of ≥ 12 weeks
- PRIOR TO PROCUREMENT: Subject has received at least one prior line of chemotherapy for metastatic pancreatic cancer. There is no limit on the number of prior treatment regimens
- PRIOR TO PROCUREMENT: Subject should not have active infection with HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) (can be pending at the time of cell procurement; only subjects meeting the criteria as so described will have cells manufactured). (Note: To meet eligibility subjects are required to be negative for HIV antibody, negative for Hepatitis B surface antigen, and negative for HCV antibody or HCV viral load.)
- PRIOR TO PROCUREMENT: Subjects currently using systemic corticosteroids at doses ≥ 10 mg prednisone daily or its equivalent will be excluded; those receiving < 10 mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed. Physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10 mg prednisone per day
- PRIOR TO PROCUREMENT: Female subjects of childbearing potential must have a negative serum pregnancy test within 72 hours prior to cell procurement. * Note: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided
- PRIOR TO PROCUREMENT: Female subjects of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 6 months after study treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label
- PRIOR TO PROCUREMENT: Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the cell infusion therapy
- PRIOR TO PROCUREMENT: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- PRIOR TO PROCUREMENT: Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee
- PRIOR TO PROCUREMENT: Subject is willing to undergo a biopsy prior to treatment, after CAR-T cell infusion and at the time of progression and the tumor is determined to be safe by the treating investigator for biopsy collection, the procedure would not be required to be performed in the operating room, and there is sufficient tissue available
- PRIOR TO PROCUREMENT: Subject has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- PRIOR TO PROCUREMENT: Left ventricular ejection fraction (LVEF) ≥ 40% as measured by echocardiography within 3 months * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO PROCUREMENT: Absolute Neutrophil Count (ANC) ≥ 1.0 × 10^9/L (obtained within 7 days of cell procurement) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO PROCUREMENT: Platelets ≥ 100 × 10^9/L (obtained within 7 days of cell procurement) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO PROCUREMENT: Creatinine clearance > 30 mL/min per Cockcroft and Gault (obtained within 7 days of cell procurement) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO PROCUREMENT: Bilirubin ≤ 1.5 × upper limit of normal (ULN) (obtained within 7 days of cell procurement) * Subjects with Gilbert’s syndrome may be enrolled despite a total bilirubin level > 1.5 mg/dL if their conjugated bilirubin is < 1.5 × ULN * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO PROCUREMENT: Aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if liver metastases present) (obtained within 7 days of cell procurement) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO PROCUREMENT: Alanine aminotransferase (ALT) ≤ 3 × ULN (≤ 5 × ULN if liver metastases present) (obtained within 7 days of cell procurement) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO PROCUREMENT: Pulse oximetry ≥ 90 % on room air (obtained within 7 days of cell procurement) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO LYMPHODEPLETION: No major surgery within 28 days to lymphodepletion
- PRIOR TO LYMPHODEPLETION: Subject has not received any investigational agents or any tumor vaccines within 3 weeks prior to lymphodepletion
- PRIOR TO LYMPHODEPLETION: Subject has not received chemotherapy or radiation therapy within the previous 3 weeks or 5 half-lives prior to lymphodepletion
- PRIOR TO LYMPHODEPLETION: Subject is not receiving a prohibited medication at the time of starting lymphodepletion up through 72 hours after the last dose of cyclophosphamide
- PRIOR TO LYMPHODEPLETION: Subjects currently using systemic corticosteroids at doses ≥ 10 mg prednisone daily or its equivalent will be excluded; those receiving < 10 mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed. Physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10 mg prednisone per day
- PRIOR TO LYMPHODEPLETION: Subject will have imaging results from within 10 days prior to lymphodepletion to confirm the presence of measurable disease per RECIST 1.1. Imaging must occur at least 3 weeks or 5 half-lives after most recent therapy, including any bridging therapy (used as baseline and to document measurable disease)
- PRIOR TO LYMPHODEPLETION: Subject must have available iC9-CAR.B7-H3 T cells that meet the Certificate of Analysis acceptance criteria
- PRIOR TO LYMPHODEPLETION: Hemoglobin (Hgb) ≥ 9 g/dL at least 1 week following last transfusion (obtained within 72 hours prior to lymphodepletion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO LYMPHODEPLETION: Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L (obtained within 72 hours prior to lymphodepletion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO LYMPHODEPLETION: Platelets ≥ 100 × 10^9/L (obtained within 72 hours prior to lymphodepletion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO LYMPHODEPLETION: Creatinine clearance > 30 mL/min per Cockcroft and Gault (obtained within 72 hours prior to lymphodepletion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO LYMPHODEPLETION: Bilirubin ≤ 1.5 × ULN (obtained within 72 hours prior to lymphodepletion) * Subjects with Gilbert’s syndrome may be enrolled despite a total bilirubin level > 1.5 mg/dL if their conjugated bilirubin is < 1.5 × ULN * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO LYMPHODEPLETION: Aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if liver metastases present) (obtained within 72 hours prior to lymphodepletion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO LYMPHODEPLETION: Alanine aminotransferase (ALT) ≤ 3 × ULN (≤ 5 × ULN if liver metastases present) (obtained within 72 hours prior to lymphodepletion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO LYMPHODEPLETION: Subject must have a negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for female participants of childbearing potential. * Note: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
- PRIOR TO LYMPHODEPLETION: Subject does not have rapidly progressive disease, per treating oncologist’s discretion
- PRIOR TO LYMPHODEPLETION: Subject is a good candidate for iC9-CAR.B7-H3 T cell therapy, per treating oncologist’s discretion
- PRIOR TO iC9-CAR-B7-H3 T CELL INFUSION: Subject has no evidence of uncontrolled infection or sepsis
- PRIOR TO iC9-CAR-B7-H3 T CELL INFUSION: Subject must have a negative serum pregnancy test within 7 days of cell infusion (does not need to be repeated if pre-lymphodepletion pregnancy test is within this window)
- PRIOR TO iC9-CAR-B7-H3 T CELL INFUSION: Creatinine clearance ≤ 2.5 × ULN (obtained within 24 hours prior to infusion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO iC9-CAR-B7-H3 T CELL INFUSION: Bilirubin ≤ 2 × ULN, unless attributed to Gilbert’s Syndrome (obtained within 24 hours prior to infusion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO iC9-CAR-B7-H3 T CELL INFUSION: Aspartate aminotransferase (AST) ≤ 5 × ULN (≤ 7 × ULN if liver metastases present) (obtained within 24 hours prior to infusion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO iC9-CAR-B7-H3 T CELL INFUSION: Alanine aminotransferase (ALT) ≤ 5 × ULN (≤ 7 × ULN if liver metastases present) (obtained within 24 hours prior to infusion) * Note: Hematology and other lab parameters that are ≥ grade 2, but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for change in severity after cell infusion and/or worsen from baseline during therapy
- PRIOR TO iC9-CAR-B7-H3 T CELL INFUSION: Subject is a good candidate for treatment with iC9-CAR.B7-H3 T cells per the clinical investigator’s discretion
Additional locations may be listed on ClinicalTrials.gov for NCT06158139.
Locations matching your search criteria
United States
North Carolina
Chapel Hill
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of administration of autologous anti-B7-H3 CAR-iC9-expressing T-lymphocytes (iC9-CAR.B7-H3 T cells) in subjects with refractory PDAC.
SECONDARY OBJECTIVES:
I. To identify a recommended phase 2 dose (RP2D) for administration of iC9-CAR.B7-H3 T cells in adult subjects with refractory PDAC.
II. To estimate progression free survival (PFS) in adult subjects with refractory PDAC following lymphodepletion and infusion of iC9-CAR.B7-H3 T cells.
III. To determine overall survival (OS) in adult subjects with refractory PDAC following lymphodepletion and infusion of iC9-CAR.B7-H3 T cells.
IV. To determine the disease control rate (DCR) mediated by iC9-CAR.B7-H3 T cell administered in adult subjects with refractory PDAC.
V. To measure B7H3 expression in tumors before and after iC9-CAR.B7-H3 T cell administration.
VI. To evaluate the feasibility of treatment with iC9-CAR.B7-H3 T cells in subjects with refractory PDAC.
VII. To determine the objective response rate (ORR) following lymphodepletion and infusion of iC9.B7-H3 CAR-T cells in subjects with pancreatic ductal adenocarcinoma (PDAC) who receive bridging therapy.
VIII. To determine the objective response rate (ORR) following lymphodepletion and infusion of iC9.B7-H3 CAR-T cells in subjects with PDAC who did not receive bridging therapy.
EXPLORATORY OBJECTIVES:
I. To evaluate the persistence, expansion, and function of iC9-CAR.B7-H3 T cells.
II. To measure and compare cytokines and immunophenotypes in the peripheral blood after iC9-CAR.B7-H3 T cell administration.
III. To evaluate genomic changes in circulating free tumor deoxyribonucleic acid (DNA) before and after iC9-CAR.B7-H3 T cell administration.
IV. To evaluate genomic, gene expression and immunological changes in tumor cells and in associated tumor microenvironment before and after iC9-CAR.B7-H3 T cell administration.
V. To determine the utility of the safety switch in iC9-CAR.B7-H3 T cells by allowing for administration of rimiducid (0.4 mg/kg dose) to subjects with ≥ grade 4 cytokine release syndrome (CRS) or immune effector cell associated neurotoxicity syndrome (ICANS), grade 3 CRS or ICANS that does not improve to grade 0-1 within 72 hours, or experiencing 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).
VI. To determine the safety and tolerability of rimiducid administration to activate the safety switch in iC9-CAR.B7-H3 T cells.
VII. To determine whether there are correlations between CAR T cell behavior and the integration location of CAR.B7-H3.
OUTLINE: This is a dose-escalation study of iC9-CAR.B7- H3 T cells followed by a dose-expansion study.
Patients undergo blood sample collection and/or leukapheresis for T cell procurement. Patients may undergo standard of care (SOC) bridging therapy to stabilize their disease per the discretion of the treating physician on study. Patients receive cyclophosphamide intravenously (IV) and fludarabine IV daily for 3 consecutive days in the absence of disease progression or unacceptable toxicity. Then, 2-14 days after lymphodepletion chemotherapy, patients receive iC9-CAR.B7- H3 T cells IV over 5-10 minutes on week 0, day 1. Patients experiencing toxicity related to T cell infusion may receive rimiducid IV over 2 hours. Additionally, patients undergo echocardiography (ECHO) during screening, as well as blood sample collection, core tumor biopsy, computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET) throughout the trial. Patients receiving rimiducid also undergo lumbar puncture (LP) with cerebral spinal fluid (CSF) collection on study.
Upon completion of study treatment, patients are followed up at weeks 1, 2, 3, 4, and 6, at months 3, 6, 9, and 12, every 6 months for the next 4 years and then once a year for the next 10 years, for a total of 15 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUNC Lineberger Comprehensive Cancer Center
Principal InvestigatorAshwin Somasundaram
- Primary IDLCCC2223-ATL
- Secondary IDsNCI-2024-03897
- ClinicalTrials.gov IDNCT06158139