Chimeric Antigen Receptor (CAR) T-cell Therapy with iC9-CAR.B7-H3 T cells for the Treatment of Patients with Recurrent Platinum Resistant or Refractory Epithelial Ovarian Cancer

Inclusion Criteria

• 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
• Age ≥ 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) of 0-2
• Subject must have histologically or cytologically confirmed epithelial ovarian, peritoneal, or fallopian tube cancer and must have a histological diagnosis of a high-grade serous histology based on local histopathological findings. Subjects with presence of ascites will be eligible
• Subject must have recurrent platinum-resistant or platinum-refractory disease defined as: * Disease that has progressed by imagining while receiving platinum OR * Disease that has recurred within 6 months of the last receipt of platinum-based chemotherapy. Rising CA-125 only is not considered as platinum-resistant or refractory disease * Having received at least 2 prior regimens (including front line therapy) * Having failed prior therapy with a PARP inhibitor if the subject has a germline or somatic BRCA mutation
• Subjects must be able to have an intraperitoneal port placed either by vascular interventional radiology or surgically in the operating room. (Note: The intraperitoneal port will not be placed until the subject is determined to be otherwise eligible for iC9-CAR.B7-H3 T cell infusion and until the subject is determined to be otherwise eligible to receive lymphodepletion). If a subject is deemed unlikely to be a candidate for successful intraperitoneal catheter placement by radiographic assessment, they will be excluded from the study
• Subject must have no intraparenchymal lung metastases (Note: Pleural effusions are not exclusionary and that subjects with intraparenchymal liver disease and subjects with retroperitoneal disease are allowed on the study)
• Subject must have no bone metastases
• Subject must not be using systemic corticosteroids at doses ≥ 10 mg prednisone daily or its equivalent; 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
• 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.
• 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.
• Subject does not have a history of gastrointestinal perforation
• Subject does not have a history of symptomatic diverticular disease, confirmed by CT or colonoscopy
• Subject is not dependent on intravenous hydration or total parenteral nutrition
• Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee
• Subject is willing to undergo a biopsy prior to treatment, after infusion and at the time of disease progression (if not at their first scan), and the tumor is determined to be safe by the treating investigator for biopsy collection
• PRITOR TO PROCUREMENT: Written informed consent to undergo cell procurement explained to, understood by and signed by the subject; subject given a copy of informed consent form for cell procurement
• PRIOR TO PROCUREMENT: Subject must have life expectancy of ≥ 12 weeks
• PRIOR TO PROCUREMENT: Imaging results must be from within 90 days prior to procurement to assess presence of evaluable disease as defined as: * Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 OR * Non-measurable disease (defined as solid and/or cystic abnormalities on radiographic imagining that do not meet RECIST 1.1 definitions for target lesions) OR * Ascites and/or pleural effusion that has been pathologically demonstrated to be disease-related in the setting of a CA-125 > 2 × upper limit of normal (ULN)
• PRIOR TO PROCUREMENT: Subject must have no known brain metastasis. A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to being screened for procurement, have been off corticosteroids for ≥ 2 weeks, and are asymptomatic
• PRIOR TO PROCUREMENT: Subject must have no active infection with HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) (tests can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells). Note: To meet eligibility subjects are required to be negative for HIV antibody, negative for hepatitis B surface antigen, negative for HCV antibody or HCV viral load
• 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: Subject must not be lactating (Note: Breast milk cannot be stored for future use while the mother is being treated on study)
• PRIOR TO PROCUREMENT: Left ventricular ejection fraction (LVEF) ≥ 40%, as measured by echocardiography (ECHO), with no additional evidence of decompensated heart failure
• PRIOR TO PROCUREMENT: Subject has no current signs and/or symptoms of bowel obstruction or signs and/or symptoms of a bowel obstruction within 3 months prior to cell procurement
• PRIOR TO PROCUREMENT: Subject does not have a history of intra-abdominal abscess within 3 months of cell procurement
• PRIOR TO PROCUREMENT: Creatinine ≤ 2 × (ULN) (obtained within 7 days of cell procurement)
• PRIOR TO PROCUREMENT: Bilirubin ≤ 1.5 × ULN (obtained within 7 days of cell procurement) * Subjects with Gilbert’s syndrome may be enrolled despite a total bilirubin level > 1.5 milligrams/deciliter (mg/dL) if their conjugated bilirubin is <1.5 × ULN
• PRIOR TO PROCUREMENT: Aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if liver metastases present) (obtained within 7 days of cell procurement)
• PRIOR TO PROCUREMENT: Alanine aminotransferase (ALT) ≤ 3 × ULN (≤ 5 × ULN if liver metastases present) (obtained within 7 days of cell procurement)
• PRIOR TO PROCUREMENT: Pulse oximetry ≥ 90 % on room air (obtained within 7 days of cell procurement)
• PRIOR TO LYMPHODEPLETION: Written informed consent to undergo therapy with iC9-CAR.B7-H3 T cells explained to, understood by and signed by the subject; subject given a copy of informed consent form
• PRIOR TO LYMPHODEPLETION: Subject has an intraperitoneal catheter/port in place. (Note: The intraperitoneal port will not be placed until the subject is determined to be otherwise eligible to receive lymphodepletion prior to iC9-CAR.B7-H3 T cell infusion.)
• 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 prior to lymphodepletion
• PRIOR TO LYMPHODEPLETION: Subject must have not received bevacizumab within the previous 6 weeks prior to lymphodepletion
• PRIOR TO LYMPHODEPLETION: Subject must have not received hormonal therapy (tamoxifen, letrozole, etc.) within the previous 3 weeks 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: Imaging results must be 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 after most recent therapy, including any bridging therapy (used as baseline and to document measurable disease). Subjects must have evaluable disease as defined as: * Measurable disease per RECIST 1.1 OR * Non-measurable disease (defined as solid and/or cystic abnormalities on radiographic imagining that do not meet RECIST 1.1 definitions for target lesions) OR * Ascites and/or pleural effusion that has been pathologically demonstrated to be disease-related in the setting of a CA-125 > 2 × ULN
• PRIOR TO LYMPHODEPLETION: Subject must not have a known brain metastasis. A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to lymphodepletion, have been off corticosteroids for ≥ 2 weeks, and are asymptomatic
• PRIOR TO LYMPHODEPLETION: Subject must have available iC9-CAR.B7-H3 T cells that meet the Certificate of Analysis acceptance criteria
• PRIOR TO LYMPHODEPLETION: Subject must not have current signs and/or symptoms of bowel obstruction or signs and/or symptoms of a bowel obstruction within 3 months prior to lymphodepletion
• PRIOR TO LYMPHODEPLETION: Subject must not have a history of intra-abdominal abscess within 3 months of lymphodepletion
• PRIOR TO LYMPHODEPLETION: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L (obtained within 72 hours prior to lymphodepletion)
• PRIOR TO LYMPHODEPLETION: Platelets ≥ 100 × 10^9/L (obtained within 72 hours of lymphodepletion)
• PRIOR TO LYMPHODEPLETION: Creatinine ≤ 2 × ULN (obtained within 72 hours of lymphodepletion)
• PRIOR TO LYMPHODEPLETION: Bilirubin ≤ 1.5 × ULN (obtained within 72 hours of 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
• PRIOR TO LYMPHODEPLETION: AST ≤ 3 × ULN (≤ 5 × ULN if liver metastases present) (obtained within 72 hours of lymphodepletion)
• PRIOR TO LYMPHODEPLETION: ALT ≤ 3 × ULN (≤ 5 × ULN if liver metastases present) (within 72 hours of lymphodepletion)
• 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
• LYMPHODEPLETION: Subject may not be lactating (Note: Breast milk cannot be stored for future use while the mother is being treated on study)
• 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 product administration (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 ≤ 3 × ULN (obtained within 72 hours prior to infusion)
• PRIOR TO iC9-CAR.B7-H3 T CELL INFUSION: Bilirubin ≤ 2 × ULN, unless attributed to Gilbert’s Syndrome (obtained within 72 hours prior to infusion)
• PRIOR TO iC9-CAR.B7-H3 T CELL INFUSION: AST ≤ 5 × ULN (≤ 7 × ULN if liver metastases present) (obtained within 72 hours prior to infusion)
• PRIOR TO iC9-CAR.B7-H3 T CELL INFUSION: ALT ≤ 5 × ULN (≤ 7 × ULN if liver metastases present) (obtained within 72 hours prior to infusion)
• 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