Phase I Study of Autologous CAR T-Cells Targeting the B7-H3 Antigen in Recurrent Epithelial Ovarian

Study Overview
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Brief Summary
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This is single center, open-label phase 1 dose escalation trial that uses modified 3+3 design to identify a recommended phase 2 dose (RP2D) of CAR.B7-H3 T cell product. An expansion cohort will enroll additional subjects at the RP2D for a total enrollment of up to 21 subjects on the protocol.

Detailed Description
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This study is intended for the patients who have been diagnosed with Epithelial Ovarian Cancer that either came back or did not improve after previous treatments. The purpose of this study is to test the safety of using a new treatment called autologous T lymphocyte chimeric antigen receptor cells against the B7-H3 antigen (CAR.B7-H3 T cells) in patients with ovarian cancer. This treatment has not been approved by the Food and Drug Administration. The study investigator's goal is to calculate the Maximum tolerated dose of the CAR.B7-H3 cells There are two parts to this study. In part 1, subject's blood sample will be used to manufacture the CAR.B7-H3 T cells. Ovarian cancer cells carry a substance called B7-H3 which is not found in other healthy cells. the subject's T cells will be modified to make CAR.B7-H3 T cells so they may attack and destroy ovarian cancer cells that carry the B7-H3 substance. The CAR.B7-H3 T cells are given through a catheter in the abdomen, after completing three rounds of lymphodepletion chemotherapy. Lymphodepletion chemotherapy prepares the body to receive the CAR.B7-H3 T cells. In part 2 of the study, the subjects will receive the CAR.B7-H3 T cells. Eligible patients will receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine for three consecutive days. If they continue to meet the eligibility criteria, the modified CAR.B7-H3 T cells will be given to them 2-14 days after the last lymphodepletion chemotherapy session. Three infusions of the CAR.B7-H3 T cells may be given to the subject through a catheter in the abdomen. Infusions will be done once a week. Lymphodepletion chemotherapy and infusion of the CAR.B7-H3 T cells will happen at UNC Cancer Hospital. On the days the subjects receive the CAR.B7-H3 T cells infusion- Blood, fluid, and tumor samples will be collected from the subject for research purposes. Tumor biopsies are a mandatory part of this research. Post infusion visits are - 3, 4, and 6 weeks. Additional visits will happen every 3 months for one year after the last infusion. Similar follow-up clinic visits will be completed annually, for a total of 5 years. This is a research study to obtain new information that may help people in the future.

Official Title
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A Phase 1 Study of Autologous Activated T-cells Targeting the B7-H3 Antigen in Subjects With Recurrent Epithelial Ovarian Cancer

Conditions
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Epithelial Ovarian Cancer

Intervention / Treatment
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* Drug: CAR.B7-H3
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria for the Study Written informed consent and HIPAA authorization for release of personal health information explained to, understood by, and signed by the subject or their legally authorized representative; subject was given a copy of the informed consent form. Older than 18 years at the time of consent. Subject has adequate performance status as defined by ECOG score of ≤ 2. Subjects must have histologically or cytologically confirmed epithelial ovarian, peritoneal or fallopian tube cancer and must have a histological diagnosis of high-grade serous histology based on local histopathological findings. Subjects must have recurrent platinum-resistant or platinum-refractory disease defined as: Disease that has progressed by imaging 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 a platinum-resistant or refractory disease. Having received at least 2 prior regimens. Have failed prior therapy with a PARP inhibitor if the subject has a germline or somatic BRCA mutation. Subjects must have an evaluable disease - defined as: Measurable disease per RECIST 1.1 OR Non-measurable disease (defined as solid and/or cystic abnormalities on radiographic imaging 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. 8. 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 to receive the CAR.B7-H3 infusion and until the subject is determined to be otherwise eligible to receive lymphodepletion). 9. Female subjects of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 180 days 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. 10. Subject is willing and able to comply with study procedures based on the judgment of the investigator or protocol designee. 11. Subject is willing to undergo a biopsy prior to treatment, at the time of final infusion, intraperitoneal catheter removal, and at the time of disease progression, and the tumor site is determined to be safe by the treating investigator for biopsy collection. Eligibility Criteria Prior to Cell Procurement Written informed consent to undergo cell procurement is explained to, understood by, and signed by the subject; the subject is given a copy of the informed consent form for cell procurement. Subject has a life expectancy of≥ 3 months. Subject has evidence of adequate organ function as defined by: Total bilirubin ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome AST / ALT ≤ 3 × ULN (Note: if intrahepatic liver metastases are present, AST and ALT must be ≤ 5 × ULN) Creatinine ≤ 2 × ULN Left ventricular ejection fraction (LVEF) • 40%, as measured by ECHO, with no additional evidence of decompensated heart failure. Imaging results from within 90 days prior to procurement to assess the presence of active disease. 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. Exclusion Criteria: Subject is pregnant or lactating (Note: Breast milk cannot be stored for future use while the mother is being treated in the study). Subject is deemed unlikely to be a candidate for successful intraperitoneal catheter placement by radiographic assessment. Subject has intraparenchymal lung metastases (note that pleural effusions are not exclusionary and that subjects with intraparenchymal liver disease and subjects with the retroperitoneal disease are allowed on the study). Subject has brain metastases. 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 eligibility, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic. Subject has current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel obstruction within 3 months prior to starting treatment. Subject has a history of an intra-abdominal abscess within the past 3 months. Subject has a history of gastrointestinal perforation. The subject has a history of symptomatic diverticular disease, confirmed by CT or colonoscopy. Subject is dependent on intravenous hydration or total parenteral nutrition. Subject has a known additional malignancy that is active and/or progressive and requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years. Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or it's equivalent; those receiving <10 mg daily may be enrolled at the discretion of the investigator. Subject has active infection with HIV, HTLV, HBV, and 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 or HIV viral load, negative for HTLV1 and 2 antibodies or PCR negative for HTLV1 and 2, negative for Hepatitis B surface antigen, negative for HCV antibody or HCV viral load.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR.B7-H3 T cell product<br>Up to 12 patients will receive three weekly CAR.B7-H3 T cell product infusions at the same dose. To determine the recommended phase 2 dose (RP2D), a modified 3+3 dose escalation design will be used to evaluate two dose levels: Dose Level 1 (7.5x10^7 cells/infusion), Dose Level 2 (2x10^8 cells/infusion). If this dose is not tolerated, then a lower dose of 3.75 × 10^6 cells/infusion will be explored. Up to 3 dose levels of CAR.B7-H3 cells will be tested with at least 3 patients enrolled at each dose cohort before dose escalation is considered based on the incidence of dose limiting toxicity (DLT). An expansion cohort will enroll up to 9 patients at the recommended phase 2 dose. Prior to receiving the infusions, patients will undergo lymphodepletion with fludarabine and cyclophosphamide. | Drug: CAR.B7-H3<br>* Two dose levels will be evaluated: Dose Level 1 (7.5x10^7 cells/infusion), dose Level 2 (2x10^8 cells/infusion). If dose limiting toxicities (DLTs) are observed per protocol, Dose Level -1 (3.75x10^6 cells/infusion) will be evaluated.<br>* Other names: Chimeric antigen receptor T cells with B7.H3 molecular target;Drug: Fludarabine<br>* 30 mg/m^2 IV for 3 consecutive days<br>* Other names: FLUDARA;Drug: Cyclophosphamide<br>* 300 mg/m^2 IV for 3 consecutive days<br>* Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) | Dose limiting toxicity (DLT) assessments will include toxicities that are at least possibly related to CAR.B7-H3 T cell product and that onset from day of initial cell product infusion through 4 weeks after the final cell product administration. DLTs are specified as ≥ Grade 3 cytokine release syndrome (CRS) event that does not decrease to Grade ≤ 2 within 7 days, Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), or any other ≥ Grade 3 non-hematologic toxicity, including allergic reactions to T cell infusions.Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), with grading (severity) from grade 1 (mild) to grade 5 (death). ICANS will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). CRS will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death). | 4 weeks after the last CAR-T cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) | Disease control rate will be defined as the percentage of subjects with complete response (CR), partial response (PR), and/or stable disease at 6 months per RECIST 1.1 criteria. Radiographic response will be measured by RECIST (Response Evaluation Criteria In Solid Tumors) Criteria, indicating if 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. | 6 months after initial CAR-T cell infusion | 
| Progression free survival (PFS) | Progression free survival (PFS) will be measured from the time of lymphodepletion prior to infusion with CAR.B7-H3 to progression (as defined per RECIST 1.1) or death. Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if 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. | From the date of lymphodepletion to the date of progression or death up to 5 years | 
| Overall survival (OS) | Overall survival (OS) will be measured from the date of lymphodepletion prior to CAR.B7-H3 T cell product administration to the date of death. | From the date of lymphodepletion to the date of death up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian Cancer