A Phase 1 Study of Autologous Activated T-cells Targeting the B7-H3 Antigen in Subjects With Recurrent Epithelial Ovarian Cancer
Overview
- Phase
- Phase 1
- Intervention
- CAR.B7-H3
- Conditions
- Epithelial Ovarian Cancer
- Sponsor
- UNC Lineberger Comprehensive Cancer Center
- Enrollment
- 4
- Locations
- 1
- Primary Endpoint
- Number of Participants With Dose Limiting Toxicities (DLTs) Based on National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE)
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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 ≤
- •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.
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.
Arms & Interventions
CAR.B7-H3 T cell product
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.
Intervention: CAR.B7-H3
CAR.B7-H3 T cell product
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.
Intervention: Fludarabine
CAR.B7-H3 T cell product
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.
Intervention: Cyclophosphamide
Outcomes
Primary Outcomes
Number of Participants With Dose Limiting Toxicities (DLTs) Based on National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE)
Time Frame: Up to 10 weeks (Up 4 weeks after the last CAR-T cell infusion)
Dose-limiting toxicity (DLT) assessments will include toxicities that are at least possibly related to the CAR.B7-H3 T cell product and that occur from the day of the initial infusion through four weeks after the final administration. DLTs are defined as toxicities of Grade ≥3. All toxicities will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, which rates severity from Grade 1 (mild) to Grade 5 (death).
Number of Participants With Dose Limiting Toxicities (DLTs) Based on Cytokine Release Syndrome (CRS)
Time Frame: Up to 10 weeks (Up 4 weeks after the last CAR-T cell infusion)
Dose-limiting toxicities (DLTs) will include any toxicity that is at least possibly related to the CAR.B7-H3 T cell product and occurs from the first infusion through 4 weeks after the final dose. DLTs are defined as Grade ≥3 cytokine release syndrome (CRS) that does not improve to Grade ≤2 within 7 days. CRS will be graded per protocol criteria on a Grade 1 (mild) to Grade 5 (death) scale.
Number of Participants With Dose Limiting Toxicities (DLTs) Based on Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
Time Frame: Up to 10 weeks (Up 4 weeks after the last CAR-T cell infusion)
Dose-limiting toxicity (DLT) assessments will include any toxicity that is at least possibly related to the CAR.B7-H3 T cell product, occurring from the day of the first infusion through four weeks after the final cell product administration. DLTs are defined as Grade ≥3 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) or any other Grade ≥3 non-hematologic toxicity, including allergic reactions to T cell infusions. ICANS will be graded using protocol-defined criteria on a scale from Grade 1 (mild) to Grade 4 (critical). Cytokine Release Syndrome (CRS), if observed, will be graded on a scale from Grade 1 (mild) to Grade 5 (death), per the criteria outlined in the protocol.
Secondary Outcomes
- Disease Control Rate (DCR)(6 months after initial CAR-T cell infusion)
- Progression Free Survival (PFS)(From the date of lymphodepletion to the date of progression or death up to 5 years)
- Overall Survival (OS)(From the date of lymphodepletion to the date of death up to 5 years)