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

This is an interventional treatment trial for Epithelial Ovarian Cancer focused on measuring Ovarian Cancer Read More

Inclusion Criteria:

Inclusion Criteria for the Study

1. Written informed consent and HIPAA authorization for release of personal health information explained to, understood by and signed by the subject; subject given a copy of the informed consent form.
2. Age • 18 years at the time of consent.
3. Subject has adequate performance status as defined by ECOG score of ≤ 2 (see APPENDIX VI - ECOG Performance Status [73]).
4. Subjects 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.

5. Subjects must have recurrent platinum-resistant or platinum-refractory disease defined as:

   a. Disease that has progressed by imaging while receiving platinum OR b. 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. c. Having received at least 2 prior regimens. d. Have failed prior therapy with a PARP inhibitor if the subject has a germline or somatic BRCA mutation.

6. Subjects must have evaluable disease - defined as:

   1. Measurable disease per RECIST 1.1 (see APPENDIX II - Tumor Measurement Based on RECIST 1.1) OR
   2. 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
   3. Ascites and/or pleural effusion that has been pathologically demonstrated to be disease-related in the setting of a CA-125 > 2 × ULN.
7. Subject may have up to 4 prior treatment regimens (including primary therapy; no more than 2 prior non-platinum-based therapies in the platinum-resistant/-refractory setting). Hormonal therapies used as single agents (i.e. tamoxifen, aromatase inhibitors) will not count towards this treatment limit, however other biologics (bevacizumab, PARP inhibitors, etc.) will count towards this treatment limit.
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 judgement of the investigator or protocol designee.
11. Subject is willing to undergo a biopsy prior to treatment, at the time of final infusion 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

1. 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.
2. Subject has life expectancy ≥ 3 months.

3. Subject has evidence of adequate organ function as defined by:

   1. Total bilirubin ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome
   2. AST / ALT ≤ 3 × ULN (Note: if intrahepatic liver metastases are present, AST and ALT must be ≤ 5 × ULN)
   3. Creatinine ≤ 2 × ULN
   4. Left ventricular ejection fraction (LVEF) • 40%, as measured by ECHO, with no additional evidence of decompensated heart failure.
4. Imaging results from within 90 days prior to procurement to assess presence of active disease.
5. 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.

5.4 Eligibility Criteria Prior to Lymphodepletion

1. Written informed consent explained to, understood by and signed by the subject; subject given a copy of informed consent form.
2. 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 the CAR.B7-H3 infusion).
3. Imaging results from within 10 days prior to lymphodepletion. Imaging must occur at least 3 weeks after most recent therapy (used as baseline measure for documentation of progression before the lymphodepletion) to document measurable or assessable disease. Imaging does not need to be repeated if it is within 10 days prior to lymphodepletion.

4. Subject must demonstrate adequate organ function prior to lymphodepletion as defined below. All tests must be obtained within 48 hours prior to lymphodepletion:

   1. Hemoglobin ≥ 9 g/dL
   2. Absolute neutrophil count ≥ 1.5 × 10^9/L
   3. Platelet count ≥100 × 10^9/L
   4. Total bilirubin ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome
   5. AST / ALT ≤ 3 × ULN (Note: if intrahepatic liver metastases are present, AST and ALT must be ≤ 5 × ULN)
   6. Creatinine ≤ 2 × ULN
5. Subject must have available autologous transduced activated T cells product that meets the Certificate of Analysis acceptance.
6. Subject had no major surgery within 28 days prior to lymphodepletion.
7. Subjects must have stopped systemic chemotherapy for at least 21 days prior to lymphodepletion.
8. Subject must have stopped radiation therapy for at least 21 days prior to lymphodepletion.
9. Subject must have stopped bevacizumab for at least 6 weeks prior to lymphodepletion.
10. Subject must have stopped hormonal therapy (tamoxifen, letrozole, etc.) for at least 21 days prior to lymphodepletion.
11. Subject has not received any investigational agents or any tumor vaccines within 21 days prior to lymphodepletion.
12. 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.

5.5 Eligibility Criteria Prior to Cellular Product Administration After Lymphodepletion

1. Subject has no evidence of uncontrolled infection or sepsis.
2. Negative serum pregnancy within 7 days of the initial cellular product administration. If the pre-lymphodepletion pregnancy test is within the 7 day window, then the pregnancy test does not need to be repeated.

3. Evidence of adequate organ function as defined by:

   a. Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome b. AST / ALT ≤ 5 × ULN, unless attributed to intrahepatic liver metastases c. Creatinine ≤ 3 × ULN

4. Subject has no clinical indication of rapidly progressing disease in the opinion of the clinical investigator.
5. Subject is a good candidate for treatment with CAR.B7-H3 cell product per the clinical investigator's discretion.

Exclusion Criteria:

1. Subject is pregnant or lactating (Note: Breast milk cannot be stored for future use while the mother is being treated on study).
2. Subject is deemed unlikely to be a candidate for successful intraperitoneal catheter placement by radiographic assessment.
3. Subject has intraparenchymal lung metastases (note that pleural effusions are not exclusionary and that subjects with intraparenchymal liver disease and subjects with retroperitoneal disease are allowed on the study).
4. Subject has current signs and/or symptoms of bowel obstruction or signs and/or symptoms of a bowel obstruction within 3 months prior to starting treatment.
5. Subject has a history of intra-abdominal abscess within the past 3 months.
6. Subject has a history of gastrointestinal perforation. Subject has a history of symptomatic diverticular disease, confirmed by CT or colonoscopy.

8. Subject is dependent on intravenous hydration or total parenteral nutrition. 9. Subject has a known additional malignancy that is active and/or progressive 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.

10. Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent; those receiving <10 mg daily may be enrolled at discretion of investigator.

11. Subject has active infection with HIV, HTLV, HBV, 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 antibody or PCR negative for HTLV1 and 2, negative for Hepatitis B surface antigen, negative for HCV antibody or HCV viral load.