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.
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.
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.
