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

• ClinicalTrials.gov Identifier: NCT04670068
• Recruitment Status: Recruiting
• First Posted: December 17, 2020
• Last Update Posted: December 3, 2021
• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborator: National Institutes of Health (NIH)
• Information provided by (Responsible Party): UNC Lineberger Comprehensive Cancer Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Epithelial Ovarian Cancer	Drug: CAR.B7-H3; Drug: Fludarabine; Drug: Cyclophosphamide	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study of Autologous Activated T-cells Targeting the B7-H3 Antigen in Subjects With Recurrent Epithelial Ovarian Cancer
• Actual Study Start Date: January 27, 2021
• Estimated Primary Completion Date: February 2025
• Estimated Study Completion Date: February 2030

Arms and Interventions

Arm

Intervention/treatment

Experimental: 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.

Drug: CAR.B7-H3; 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.; Other Name: Chimeric antigen receptor T cells with B7.H3 molecular target; Drug: Fludarabine; 25 mg/m^2 IV for 3 consecutive days; Other Name: FLUDARA; Drug: Cyclophosphamide; 300 mg/m^2 IV for 3 consecutive days; Other Name: Cytoxan

Outcome Measures

Primary Outcome Measures :

1. Incidence of dose limiting toxicities (DLTs) [ Time Frame: 4 weeks after the last CAR-T cell infusion ]
   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).

Secondary Outcome Measures :

1. Disease control rate (DCR) [ Time Frame: 6 months after initial CAR-T cell infusion ]

   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.

2. Progression free survival (PFS) [ Time Frame: From the date of lymphodepletion to the date of progression or death up to 5 years ]

   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.

3. Overall survival (OS) [ Time Frame: From the date of lymphodepletion to the date of death up to 5 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Catherine Cheng; (919) 445-4208; catherine_cheng@med.unc.edu

Contact: Caroline Babinec; 919-962-7426; caroline_babinec@med.unc.edu

Locations

United States, North Carolina

Lineberger Comprehensive Cancer Center; Recruiting

Chapel Hill, North Carolina, United States, 27599

Contact: Paola Gehrig 919-966-1194 paola_gehrig@med.unc.edu

Sponsors and Collaborators

UNC Lineberger Comprehensive Cancer Center

National Institutes of Health (NIH)

Investigators

• Principal Investigator: Paola Gehrig; UNC

More Information

Additional Information:

Related Info 

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT04670068
• Other Study ID Numbers: LCCC1818-ATL
• First Posted: December 17, 2020
• Last Update Posted: December 3, 2021
• Last Verified: June 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by UNC Lineberger Comprehensive Cancer Center:

Ovarian Cancer

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Cyclophosphamide; Fludarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists