Clinical Trials /

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

NCT04670068

Description:

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.

Related Conditions:
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Primary Peritoneal High Grade Serous Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: LCCC1818-ATL
  • NCT ID: NCT04670068

Conditions

  • Epithelial Ovarian Cancer

Interventions

DrugSynonymsArms
CAR.B7-H3Chimeric antigen receptor T cells with B7.H3 molecular targetCAR.B7-H3 T cell product
FludarabineFLUDARACAR.B7-H3 T cell product
CyclophosphamideCytoxanCAR.B7-H3 T cell product

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
CAR.B7-H3 T cell productExperimentalUp 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.
  • CAR.B7-H3
  • Fludarabine
  • Cyclophosphamide

Eligibility 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:

               1. Disease that has progressed by imaging while receiving platinum OR

               2. 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.

               3. Having received at least 2 prior regimens.

               4. 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.

        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 × 109/L

               3. Platelet count • 100 × 109/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.

        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:

               1. Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome

               2. AST / ALT ≤ 5 × ULN, unless attributed to intrahepatic liver metastases

               3. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose limiting toxicities (DLTs)
Time Frame:4 weeks after the last CAR-T cell infusion
Safety Issue:
Description: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

Measure:Disease control rate (DCR)
Time Frame:6 months after initial CAR-T cell infusion
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:From the date of lymphodepletion to the date of progression or death up to 5 years
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:From the date of lymphodepletion to the date of death up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • Ovarian Cancer

Last Updated

December 17, 2020