Clinical Trials /

CAR T Cells in Mesothelin Expressing Cancers

NCT03054298

Description:

Phase I study to establish safety and feasibility of intravenous or intrapleural administered lentiviral transduced huCART-meso cells with or without lymphodepletion by way of administering cyclophosphamide.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Lung Adenocarcinoma
  • Malignant Pleural Mesothelioma
  • Ovarian Serous Adenocarcinoma
  • Peritoneal Mesothelioma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CAR T Cells in Mesothelin Expressing Cancers
  • Official Title: Phase I Study of Human Chimeric Antigen Receptor Modified T Cells in Patients With Mesothelin Expressing Cancers

Clinical Trial IDs

  • ORG STUDY ID: 826085 (UPCC 02916)
  • NCT ID: NCT03054298

Conditions

  • Lung Adenocarcinoma
  • Ovarian Cancer
  • Peritoneal Carcinoma
  • Fallopian Tube Cancer
  • Mesotheliomas Pleural
  • Mesothelioma Peritoneum

Interventions

DrugSynonymsArms
huCART-meso cellsCohort 1

Purpose

Phase I study to establish safety and feasibility of intravenous or intrapleural administered lentiviral transduced huCART-meso cells with or without lymphodepletion by way of administering cyclophosphamide.

Detailed Description

      This is a Phase I study evaluating the safety and feasibility of lentiviral transduced
      huCART-meso cells with and without cyclophosphamide and via different routes of
      administration.

        -  Cohort 1 (N=3-6): will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced
           huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen.

        -  Cohort 2 (N=3-6): will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced
           huCART-meso cells on day 0, following a flat dose of 1 gram/m2 of cyclophosphamide
           administered 2-4 days prior to huCARTmeso cells (day -4 to day -2).

        -  Cohort 3 (N=3-6): will receive a single dose of 1-3x10^8 /m^2 lentiviral transduced
           huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen. **Cohort 3
           permanently closed**

        -  Cohort 4 subjects (N=3-6) will receive a single dose of 1-3x10^8 /m^2 lentiviral
           transduced huCART-meso cells on day 0, following a flat dose of 1 gram/m^2 of
           cyclophosphamide administered 2-4 days prior to huCART-meso cells (day -4 to day -2).
           **Cohort 4 permanently closed**

        -  Cohort 5 (N=up to 6): will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced
           huCART-meso cells on day 0 by intrapleural infusion (IP) through an indwelling pleural
           catheter without any conditioning chemotherapeutic regimen. The safety of this dose
           level has been established by Cohorts 1 and 2.

        -  Cohort 6 (N=up to 6): will receive lentiviral transduced huCART-meso cells at a dose of
           1-3x10^7 via IV infusion on Day 0, following a flat dose of 1 gram/m^2 of
           cyclophosphamide administered 2-4 days prior to huCART-meso cells (~Day -4 to -2). This
           initial infusion may be followed by up to two additional IV infusions of huCART-meso
           cells at the same dose level, given between 21-42 days apart, if the subject meets
           eligibility to receive additional infusions. Cyclophosphamide will not be repeated prior
           to subsequent doses of huCART-meso cells. Enrollment into Cohort 6 will occur in
           parallel with Cohort 5.

      The Maximum Tolerated Dose (MTD) is defined as the dose at which 0-1 DLT occurs in 6
      evaluable subjects tested within the dose range of this study. The maximum tolerated dose has
      been established as 1-3x10^7/m^2 lentiviral transduced huCART-meso cells.

      Adverse events will be collected and evaluated during the protocol specified adverse event
      reporting period
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1Active ComparatorSingle dose of 1-3x10^7/m^2 lentiviral transduced huCART-meso cells
  • huCART-meso cells
Cohort 2Active ComparatorCyclophosphamide 1 grams/m^2 administered 2-4 days prior to a single dose of 1-3x10^7 /m^2 lentiviral transduced huCART-meso cells
  • huCART-meso cells
Cohort 3Active ComparatorPERMANENTLY CLOSED
  • huCART-meso cells
Cohort 4Active ComparatorPERMANENTLY CLOSED
  • huCART-meso cells
Cohort 5Active ComparatorSingle dose of 1-3x10^7 /m^2 lentiviral transduced huCART-meso cells on day 0 by intrapleural infusion (IP) through an indwelling pleural catheter. Subjects in this cohort will be enrolled after safety is demonstrated at this dose level by completion of Cohorts 1 and 2. Subjects in Cohort 5 may be enrolled in parallel to Cohort 6.
  • huCART-meso cells
Cohort 6Active ComparatorSingle dose of 1-3x10^7 lentiviral transduced huCART-meso cells via IV infusion on Day 0, following a flat dose of 1 gram/m^2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells (~Day -4 to -2). This initial infusion of huCART-meso cells may be followed by up to two (2) additional IV infusions of huCART-meso cells at the same dose level and administered between 21-42 days apart should subjects continue to meet eligibility criteria for each additional infusion. Should subjects remain eligible for additional infusions of huCART-meso cells, cyclophosphamide will not be repeated prior to subsequent doses of huCART-meso cells.
  • huCART-meso cells

Eligibility Criteria

        Inclusion Criteria

          1. Histologically confirmed cancer (one of the following):

               1. Cohorts 1-4 and Cohort 6 participants:

                  **Note: Cohorts 3 and 4 permanently closed**

                    -  Metastatic or recurrent lung adenocarcinoma.

                    -  Persistent or recurrent serous epithelial ovarian cancer or primary
                       peritoneal carcinoma or fallopian tube carcinoma

                    -  Malignant pleural and peritoneal mesothelioma (histologically confirmed
                       epithelial)

               2. Cohort 5 participants:

                    -  Metastatic or recurrent lung adenocarcinoma with documented pleural effusion

                    -  Persistent or recurrent serous epithelial ovarian cancer or primary
                       peritoneal carcinoma or fallopian tube carcinoma with documented pleural
                       effusion

                    -  Malignant pleural and peritoneal mesothelioma (histologically confirmed
                       epithelial) with documented pleural effusion

          2. Confirmation of tumor mesothelin expression (≥50% of tumor cells)

          3. Failure of at least one prior standard of care chemotherapy for advanced stage
             disease. Prior therapies against PD-1 or PDL-1 are NOT permissible.

          4. Subjects must have measureable disease as defined by RECIST 1.1 criteria or modified
             RECIST criteria (mesothelioma only).

          5. Subjects with asymptomatic CNS metastases that have been treated (and are off steroids
             for the treatment of CNS disease) are allowed. They must meet the following at the
             time of enrollment:

               1. No concurrent treatment for the CNS disease

               2. No progression of CNS metastasis on MRI at screening scans

               3. No evidence of leptomeningeal disease or cord compression

          6. Subjects > 18 years of age.

          7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          8. Satisfactory organ and bone marrow function as defined by the following:

               -  Absolute neutrophil count > 1,000/μl

               -  Platelets >75,000/μl

               -  Hemoglobin > 9 g/dL

               -  Bilirubin < 2.0x the institutional normal upper limit unless secondary to bile
                  duct obstruction by tumor

               -  Creatinine < 1.5x the institutional normal upper limit

               -  Albumin ≥ 2

               -  Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5x the
                  institutional normal upper limit viii. Cardiac ejection fraction of >40% as
                  measured by resting echocardiogram, with no clinically significant pericardial
                  effusion.

          9. Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤
             1.5 and a PTT < 1.2 time the upper limit of normal unless the patient is
             therapeutically anti-coagulated for history of cancer-related thrombosis and has
             stable coagulation parameters.

         10. Provide written informed consent.

         11. Subjects of reproductive potential must agree to use acceptable birth control methods,
             including:

               -  Abstinence

               -  Condoms (male or female) with or without a spermicidal agent

               -  Diaphragm or cervical cap with spermicide

               -  Intrauterine device (IUD)

               -  Hormonal-based contraception

        Exclusion Criteria

          1. Sarcomatoid mesothelioma histology which is known in the literature to not express
             mesothelin; biphasic mesothelioma is also excluded.

          2. Known leptomeningeal carcinomatosis or spinal cord compression. Screening for this is
             not required unless suspicious symptoms.

          3. Subjects with symptomatic CNS metastases are excluded.

          4. Participation in a therapeutic investigational study within 4 weeks prior to
             eligibility confirmation by physician-investigator, or anticipated treatment with
             another investigational product while on study. This refers to non-commercially
             approved investigational drugs different than those used in this protocol.

          5. Active invasive cancer other than the one of the three cancers in this study. Subjects
             with active non-invasive cancers (such as non-melanoma skin cancer, superficial
             cervical and bladder and prostate cancer with PSA level < 1.0) are not excluded.

          6. HIV infection

          7. Active hepatitis B or hepatitis C infection

          8. Active autoimmune disease (including but not limited to: systemic lupus erythematosus,
             Sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory
             bowel disease, etc.) requiring immunosuppressive therapy within four (4) weeks prior
             to eligibility confirmation by physician-investigator, with the exception of thyroid
             replacement.

          9. Subjects with ongoing or active infection.

         10. Planned concurrent treatment with systemic high dose corticosteroids. Subjects may be
             on a stable low dose of steroids (≤10mg equivalent of prednisone) for chronic
             respiratory conditions or adrenal insufficiency. Corticosteroids treatment as
             anti-emetic prophylaxis on the day of cyclophosphamide administration is allowed per
             institutional guidance.

         11. Subjects requiring supplemental oxygen therapy.

         12. Prior therapy with lentiviral gene modified cells.

         13. History of allergy or hypersensitivity to study product excipients (human serum
             albumin, DMSO, and Dextran 40)

         14. Any clinically significant pericardial effusion, Class II-IV cardiovascular disability
             according to the New York Heard Association Classification (see Appendix 3) or other
             cardiovascular condition that would preclude assessment of mesothelin induced
             pericarditis, or which may worsen as a result of expected toxicities in this study.
             This determination will be made by a cardiologist if cardiac issues are suspected.

         15. Any clinically significant pleural or peritoneal effusion that cannot be drained with
             standard approaches. An indwelling drainage device placed prior to eligibility
             confirmation by physician / investigator is acceptable.

         16. Pregnant or breastfeeding women.

         17. Subjects with Interleukin-15 (IL15) > 100 pg/ml

         18. Treatment with a PD-1 or PD-L1 inhibitor, including but not limited to nivolumab,
             pembrolizumab, atezolizumab, and/or durvalumab, within two (2) months prior to
             eligibility confirmation by investigator.

         19. Subjects with significant lung disease as follows:

               -  Subjects with radiographic evidence of greater than lobar lymphangitic pulmonary
                  involvement, greater than lobar bronchial wall thickening suggestive of
                  peribronchial lymphatic disease extension, and/or evidence of extensive bilateral
                  parenchymal metastatic burden.

               -  Subjects with radiographic and/or clinical evidence of active radiation
                  pneumonitis.

               -  Subjects with radiographic evidence of underlying interstitial lung disease,
                  including evidence of unresolved drug toxicity from any agent (e.g. chemotherapy,
                  targeted agents, amiodarone, nitrofurantoin, etc.)

        **No exceptions to eligibility will be granted.**
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame:2 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Clinical anti-tumor effect by standard criteria (RECIST)
Time Frame:Day 28, Month 3 and 6
Safety Issue:
Description:
Measure:Clinical anti-tumor effect by standard criteria [modified RECIST for mesothelioma]
Time Frame:Day 28, Month 3 and 6
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:Year 2
Safety Issue:
Description:
Measure:Progression overall survival
Time Frame:Year 2
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Pennsylvania

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