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CAR T Cells in Mesothelin Expressing Cancers

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ClinicalTrials.gov Identifier: NCT03054298
Recruitment Status : Recruiting
First Posted : February 15, 2017
Last Update Posted : April 18, 2019
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Lung Adenocarcinoma Ovarian Cancer Peritoneal Carcinoma Fallopian Tube Cancer Mesotheliomas Pleural Mesothelioma Peritoneum Biological: huCART-meso cells Phase 1

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Human Chimeric Antigen Receptor Modified T Cells in Patients With Mesothelin Expressing Cancers
Actual Study Start Date : March 1, 2017
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2021


Arm Intervention/treatment
Active Comparator: Cohort 1
Single dose of 1-3x10^7/m^2 lentiviral transduced huCART-meso cells
Biological: huCART-meso cells
Intravenous or intrapleural lentiviral transduced huCART-meso cells in 6 cohorts with and without cyclophosphamide in a 3+3 dose escalation design.

Active Comparator: Cohort 2
Cyclophosphamide 1 grams/m^2 administered 2-4 days prior to a single dose of 1-3x10^7 /m^2 lentiviral transduced huCART-meso cells
Biological: huCART-meso cells
Intravenous or intrapleural lentiviral transduced huCART-meso cells in 6 cohorts with and without cyclophosphamide in a 3+3 dose escalation design.

Active Comparator: Cohort 3
PERMANENTLY CLOSED
Biological: huCART-meso cells
Intravenous or intrapleural lentiviral transduced huCART-meso cells in 6 cohorts with and without cyclophosphamide in a 3+3 dose escalation design.

Active Comparator: Cohort 4
PERMANENTLY CLOSED
Biological: huCART-meso cells
Intravenous or intrapleural lentiviral transduced huCART-meso cells in 6 cohorts with and without cyclophosphamide in a 3+3 dose escalation design.

Active Comparator: Cohort 5
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. 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.
Biological: huCART-meso cells
Intravenous or intrapleural lentiviral transduced huCART-meso cells in 6 cohorts with and without cyclophosphamide in a 3+3 dose escalation design.

Active Comparator: Cohort 6
Single 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.
Biological: huCART-meso cells
Intravenous or intrapleural lentiviral transduced huCART-meso cells in 6 cohorts with and without cyclophosphamide in a 3+3 dose escalation design.




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Clinical anti-tumor effect by standard criteria (RECIST) [ Time Frame: Day 28, Month 3 and 6 ]
  2. Clinical anti-tumor effect by standard criteria [modified RECIST for mesothelioma] [ Time Frame: Day 28, Month 3 and 6 ]
  3. Progression-free survival [ Time Frame: Year 2 ]
  4. Progression overall survival [ Time Frame: Year 2 ]


Information from the National Library of Medicine

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03054298


Contacts
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Contact: Janos L Tanyi, MD, PhD 855-216-0098 PennCancerTrials@emergingmed.com

Locations
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United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Janos L Tanyi, MD,PhD    855-216-0098    PennCancerTrials@emergingmed.com   
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Janos L Tanyi, MD, PhD University of Pennaylvania

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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03054298     History of Changes
Other Study ID Numbers: 826085 (UPCC 02916)
First Posted: February 15, 2017    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Adenocarcinoma
Mesothelioma
Fallopian Tube Neoplasms
Adenocarcinoma of Lung
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Adenoma
Neoplasms, Mesothelial
Fallopian Tube Diseases
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists