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CAR T Cell Immunotherapy for Pancreatic Cancer

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ClinicalTrials.gov Identifier: NCT03323944
Recruitment Status : Recruiting
First Posted : October 27, 2017
Last Update Posted : July 17, 2019
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:

This study will evaluate an immunotherapy approach to pancreatic cancer, where subjects' own immune cells are engineered to treat their cancer.

Specifically, the study seeks to determine the safety and feasibility of intravenous administration of transduced huCART-meso cells in subjects with histologically confirmed unresectable or metastatic pancreatic adenocarcinoma both with and without cyclophosphamide as lymphodepleting chemotherapy.


Condition or disease Intervention/treatment Phase
Pancreatic Cancer Cancer of the Pancreas Biological: huCART-meso cells Phase 1

Detailed Description:

This is a Phase I study evaluating the feasibility of producing as well as the safety of administering lentiviral transduced huCART-meso cells in up to three (3) cohorts both with and without cyclophosphamide in a three-plus-three (3+3) dose escalation design.

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

    - If one (1) Dose Limiting Toxicity (DLT) occur in three (3) subjects, the study will enroll an additional three (3) subjects at the same dose level. If zero (0) DLTs occur in three (3) subjects, or if one (1) DLT occurs in six (6) subjects, the study will begin to enroll subjects into Cohort 2. However, if two (2) DLTs occur at this dose level at any time, enrollment in Cohort 1 will be stopped, and the administered dose will be de-escalated by 10-fold to 1-3x10^6 cells/m^2, and enrollment into Cohort -1 will begin.

  • Cohort 2 (N=3-6): subjects 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/m^2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells (~day -4 to day -2).

    - If zero (0) or one (1) DLTs occur in three (3) subjects, the study will enroll an additional three (3) subjects to confirm tolerability. If two (2) DLTs occur in three (3) subjects or two (2) DLTs occur in six (6) subjects, further infusions in this cohort will be halted.

  • Cohort -1 (N=3-6): subjects will receive a single dose of 1-3x10^6 cells/m^2 lentiviral transduced huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen. Up to six (6) subjects will be infused in Cohort -1 with not more than one (1) DLT occurring in six (6) subjects to establish the Maximum Tolerated Dose (MTD).

These cohorts will be used to establish the safety of this investigational product (huCART-meso cells) as well as the target dose level in the target study population. If safety is established, the study will be further amended to explore the safety of local delivery methods.

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 : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Human Chimeric Antigen Receptor Modified T Cells (CAR T Cells) in Patients With Pancreatic Cancer
Actual Study Start Date : September 15, 2017
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1: huCART-meso cells without lymphodepletion
Subjects will receive a single dose of 1-3x10^7/m^2 lentiviral transduced huCART-meso cells without any conditioning chemotherapeutic regimen.
Biological: huCART-meso cells
Intravenous administration of permanently modified CAR T cells that target mesothelin, given as single agent or in combination with a lymphodepleting dose of cyclophosphamide.

Experimental: Cohort 2: huCART-meso cells following lymphodepletion
Subjects will receive a single dose of 1-3x10^7/m^2 lentiviral transduced huCART-meso cells following a flat dose of 1 gram/m^2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells (approximately day -4 to day -2).
Biological: huCART-meso cells
Intravenous administration of permanently modified CAR T cells that target mesothelin, given as single agent or in combination with a lymphodepleting dose of cyclophosphamide.

Experimental: Cohort -1: low-dose huCART-meso cells without lymphodepletion
Subjects will receive a single dose of 1-3x10^6 cells/m^2 lentiviral transduced huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen.
Biological: huCART-meso cells
Intravenous administration of permanently modified CAR T cells that target mesothelin, given as single agent or in combination with a lymphodepleting dose of cyclophosphamide.




Primary Outcome Measures :
  1. Number of study subjects with treatment-related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03 [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Tumor response rates measured according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria [ Time Frame: Day 28, Month 3, Month 6 ]
  2. Progression-free survival (PFS) [ Time Frame: 2 years ]
  3. Overall survival (OS) [ Time Frame: 2 years ]


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 unresectable or metastatic pancreatic adenocarcinoma
    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.
    4. Subjects must have measurable disease as defined by RECIST 1.1 criteria.
    5. Subjects must be greater than eighteen (> 18) years of age.
    6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
    7. Satisfactory organ and bone marrow function as defined by the following:

      • Absolute neutrophil count must not be less than one thousand cells per microliter (≥1,000/μL)
      • Platelets must be greater than seventy five thousand per micro liter (>75,000/μL)
      • Hemoglobin must be greater than nine grams per deciliter (> 9 g/dL)
      • Bilirubin must be less than two times (< 2.0x) the institutional normal upper limit
      • Creatinine must be less than one and one half times (< 1.5x) the institutional normal upper limit
      • Albumin must not be less than two (≥ 2)
      • Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be less than five times (< 5x) the institutional normal upper limit
      • Cardiac ejection fraction of greater than forty percent (>40%) as measured by resting echocardiogram, with no clinically significant pericardial effusion.
    8. Blood coagulation parameters: PT such that international normalized ratio (INR) is not greater than one and one half (≤ 1.5) and a PTT must be less than one and two-tenths times (< 1.2x) the upper limit of normal unless the subject is therapeutically anti-coagulated for history of cancer-related thrombosis and has stable coagulation parameters.
    9. Subjects must provide written informed consent.
    10. Subjects of reproductive potential must agree to use acceptable birth control methods
  • Exclusion Criteria:

    1. Participation in an interventional research study within four (4) weeks prior to enrollment, 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.
    2. Active invasive cancer other than pancreatic adenocarcinoma. Subjects with active non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and bladder cancer, or prostate cancer with PSA level less than one (< 1.0)) are not excluded.
    3. HIV infection
    4. Active hepatitis B or hepatitis C infection
    5. 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 enrollment visit, with the exception of thyroid replacement.
    6. Subjects with ongoing or active infection.
    7. 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.
    8. Patients requiring supplemental oxygen therapy.
    9. Prior therapy with lentiviral gene modified cells.
    10. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
    11. Any clinically significant pericardial effusion, Class II-IV cardiovascular disability according to the New York Heard Association Classification or other cardiovascular condition that would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of toxicities expected for this study. This determination will be made by a cardiologist if cardiac issues are suspected.
    12. Any clinically significant pleural or peritoneal effusion that cannot be drained with standard approaches. An indwelling drainage device placed prior to enrollment is acceptable.
    13. Pregnant or breastfeeding women.

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): NCT03323944


Contacts
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Contact: Mark O'Hara, MD 855-216-0098 PennCancerTrials@emergingmed.com
Contact: Mark O'Hara, MD 800-789-7366 Mark.O'hara@uphs.upenn.edu

Locations
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United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Mark O'Hara, MD    800-789-7366    Mark.O'hara@uphs.upenn.edu   
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Mark O'Hara, MD Assistant Professor of Medicine, Penn Medicine

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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03323944     History of Changes
Other Study ID Numbers: 827644 (UPCC 14217)
First Posted: October 27, 2017    Key Record Dates
Last Update Posted: July 17, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Pennsylvania:
metastatic adenocarcinoma, pancreas
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases