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Mesothelin-Specific T-Cells (FH-TCR-Tᴍsʟɴ) for the Treatment of Metastatic Pancreatic Ductal Adenocarcinoma

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ClinicalTrials.gov Identifier: NCT04809766
Recruitment Status : Recruiting
First Posted : March 22, 2021
Last Update Posted : November 17, 2021
Sponsor:
Collaborator:
Lonza Walkersville, Inc.
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE March 19, 2021
First Posted Date  ICMJE March 22, 2021
Last Update Posted Date November 17, 2021
Estimated Study Start Date  ICMJE December 15, 2021
Estimated Primary Completion Date November 10, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 19, 2021)
  • Incidence of adverse events [ Time Frame: Up to 4 weeks after the last T cell infusion ]
    Toxicity (adverse events) will be recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.
  • Dose limiting toxicities [ Time Frame: Up to 14 days after each T cell infusion ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 19, 2021)
  • Overall response rate [ Time Frame: Up to 15 years ]
    Response will be defined as best overall response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of complete or partial response. Overall response rates as well as individual categories of response (complete response, partial response, stable disease, and partial disease) will be determined using RECIST 1.1.
  • Progression free survival [ Time Frame: Up to 15 years ]
    Will be estimated using the Kaplan-Meier method, with time zero the time of first T cell infusion.
  • Overall survival [ Time Frame: Up to 15 years ]
    Will be estimated using the Kaplan-Meier method, with time zero the time of first T cell infusion.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mesothelin-Specific T-Cells (FH-TCR-Tᴍsʟɴ) for the Treatment of Metastatic Pancreatic Ductal Adenocarcinoma
Official Title  ICMJE Phase I Study of Autologous Transgenic T-Cells Expressing High Affinity Mesothelin-Specific T-Cell Receptor (TCR) (FH-TCR Tᴍsʟɴ) in Patients With Metastatic Pancreatic Ductal Adenocarcinoma
Brief Summary This phase I trial evaluates the side effects and best dose of mesothelin-specific T-cells (FH-TCR-Tᴍsʟɴ) in treating patients with pancreatic ductal adenocarcinoma that has spread to other places in the body (metastatic). Chemotherapy drugs, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading, and may help increase the efficacy from the infused T cells. FH-TCR-Tᴍsʟɴ is an autologous T cell therapy targeting mesothelin, an antigen overexpressed by pancreatic cancer cells. T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize mesothelin, a protein on the surface and inside tumor cells. These mesothelin-specific T cells may help the body's immune system identify and kill mesothelin+ tumor cells. Giving chemotherapy with FH-TCR-Tᴍsʟɴ may kill more tumor cells in the treatment of patients with metastatic pancreatic ductal adenocarcinoma.
Detailed Description

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 4 cohorts.

COHORTS I, II, AND III:

LYMPHODEPLETION CHEMOTHERAPY: Patients receive cyclophosphamide intravenously (IV) and fludarabine IV on days 39-41.

T-CELL THERAPY: Patients receive FH-TCR-Tᴍsʟɴ IV over 60-120 minutes on days 0, 21, and 42 in the absence of disease progression or unacceptable toxicity.

COHORT IV:

LYMPHODEPLETION CHEMOTHERAPY: Patients receive cyclophosphamide IV and fludarabine IV on days -3 to -1.

T-CELL THERAPY: Patients receive FH-TCR-Tᴍsʟɴ IV over 60-120 minutes on days 0, 21, and 42 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 15 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Pancreatic Ductal Adenocarcinoma
  • Stage IV Pancreatic Cancer AJCC v8
Intervention  ICMJE
  • Biological: Autologous Mesothelin-specific TCR-T Cells
    Receive FH-TCR Tᴍsʟɴ IV escalating doses
  • Drug: Cyclophosphamide
    Given IV dose
    Other Names:
    • Endoxan
    • Cytoxan
    • Neosar
    • Procytox
    • Revimmune
    • Cytophosphane
  • Drug: Fludarabine
    Given IV dose
    Other Name: Fluradosa
Study Arms  ICMJE
  • Experimental: Cohorts I, II, and III (FH-TCR Tᴍsʟɴ)

    LYMPHODEPLETION CHEMOTHERAPY: Patients receive cyclophosphamide IV and fludarabine IV on days 39-41.

    T-CELL THERAPY: Patients receive FH-TCR-Tᴍsʟɴ IV over 60-120 minutes on days 0, 21, and 42 in the absence of disease progression or unacceptable toxicity.

    Interventions:
    • Biological: Autologous Mesothelin-specific TCR-T Cells
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
  • Experimental: Cohort IV (FH-TCR Tᴍsʟɴ)

    LYMPHODEPLETION CHEMOTHERAPY: Patients receive cyclophosphamide IV and fludarabine IV on days -3 to -1.

    T-CELL THERAPY: Patients receive FH-TCR-Tᴍsʟɴ IV over 60-120 minutes on days 0, 21, and 42 in the absence of disease progression or unacceptable toxicity.

    Interventions:
    • Biological: Autologous Mesothelin-specific TCR-T Cells
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 19, 2021)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 10, 2037
Estimated Primary Completion Date November 10, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Tissue confirmation of pancreatic ductal adenocarcinoma and expression of mesothelin (MSLN): Participants must have metastatic disease. Confirmation of diagnosis must be or have been performed by internal pathology review of archival, initial or subsequent biopsy or other pathologic material at Fred Hutchinson Cancer Research Center (FHCRC)/University of Washington (UW). Baseline tissue will be stained by immunohistochemistry (IHC) to confirm MSLN expression
  • Measurable disease by RECIST 1.1 criteria with at least two lesions: Participants must have measurable metastatic disease. Baseline imaging (for example diagnostic computed tomography [CT] chest/abdomen/pelvis) must be obtained within 28 days prior to start of first planned FHMSLN-TCR infusion. Magnetic resonance imaging (MRI) can be substituted for CT in patients unable to have CT contrast
  • Previous treatment with chemotherapy: Patients may have been previously treated with at least one prior systemic therapy for metastatic disease
  • Human leukocyte antigen (HLA) type HLA-A*02:01: Participants must be HLA-A*02:01 in order for the infused transgenic T cells to recognize antigen-major histocompatibility complex (MHC) complexes on their tumor. HLA typing should be determined though a molecular approach in a clinical laboratory licensed for HLA typing
  • Life expectancy must be > 3 months at trial entry
  • Capable of understanding and providing a written informed consent
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Tumor tissue amenable to safe biopsy and subject willing to undergo serial tumor biopsies at baseline (prior to first T cell infusion), 3 weeks (prior to second T cell infusion), and 8 weeks +/- 1 week after the first T-cell infusion (approximately 2 weeks +/- 1 week weeks after the 3rd infusion), if safe and feasible: Should there be no tumor tissue that is accessible for biopsy, patients will still be considered for participation, at discretion of the investigator. Similarly, should an investigator determine that a biopsy cannot be performed safely for clinical reasons, biopsies may be cancelled or rescheduled
  • Participants must be at least 3 weeks from last systemic treatment for metastatic disease: At least 3 weeks must have passed since any: immunotherapy (for example, T cell infusions, immunomodulatory agents, interleukins, vaccines), small molecule or chemotherapy cancer treatment, other investigational agents. There is no washout period for radiation, as long as the irradiated lesion is not the lesion being evaluated for RECIST measurements on the protocol. Bisphosphonates are permitted but concurrent treatment with RANK-ligand inhibitors (i.e., denosumab) is not permitted within 8 weeks of treatment
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) > 60 mL/min
  • Total bilirubin (bili) =< 1.5 X ULN. Patients with suspected Gilbert syndrome may be included if total bili > 3 mg/dL but no other evidence of hepatic dysfunction
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN
  • =< grade 1 dyspnea and oxygen saturation (SaO2) >= 92% on ambient air. If pulmonary function tests (PFTs) are performed based on the clinical judgement of the treating physician, patients with forced expiratory volume in 1 second (FEVI) >= 50% of predicted and carbon monoxide diffusing capability test (DLCO) (corrected) of >= 40% of predicted will be eligible
  • Patients >= 60 years of age are required to have left ventricular ejection fraction (LVEF) evaluation performed within 1 year prior to study treatment. LVEF may be established with echocardiogram or multigated acquisition scan (MUGA) scan, and left ejection fraction must be >= 35%. Cardiac evaluation for other patients is at the discretion of the treating physician
  • Absolute neutrophil count (ANC) > 1500 cells/ mm^3
  • Negative serum pregnancy test within 14 days before enrollment for women of childbearing potential, defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year
  • Fertile male and female patients must be willing to use an effective contraceptive method before, during, and for at least 4 months after the FH-TCR-TMSLN infusion

Exclusion Criteria:

  • Expression of HLA B*1302: Participants will be excluded due to the risk of alloreactivity to this allele
  • Pregnancy or lactation
  • Active autoimmune disease: Patients with active autoimmune disease requiring immunosuppressive therapy are excluded. Case by case exemptions are possible with approval by principal investigator (PI)
  • Prior solid organ transplant or allogeneic hematopoietic stem cell transplant
  • Corticosteroid therapy at a dose equivalent of > 0.5 mg/kg of prednisone per day
  • Concurrent use of other investigational anti-cancer agents
  • Active uncontrolled infection: HIV positive participants on HAART with a CD4 count > 500 cells/mm^3 are considered controlled, as are individuals with a history of hepatitis C who have successfully completed antiviral therapy with an undetectable viral load, and those with hepatitis B who have hepatitis well controlled on medication
  • Uncontrolled concurrent illness: Participants may not have uncontrolled or concurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Untreated brain metastases: Participants with small asymptomatic brain metastases (< 1 cm) or those with brain metastases previously treated and controlled with surgery or radiotherapy will be considered for inclusion at discretion of principal investigator, so long as all other eligibility criteria are met
  • Active treatment for prior immune related adverse event to any immunotherapy: Participants receiving ongoing treatment for prior serious immune-related adverse events are excluded, with exception of hormone supplementation or corticosteroid therapy at equivalent of up to 0.5 mg/kg prednisone per day, unless otherwise approved by PI
  • Significant underlying neurologic disease: Study participants must not have significant active underlying neurologic disease, unless approved by PI. Neuropathy related to diabetes or prior chemotherapy is acceptable
  • Other medical, social, or psychiatric factor that interferes with medical appropriateness and/or ability to comply with study, as determined by the PI
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: IMTX Intake Coordinator 866-268-6129 immunotherapy@seattlecca.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04809766
Other Study ID Numbers  ICMJE RG1007292
NCI-2020-08496 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10417 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE Lonza Walkersville, Inc.
Investigators  ICMJE
Principal Investigator: Elena G. Chiorean Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP