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.
OUTLINE:
This is a dose-escalation study. Patients are assigned to 1 of 3 cohorts.
COHORT I:
LYMPHODEPLETION CHEMOTHERAPY: Patients receive cyclophosphamide intravenously (IV) and
fludarabine IV on days 25-27.
T-CELL THERAPY: Patients receive FH-TCR-Tᴍsʟɴ IV over 60-120 minutes on days 0, 14, and 28 in
the absence of disease progression or unacceptable toxicity.
COHORT II:
LYMPHODEPLETION CHEMOTHERAPY: Patients receive cyclophosphamide IV and fludarabine IV on days
11-13.
T-CELL THERAPY: Patients receive FH-TCR-Tᴍsʟɴ IV over 60-120 minutes on days 0 and 14 in the
absence of disease progression or unacceptable toxicity.
COHORT III:
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 and 14 in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up to 15 years.
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
- If fertile, willingness to comply with reproductive requirements
- 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), 2 weeks and 4-6 weeks after the
first T-cell 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
Exclusion Criteria:
- Expression of HLA B*1302: Participants will be excluded due to the risk of
alloreactivity to this allele
- Pregnancy or lactation: Participants of childbearing potential must have a negative
serum pregnancy test within the 2 weeks (14 days) preceding FH-TCR-TMSLN infusion.
Childbearing potential is defined as women who have not been surgically sterilized and
who are not postmenopausal (free of menses for at least 1 year)
- 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 m 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
