We encourage participation in clinical trials for research leading to a cure for mesothelioma. It is known that nationally the statistics for participation in adult cancer trials is between 3-5% of adults who have a cancer diagnosis.

For mesothelioma patients and families that are interested in clinical trials, researching clinical trials and eligibility can be a time-consuming barrier to participation. The information about clinical trials is available on www.clinicaltrials.gov

Our goal is to feature one mesothelioma clinical trial monthly and break it down to understandable terms, to decipher the eligibility requirements, and to possibly encourage participation in these trials.

Listing- ClinicalTrials.gov- NCT02408016

Official Title- Phase I/II Study in WT1-Expressing Non- Small Cell Lung Cancer and Mesothelioma, Comparing Cellular Adoptive Immunotherapy With Polyclonal Autologous Central Memory to Naïve CD8+ T Cells That Have Been Transduced to Express a WT1- Specific T-Cell Receptor

Sponsor- Fred Hutchinson Cancer Research Center

Location- Fred Hutch/University of Washington Cancer Consortium Seattle Washington 98109

Principal Investigator-Sylvia M. Lee- 206 288 2274 smlee@fredhutch.org

Contact- Sylvia M. Lee   206 288 2274   smlee@fredhutch.org

Purpose- This phase 1/11 trial studies the side effects and best dose of genetically modified T cells in treating patients with stage 111-IV non-small cell lung cancer (NSCLC) or mesothelioma. Many types of cancer cells, including NSCLC and mesothelioma, but not most normal cells, have a protein called Wilms tumor (WT)1 on their surfaces. This study takes a type of immune cell from patients, called T cells, and modifies their genes in the laboratory so that they are programmed to find cells with WT1 and kill them. The T cells are then given back to the patient. Cyclophosphamide and aldesleukin may also stimulate the immune system to attack cancer cells. Giving cyclophosphamide and aldesleukin with laboratory – treated T cells may help the body build an immune response to kill tumor cells.

Screening– Documentation of NSCLC or mesothelioma by histopathological sample

• Patient must be able to give informed consent
• Patient must be able to provide blood and tumor samples and undergo the procedures
• Required for this protocol

Eligibility Criteria—Inclusion therapy- Three arms of study- For Arm 1

• Patient must express human leukocyte antigen (HLA)- A*0201
• Evidence of WT1 tumor expression
• Patients must have received at least one line of therapy for NSCLC or mesothelioma or previously documented to have declined therapy

NSCLC patients with a mutation in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) must have demonstrated progression or intolerance to at least one of the corresponding targeted therapies (for example erlotinib or crizotinib)

Bi-dimensionally measurable disease by palpation, clinical exam, or radiological imaging (X-ray, computed tomography (CT) scan, positron emission tomography (PET) scan, magnetic resonance imaging (MRI) or ultrasound)

Ninety days must have passed since the last doses of radiation or chemoradiation treatment involving lung tissue or thorax prior to T cell infusion

Patients treated with prior immunotherapy including and not limited to vaccines, cytokines. T cell stimulating agents, cytokines, T cell stimulating agents, cytoxic T lymphocyte antigen 4 (CTLA4) inhibitors and programmed death (PD)-1 check point inhibitors are allowed on therapy provided they did not have any severe grade 4 toxicities due to prior therapy and any toxicities due to prior therapy should have resolved. If resolvable to less than or equal to grade one

ELIGIBILITY FOR TREATMENT ON ARM 2

• Patients must express HLA-A*0201
• Evidence of WT 1 tumor expression
• Ninety days must have passed since the last definitive doses of radiation or chemoradiation treatment prior to T cell infusion

Exclusion Criteria– EXCLUSION FOR ENROLLMENT / SCREENING (ARMS 1 AND 2)

• . Performance status by Eastern Cooperative Oncology Group (ECOG) performance status >=2
• Active autoimmune disease in which possible progression during treatment would be considered unacceptable by the investigators
• Any condition or organ toxicity deemed by the (PI) or the attending physician to place the patient at unacceptable risk for the treatment of the protocol
• Men or women of reproductive ability who are willing to use effective contraception or abstinence; women of childbearing potential must have a negative urine test within two weeks prior to first infusion.
• Pregnant women and nursing mothers will be eligible for screening only to test HLA type by saliva or buccal swab and WT1 expression from previously collected tissue sample
• Clinically significant and ongoing immune suppression including, but not limited to, systemic immunosuppressive agents such as cyclosporine or corticosteroids

EXCLUSION FOR TREATMENT (ARMS 1 and 2)

• Exclusions for the leukapheresis procedure (can be performed later as symptoms resolve)
• Infection with or without antibiotic treatment
• Recent hepatitis exposure
• Pregnancy or nursing
• HIV or human T-lymphotropic virus (HTLV) infection
• Positive result on standard test for Syphilis
• Unable to generate antigen-specific WT1-specific CD8+T cells for infusions; however, the patient will have the option to receive WT1-specific T- cells if a lower than planned number of cells is available
• Documented infections or known oral temperatures >38.2 degrees Celsius © fewer than 72 hours prior to receiving study treatment or systemic infection requiring chronic maintenance; the start of treatment may be delayed
• Systemic steroids should be stopped 2 weeks before the start of treatment; topical and inhaled steroids are allowed
• Untreated central nervous system (CNS) metastasis that are > 1cm or symptomatic are not allowed; (patients with CNS metastases >1 cm or symptomatic that have been treated and demonstrated to be radiologically and clinically stable for at least 4 weeks are allowed
• WBC- White blood cells < 2,000/ul
• Hemoglobin (Hb) <8 g/dl
• ANC- Absolute neutrophil count < 1000/ul
• Platelets < 50,000/ul
• Creatinine >1.5x the upper limit of normal
• Aspartate aminotransferase/ alanine aminotransferase (AST/ALT) > 5x upper limits of normal (ULN)
• Bilirubin >3 x ULN that cannot be attributed to NSCLC metastasis
• HIV or HTLV infection
• New York Heart Association functional class lll-lV heart failure, symptomatic pericardial effusion, stable or unstable angina, symptoms of coronary artery disease (CAD), congestive heart failure, clinically significant hypotension or history of an ejection fraction of =<30%

Clinically significant pulmonary dysfunction, as determined by medical history and physical exam, patients identified will undergo pulmonary functions testing and those with forced expiratory volume in the 1 second (FEV1) < 2.0 L or diffusion capacity of the lungs for carbon monoxide (DLCO) (corrected for Hb) < 50% will be excluded

How the Research Study is Designed to Work- Patients are assigned to 1 of 3 treatment arms. This is a phase 1, dose escalation study of autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes followed by a phase 11 study. Once the cells have been reconstucted the cells are given back to the patient with intent that cells will attack to tumor cells.

Sources: www.ClinicalTrials.gov

With any clinical trial, all participation is voluntary. Before enrollment a detailed consent form will be reviewed with the participant and signed. The participant can withdraw from a clinical trial at any point in time. Think about participating if able, the only way to progress to a cure for mesothelioma is through clinical trials.

Please do not hesitate to contact us with any questions.