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Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma

Information source: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Advanced Pleural Malignant Mesothelioma; HLA-A*0201 Positive Cells Present; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Pleural Malignant Mesothelioma; Stage III Pleural Mesothelioma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Pleural Mesothelioma

Intervention: Aldesleukin (Biological); Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes (Biological); Cyclophosphamide (Drug); Laboratory Biomarker Analysis (Other); Therapeutic Conventional Surgery (Procedure)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
Sylvia Lee, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Summary

This phase I/II trial studies the side effects and best dose of genetically modified T cells in treating patients with stage III-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.

Clinical Details

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 Nave CD8+ T Cells That Have Been Transduced to Express a WT1-Specific T Cell Receptor

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Evidence and nature of toxicity based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Feasibility of naive T cell (TN) and central memory T cell (TCM) subsets, measured as the proportion of patients for which T cells are successfully generated and infused

Persistence of transduced T cells

Secondary outcome:

Frequency of transferred T cells at biopsied tumor sites between the Tn and Tcm groups

Functional capacity of transferred cells, measured by production of intracellular cytokines

TTP based on RECIST criteria and immune-related response criteria

Detailed description: PRIMARY OBJECTIVES: I. Determine the safety, and potential toxicities associated with treating patients with metastatic NSCLC and mesothelioma with polyclonal autologous central memory and naïve cluster of differentiation (CD)8+ T cells that have been transduced to express a WT1-specific T-cell receptor (TCR) (Arm 1 and Arm 2). II. Determine the feasibility of treating patients with metastatic NSCLC and mesothelioma with polyclonal autologous central memory and naïve CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 1 and Arm 2). III. Determine and compare the in vivo persistence in blood and tumor of transferred polyclonal autologous central memory and naïve CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 1 and Arm 2). SECONDARY OBJECTIVES: I. Determine the antitumor efficacy for patients with metastatic NSCLC and mesothelioma (Arm 1), as measured by time to progression (TTP) based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1. 1 criteria. II. Determine the in vivo functional capacity of adoptively transferred polyclonal autologous CD8+ T cells that have been transduced to express a WT1-specific TCR, and assess the acquisition of phenotypic characteristics associated with T cell exhaustion (Arm 1 and Arm 2). III. Determine the migration to tumor sites of adoptively transferred polyclonal autologous CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 2). IV. Evaluate the tumor response and T cell infiltration in tumors of patients with stage IIIA NSCLC treated in the neo-adjuvant setting. OUTLINE: This is a phase I, dose-escalation study of autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes followed by a phase II study. Patients are assigned to 1 of 3 treatment arms. ARM I, STAGE I: Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes intravenously (IV) on days 0 and 14, cyclophosphamide IV on days 11 and 12, and aldesleukin (IL-2) subcutaneously (SC) twice daily (BID) for 14 days. Patients who have received radiation to the chest/lung tissue may receive T lymphocytes 90 days after completion of radiation.

ARM I, STAGE II: Patients receive cyclophosphamide IV on days - 3 and -2, autologous

WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV on day 0, and aldesleukin SC BID for 14 days. ARM II: Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV between 24-96 hours after the last dose of chemotherapy and receive aldesleukin SC BID for 14 days. Patients then undergo surgery within 3-4 weeks after the T-cell infusion. After completion of study treatment, patients are followed up at 3, 6, and 12 months and then annually for 14 years.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: ELIGIBILITY FOR ENROLLMENT/SCREENING (ARMS 1 AND 2)

- Histopathological documentation of NSCLC or mesothelioma

- Patients must be able to give informed consent

- Patients must be able to provide blood and tumor samples and undergo the procedures

required for this protocol ELIGIBILITY FOR TREATMENT ON ARM 1

- Patients 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 radiographic

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, cytotoxic 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 3 toxicities due to prior therapy and any toxicities due to prior therapy should have resolved, if resolvable to less than or equal to grade 1 ELIGIBILITY FOR TREATMENT ON ARM 2

- Patients must express HLA-A*0201

- Evidence of WT1 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)

- Eastern Cooperative Oncology Group (ECOG) performance status >= 2

- Active autoimmune disease (eg, systemic lupus erythematosus, vasculitis, infiltrating

lung disease, inflammatory bowel disease) in which possible progression during treatment would be considered unacceptable by the investigators

- Any condition or organ toxicity deemed by the principal investigator (PI) or the

attending physician to place the patient at unacceptable risk for treatment on the protocol

- Pregnant women, nursing mothers, men or women of reproductive ability who are

unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative urine pregnancy test within 2 weeks prior to entry

- Clinically significant and ongoing immune suppression including, but not limited to,

systemic immunosuppressive agents such as cyclosporine or corticosteroids, chronic lymphocytic leukemia (CLL), uncontrolled human immunodeficiency virus (HIV) infection, or solid organ transplantation EXCLUSION FOR TREATMENT (ARMS 1 AND 2)

- Exclusions for the leukapheresis procedure (this can be performed at a later time of

symptoms resolve):

- Infection, with or without antibiotic treatment

- Recent hepatitis exposure (hepatitis B or C antigenemia)

- Pregnancy or nursing

- HIV or human T-lymphotropic virus (HTLV) infection

- Positive result on Standard Test for Syphilis (STS)

- 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 temperature > 38. 2 degrees Celsius (C) 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

- Symptomatic and untreated central nervous system (CNS) metastasis; patients must be

clinically and radiologically stable for at least 4 weeks and off steroids for a minimum of 2 weeks prior to study treatment

- White blood cells (WBC) < 2,000/ul

- Hemoglobin (Hb) < 8 g/dL

- Absolute neutrophil count (ANC) < 1,000/ul

- Platelets < 50,000/ul

- New York Heart Association functional class III-IV heart failure, symptomatic

pericardial effusion, stable or unstable angina, symptoms of coronary artery disease, congestive heart failure, clinically significant hypotension or an ejection fraction of =< 30% (echocardiogram or multi-gated acquisition scan [MUGA])

- Clinically significant pulmonary dysfunction, as determined by medical history and

physical exam; patients so identified will undergo pulmonary functions testing and those with forced expiratory volume in 1 second (FEV1) < 2. 0 L or diffusion capacity for carbon monoxide (DLCO) (corrected for Hb) < 50% will be excluded

- Creatinine >1. 5 × the upper limit of normal

- Aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 5 × upper limits of

normal (ULN)

- Bilirubin > 3 × ULN that cannot be attributed to NSCLC metastasis

- HIV or HTLV infection

Locations and Contacts

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
Sylvia M. Lee, Phone: 206-288-2274
Sylvia M. Lee, Principal Investigator
Additional Information

Starting date: May 2015
Last updated: June 16, 2015

Page last updated: August 23, 2015

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