Phase I/II Study to Assess the Safety and Activity of Enhanced TCR Transduced Autologous T Cells in Metastatic Melanoma

Study Overview
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Brief Summary
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The purpose of this early (phase I/II) clinical trial is to assess the effects (both good and bad) of genetically modified T cells after chemotherapy on your cancer and general health.

Detailed Description
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Purpose of this study is to evaluate the safety and tolerability of autologous genetically modified T cells. Genetic material is transferred into the subject's previously harvested autologous T cells to redirect them to target melanoma cells rather than their usual target. Study subjects must have histologically or cytologically melanoma stage 3/4 and their tumor must express HLA Class 1 allele HLA-A*0201 for NY-ESO-1/LAGE. Subjects must also have measureable disease on study entry, as defined by at least one lesion that can be measured in at least one dimension >= 10mm with spiral CT scan.

Official Title
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Phase I/II Study to Assess the Safety and Activity of Enhanced TCR Transduced Autologous T Cells in Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Genetic: Autologous genetically modified T cells, NY-ESO-1ᶜ²⁵⁹T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients must have histologically or cytologically confirmed melanoma stage III/IV, unresectable Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CT scan One prior cytotoxic therapy for the treatment of metastatic disease is allowed. Unlimited regimens using biological agents (vaccines), immunotherapy, or targeted agents is permitted. For example, BRAF inhibitors and ipilimumab are permitted. Patients must have fully recovered from the acute toxicities related to any prior therapy. Prior therapy must be completed ≥28 days before the first dose of cyclophosphamide. Age ≥18 Life expectancy of greater than 3 months ECOG performance status ≤ 1 Patients must have normal organ and marrow function as defined below: Leukocytes ≥ 3,000/mcL Absolute Neutrophil Count (ANC) ≥ 1,500/mcL Platelets ≥ 100,000/mcL Total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal Creatinine ≤ 2.0 mg/dl Or Creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal The patient must express HLA class I allele HLA-A*0201 for NY-ESO-1/LAGE. Patient must have proven positive tumor sample for NY-ESO-1 as determined by an H score for immunohistochemistry staining. Positive expression is defined as an H score ≥ 100 where the H score = [2 x (% cells 2+) + 3 x (% cells 3+)]. NOTE: The percentages of negative or weakly stained nuclei (i.e. 1+) are not to be included in the calculation of the H score. Female subjects of childbearing potential must have a negative pregnancy test and both male and female (of childbearing potential) subjects must agree to use reliable methods of contraception during the study. Ability of the patient (or legally authorized representative if applicable) to understand and the willingness to sign a written informed consent document. Exclusion Criteria Patients who have had 2 or more regimens containing cytotoxic chemotherapy for metastatic melanoma. Patients may not be receiving any other investigational agents. Patients with active brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide or other agents used in the study. Active infection Prior malignancy (except non-melanoma skin cancer) within 3 years. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. All patients will undergo a cardiac stress test for evaluation of cardiac function. Pregnant or nursing females Active infection with HIV, HBV or HCV as defined below, due to the immunosuppressive effects of cyclophosphamide used and the unknown risks associated with viral replication. Positive serology for HIV Active Hepatitis B infection as determined by test for hepatitis B surface antigen. Active Hepatitis C. Patients will be screened for HCV antibody. If the HCV antibody is positive, a screening HCV RNA by any RT-PCR or bDNA assay must be performed at screening by a local laboratory with a CLIA certification or its equivalent. Eligibility will be determined based on a negative screening value. The test is not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NY-ESO-1/LAGE-1 and HLA-A*02 Positive Subjects<br> | Genetic: Autologous genetically modified T cells, NY-ESO-1ᶜ²⁵⁹T<br>* Cytoreductive chemotherapy followed by infusion of NY-ESO-1ᶜ²⁵⁹T<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Related to Study Treatment | Number of Participants with NCI CTC V.4 Adverse Events related to study treatment greater than or equal to Grade 3 | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response | Number of participants with response as assessed by RECIST (version 1.1) criteria. | Change from Baseline, every 4 weeks until Month 5 and then every other month through Month 11 | 
| Determine the Functional Properties and Phenotype of Modified T-cells From Peripheral Blood and Tumor Sites. | Measurement of functionality of NY-ESO-1ᶜ²⁵⁹T cells in the blood and tumor sites. | 8 Weeks post T-cell infusion | 
| Peak Persistence of Modified T-cells in the Peripheral Blood | Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood (copies of WPRE per µg of genomic PBMC DNA) | Days 1, 5-9, 12-16, weekly thereafter through Week 12, monthly thereafter through Month 12, and during LTFU | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Cell Therapy, T Cell Therapy, NY-ESO-1, Immuno-oncology, Metastatic, Previously treated, T Cell Receptor