Genetically Engineered PBMC and PBSC Expressing NY-ESO-1 TCR After a Myeloablative Conditioning Regimen to Treat Patients With Advanced Cancer

Study Overview
=================
Brief Summary
-----------------
This phase I clinical trial evaluates the safety and feasibility of administering NY-ESO-1 TCR (T cell receptor)engineered peripheral blood mononuclear cells (PBMC) and peripheral blood stem cells (PBSC) after a myeloablative conditioning regimen to treat patients with cancer that has spread to other parts of the body. The conditioning chemotherapy makes room in the patient?s bone marrow for new blood cells (PBMC) and blood-forming cells (stem cells) to grow. Giving NY-ESO-1 TCR PBMC and stem cells after the conditioning chemotherapy is intended to replace the immune system with new immune cells that have been redirected to attack and kill the cancer cells and thereby improve immune system function against cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To determine the safety of administering the combination of autologous peripheral blood mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) following a reduced intensity conditioning regimen, both of which have been genetically modified to express NY-ESO-1 TCR. SECONDARY OBJECTIVES: I. To determine the feasibility of delivering the combination of TCR transduced autologous PBMC and CD34+ PBSC to patients. II. To determine the persistence of NY-ESO-1 TCR transduced PBMC and the progeny of TCR transduced PBSC in serial peripheral blood samples. III. Objective response rate (ORR). EXPLORATORY OBJECTIVE: I. To explore the use of positron emission tomography (PET)-based imaging using the PET tracer 9-4-[18F]fluoro-3-(hydroxymethyl)butylguanine ([18F]FHBG) with the goal of determining whether the adoptively transferred NY-ESO-1 TCR transduced PBSC home to bone marrow, differentiate into T cells and expand in secondary lymphoid organs and tumor deposits. OUTLINE: G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem cells. Patients receive G-CSF subcutaneously (SC) on mobilization days 1-8 and plerixafor SC on mobilization days 4-7, during mobilization, patients will undergo mobilized leukapheresis to obtain PBSC. Patients also undergo an unmobilized leukapheresis on day -5 before infusion of cells in order to obtain PBMC. CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) on days -4 to -2 and fludarabine IV over 30 minutes on days -3 to -2. Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours, patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive aldesleukin (interleukin-2 (IL) or IL-2) SC twice daily (BID) for up to 7 days. Patients undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60, 90, and 120. Patients receive the PET tracer 18F-FHBG IV, and after 1 hour, undergo PET/computed tomography (CT) on days 25 and 120. After completion of study treatment, patients are followed up every 2-3 months for 2 years, every 6 months for 5 years, and annually for 15 years.

Official Title
-----------------
Adoptive Transfer of NY-ESO-1 TCR Engineered Peripheral Blood Mononuclear Cells (PBMC) and Peripheral Blood Stem Cells (PBSC) After a Myeloablative Conditioning Regimen, With Administration of Interleukin-2, in Patients With Advanced Malignancies

Conditions
-----------------
Sarcoma, HLA-A*0201 Positive Cells Present, Locally Advanced Malignant Neoplasm, NY-ESO-1 Positive, Unresectable Malignant Neoplasm

Intervention / Treatment
-----------------
* Other: 18F-FHBG
* Biological: Aldesleukin
* Drug: Busulfan
* Biological: Cellular Therapy
* Procedure: Computed Tomography
* Biological: Filgrastim
* Drug: Fludarabine
* Procedure: Leukapheresis
* Drug: Plerixafor
* Procedure: Positron Emission Tomography


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Stage IV or locally advanced unresectable cancers for which no alternative therapies with proven survival advantage are available NY-ESO-1 positive malignancy by immunohistochemistry (IHC) utilizing commercially available NY-ESO-1 antibodies HLA-A*0201 (HLA-A2.1) positivity by molecular subtyping Age greater than or equal to 16 years old; if patients 16-17 years old are enrolled in the trial, they will only be enrolled after 3 patients >= 18 years old have been treated, and the treatment has been shown to be safe A minimum of one measurable lesion defined as: Meeting the criteria for measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be accurately measured and recorded by color photography with a ruler to document the size of the target lesion(s) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 Adequate bone marrow and major organ function to undergo a PBSC transplant determined within 30-60 days prior to enrollment using standard phase 1 criteria for organ function defined as: Absolute neutrophil count (ANC) >= 1.5 x 10^9 cells/L Platelets >= 100 x 10^9/L Hemoglobin >= 9 g/dL Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x ULN (upper limit of normal) (=< 5 x ULN, if documented liver metastases are present) Total bilirubin =< 2 x ULN (except patients with documented Gilbert?s syndrome) Creatinine < 2 mg/dl (or a glomerular filtration rate > 60) Must be willing and able to accept at least three leukapheresis procedures Must be willing and able to undergo three research PET scans Must be willing and able to provide written informed consent Exclusion Criteria: Inability to purify >= 2.5 x 10^6 CD34-enriched cells/kg of patient weight from the pooled G-CSF mobilized leukapheresis products Previously known hypersensitivity to any of the agents used in this study; known sensitivity to busulfan or fludarabine Received systemic treatment for cancer, including immunotherapy, within 28 days prior to initiation of conditioning chemotherapy administration within this protocol Potential requirement for systemic corticosteroids or concurrent immunosuppressive drugs based on prior history or received systemic steroids within the last 2 weeks prior to enrollment (inhaled or topical steroids at standard doses are allowed) Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired immune deficiency state, which would increase the risk of opportunistic infections and other complications during chemotherapy-induced lymphodepletion; if there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would increase the likelihood of hepatic toxicities from the chemotherapy conditioning regimen and supportive treatments; if there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol Known clinically active brain metastases; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases Pregnancy or breast-feeding; female patients must be surgically sterile or be postmenopausal for two years, or must agree to use effective contraception during the period of treatment and for 6 months afterwards; all female patients with reproductive potential must have a negative pregnancy test (serum/urine) within 14 days from starting the conditioning chemotherapy; the definition of effective contraception will be based on the judgment of the study investigators Since IL-2 is administered following cell infusion: Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia with evidence of ischemia on a cardiac stress test (stress thallium, stress multigated acquisition [MUGA], dobutamine echocardiogram or other stress test) Similarly, patients with a baseline left ventricular ejection fraction (LVEF) < 45% will be excluded. Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (heart rate >120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular contractions [PVCs] per minute), ventricular tachycardia or 3rd degree heart block will be excluded from the study unless cleared by a cardiologist Patients with pulmonary function test abnormalities as evidenced by a (forced expiratory volume 1 [FEV1]/forced vital capacity [FVC ] < 70% of predicted for normality will be excluded Bone marrow involvement based on PET/CT scan at screening Active or recent herpes simplex virus (HSV) infection or cytomegalovirus (CMV) based on symptoms with positive swab culture and/or positive IgM (immunoglobulin M) screening Liver metastases with no other metastatic sites

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Genetically engineered PBMC and PBSC)<br>G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem cells. Patients receive G-CSF SC on mobilization days 1-8 and plerixafor SC on mobilization days 4-7. Patients also undergo an unmobilized leukapheresis on day -5 before infusion of cells. CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan IV on days -4 to -2 and fludarabine IV over 30 minutes on days -3 to -2. Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours, patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive aldesleukin SC BID for up to 7 days. Patients undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60, 90, and 120. Patients receive 18F-FHBG IV, and after 1 hour, undergo PET/CT on days 25 and 120. | Other: 18F-FHBG<br>* Given IV<br>* Other names: Reporter Probe 18F-FHBG;Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Biological: Cellular Therapy<br>* Given LV-NYESO TCR/sr39TK PBSC IV and RV-NYESO TCR PBMC IV<br>* Other names: Cell Therapy;Procedure: Computed Tomography<br>* Undergo PET/CT<br>* Other names: tomography;Biological: Filgrastim<br>* Given SC<br>* Other names: Zarxio;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Procedure: Leukapheresis<br>* Undergo leukapheresis<br>* Other names: Therapeutic Leukopheresis;Drug: Plerixafor<br>* Given SC<br>* Other names: SDZ SID 791;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicity | Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the Common Toxicity Criteria at each study visit. Subjects will be monitored by medical histories, physical examinations and blood studies to detect potential toxicities from the treatment. If there are no dose limiting toxicities observed, the cohort will be expanded to 12 subjects. If 1/3 are observed, up to 6 subjects will be recruited. If less than 2/6 are observed, the cohort will be expanded to a total of 12 subjects. If a dose limiting toxicity is observed in 2 or more of 6 subjects, the | Up to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detection of replication competent retrovirus and replication competent lentivirus | Will be assessed by polymerase chain reaction. | Up to 12 months post cell administration | 
| Duration of overall complete response | Will evaluate duration of overall complete response. | From the time measurement criteria has been first met for complete response until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years | 
| Duration of overall response | Will evaluate duration of overall response. | From the time measurement criteria is met for complete response/partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years | 
| Persistence of transduced T cells | Analysis will be performed using immune monitoring techniques. The number of days until the percentage of cells expressing both NYESO- 1 TCR and CD3 drops below the baseline percentage. | Time Frame: Up to 2 years after transgenic cell adoptive transfer | 
| Engraftment and persistence of transduced progeny T cells | Analysis will be performed using immune monitoring techniques. The number of days until the vector copy number in the progeny T cells is undetectable. | Time Frame: Up to 2 years after transgenic cell adoptive transfer | 
| Engraftment and persistence of transduced T cells and progeny T cells | Analysis will be performed both using immune monitoring and molecular techniques. The number of days until the vector copy number in the T cells is undetectable. | Time Frame: Up to 2 years after transgenic cell adoptive transfer | 
| Feasibility of generation NY-ESO-1 TCR transgenic T cells and NY-ESO-1 TCR/sr39TK transgenic stem cells that meet the lot release criteria | Feasibility of manufacturing will be assessed as: The number of manufacturing products meeting the lot release criteria after an acceptable number of CD34+ cells have been obtained. | Time Frame: Up to 1 month after transgenic cell adoptive transfer | 
| Immunological monitoring will consist primarily of quantifying T cells bearing surface NY-ESO-1 TCR | Will be assessed by NY-ESO-1126-157/MHC (major histocompatibility complex) dextramer analysis. Functional assays like enzyme-linked immunosorbent assay, intracellular cytokine staining, and/or multicytokine array assays will complement the results. Immunological assays will be compared between 1) pre-infusion peripheral blood mononuclear cells and peripheral blood stem cells, 2) an aliquot of the engineered peripheral blood lymphocytes and stem cells at the time of infusion and 3) cells recovered from patients? peripheral blood after adoptive transfer. | Up to 15 years | 
| Objective response | Potential objective responses to this combinatorial immunotherapy will be recorded following Response Evaluation Criteria in Solid Tumors version 1.1 criteria. | Up to 15 years | 
| Persistence of TCR gene transduced cells | Will be assessed by semi quantitative deoxyribonucleic acid-polymerase chain reaction using primers specific for vector sequence. | Up to 15 years | 
| Time to disease progression | Will evaluate length of time until disease progression. | Time from the date of cell infusion (day 0) to the date of progressive disease first documented, or death whichever occurs first, assessed up to 15 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
T cells, stem cells, gene therapy, NYESO, Sarcoma