Redirected Auto T Cells for Advanced Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to 1) evaluate the safety and tolerability of autologous genetically modified T cells transduced to express the high affinity NY-ESO-1c259 TCR in HLA-A2+ subjects and 2) measure the incidence of GVHD in patients following infusion of TCR modified autologous T cells.

Detailed Description
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The primary objective 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 myeloma cells rather than their usual target. Study subjects must have systemic or multifocal myeloma requiring autologous stem cell transplantation whose disease has relapsed or incompletely responded to prior therapy or have high-risk features. Subjects must also have measureable disease on study entry, as defined by quantifiable or detectable levels of serum or urine paraprotein or elevated serum free light chains with an abnormal ratio.

Official Title
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A Phase I/IIa, Dual-cohort, Two-site, Clinical Trial Evaluating the Safety and Activity of Redirected Autologous T Cells Expressing a High Affinity TCR Specific for NY-ESO-1 Administered Post ASCT in Patients With Advanced Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Genetic: Autologous Genetically modified T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Myeloma has relapsed, progressed, or failed to respond after at least one prior course of therapy (consisting of at least 2 treatment cycles or months of therapy) Myeloma has responded partially to initial therapy but a complete response (immunofixation negative and normal serum free light chain) has NOT developed after a minimum of 3 cycles or months of initial therapy Myeloma has high-risk features as defined by the presence of one or more cytogenetic abnormalities known to confer a poor outcome even after standard auto-transplants: complex karyotype (≥ to 3 abnormalities), t(4;14), t(14;16), del (17) (p13.1), and/or chromosome 13 abnormalities. These patients may be enrolled even while in complete or near-complete remission Measurable disease on study entry, as defined by quantifiable or detectable levels of serum or urine paraprotein or elevated serum free light chains with abnormal ratio Patients who are in complete remission at the time of proposed study entry (serum and urine immunofixation consistently negative and normal serum free light chains) are not eligible unless their disease meets the criteria for high-risk as defined in protocol Ages 18-80 ECOG performance status 0-2 (unless due solely to bone pain) Prior to Lenalidomide maintenance phase, all study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist® Females 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. Lenalidomide treatment phase: able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin) HLA-A201 patients must have confirmed expression of NY-ESO-1 and/or LAGE. HLA-A2 patients must have the A-201 allele Adequate vital organ function as defined below: Serum creatinine ≤3.0 mg/dl and not on dialysis WBC at least 3000/mm³, platelet count at least 100,000/mm³ SGOT ≤ to 2 x upper limit of normal and bilirubin ≤ to 2.0 mg/dl (unless due to Gilbert's syndrome) Left ventricular ejection fraction (LVEF) ≥ 45%. A lower LVEF is permissible if a formal cardiologic evaluation reveals no evidence for clinically significant functional impairment Adequate pulmonary function with mechanical parameters ≥ 40% predicted (FEV1, FVC, TLC, DLCO). Patients who are unable to complete PFTs due to bone pain or fracture must have a high resolution CT scan of the chest and must have acceptable arterial blood gases defined as a room air PO2 greater than 70 mmHg Patients should have recovered from any toxicities related to prior therapy or at least returned to their baseline level of organ function. Patients should be off of glucocorticoids for at least 2 weeks and/or other therapies for at least 1 week prior to enrollment Exclusion Criteria: Pregnant or nursing females HIV or HTLV-1/2 seropositivity History of myelodysplasia History of chronic active hepatitis or liver cirrhosis (if suspected by laboratory studies, should be confirmed by liver biopsy) Active Hepatitis B (as defined by positive Hepatitis B surface antigen); positive Hepatitis C virus (HCV) antibody is NOT an exclusion Prior allogeneic transplant History of severe autoimmune disease requiring steroids or other immunosuppressive treatments Active immune mediated diseases including: connective tissue diseases, uveitis, sarcoidosis, inflammatory bowel disease, multiple sclerosis Evidence or history of other significant cardiac, hepatic, renal, ophthalmologic, psychiatric, or gastrointestinal disease which would likely increase the risks of participating in the study Active bacterial, viral, or fungal infections

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Autologous Genetically modified T cells<br>Patients with advanced myeloma and who are candidates for autologous stem cell transplants, or syngeneic stem cell transplants (SSCT), will be eligible. Prior to full screening on this study, patients will undergo prescreening to evaluate HLA-A type and presence of NY-ESO-1c259T/LAGE antigen. Patients will undergo a steady-state mononuclear cell apheresis for T cell collection, with an optional second collection. Once mononuclear cells have been collected, patients (or donors in the case of SSCT) will then undergo hematopoietic stem cell mobilization. Patients will receive a dose >0.1-1 x 10¹º anti-CD3/anti-CD28-costimulated autologous T cells which have been genetically modified to express high affinity NY-ESO-1c259 TCRs. | Genetic: Autologous Genetically modified T cells<br>* Patients will undergo myeloma restaging at days +42, +100, 6 months, 9 months and 1 year post infusion. At this point, in accordance with FDA Guidelines, all patients will enter long term follow up (LTFU) and be followed biannually for monitoring for gene transfer delayed adverse events until year 5 post infusion. From year 5, all patients will require annual LTFU visits for monitoring for delayed adverse events until year 15 after receiving the genetically modified T cells. Patients whose disease progresses prior to year 1 will enter LTFU at time of progression; however these patients will be seen quarterly from progression until year 1 post infusion and then follow the LTFU schedule mentioned above.<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 Adverse Events related to study treatment | Day -40 to Year 1 post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria | Objective Response Rate (ORR) of sCR (stringent complete response), CR (complete response), VGPR (very good partial response), PR (partial response) | Change from Baseline at Day 42, 100, 180, 270 and Year 1 | 
| Best Objective Response (BOR) | Number of participants with Best Objective Response of sCR, CR, VGPR, or PR | Best Objective Response prior to initiation of lenalidomide and at Year 1 | 
| Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) | Calculated median DOR, PFS, OS | DOR: Initial date of response to date of progressive disease or death PFS: Date of first T -cell infusion to earliest date of disease progression of death due to any cause OS: Date of first T-cell infusion to date of death from any cause. | 
| Peak Persistence of Modified T-cells in the Peripheral Blood | Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood | Post-infusion through Day 42 | 
| Marrow Antigen Expression Pre-and Post-infusion | Number of participants with NY-ESO-1 and LAGE or LAGE-1a expression in the marrow post-infusion | Pre- and post-infusion | 
| Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells | Number of participants with engraftment in blood and bone marrow | Post Treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma, Received initial treatment previously, Autologous stem cell transplantation