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Multiple Myeloma

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Proteasome Inhibitors

Patients with a confirmed diagnosis of myeloma, with measurable disease, and who have received prior therapy for their myeloma that includes an IMiDs and a proteasome inhibitor and who have relapsed or progressive disease, will receive treatment with NY-ESO-1c259-modified T cells. An intended total dose of ≥0.1-1e10 total cells will be administered as a single infusion. A low dose infusion of 1e8 to \< 1e9 will be allowed for patients if cells do not expand sufficiently to reach the target dose range.

An intended total dose of ≥0.1-1e10 total cells will be administered as a single infusion. A low dose infusion of 1e8 to \< 1e9 will be allowed for patients if cells do not expand sufficiently to reach the target dose range.

For patients whose disease progresses and whose tumor still expresses tumor antigen and HLA-A201, a second infusion of up to 5e10 cells may be given.

Treatment with NY-ESO-1c259-modified T cells

Edward Stadtmauer, MD

This study will enroll patients with multiple myeloma who have received prior therapy for their disease but their disease has progressed or relapsed.

The primary objective of the study is to evaluate the safety and tolerability of autologous genetically modified T cells transduced to express the high affinity NY-ESO-1c259 TCR in HLA-A201 patients. Eligibility screening will be performed in two steps. First, patients will undergo prescreening to determine if they have the correct HLA type in order to respond to the engineered T cell therapy, and to test for presence of the target antigen, NY-ESO-1 and LAGE-1, in their tumor cells. Patients, who are HLA-A201 positive and test positive for expression of NY-ESO-1 and/or LAGE-1 in their myeloma tumor will move on to complete all screening procedures to determine eligibility for the study.

Patients will initially undergo a steady-state mononuclear cell apheresis for T cell collection. About 3-4 weeks later (to allow expansion/engineering/releasing the engineered T cells), patients will receive a short course of cytoreductive chemotherapy prior to receiving the engineered T cell infusion, comprised of 1.5 gm/m2 of cyclophosphamide, mesna will be given if in accordance with institutional standards.

At day 0, patients will receive a dose of ≥0.1-1 x 1010 anti-CD3/anti-CD28-costimulated autologous T cells which have been genetically modified to express affinity-enhanced NY-ESO-1 T cell receptors (TCRs). A minimum dose of 0.1≤x\<1 x 109 will be permitted. Patients receiving this low dose level will be evaluated separately for safety and efficacy.

Patients will undergo myeloma restaging approximately 1 week prior to the T cell infusion, and post infusion at days +28, +42 (week 6), +100 and 6 months post infusion and then every 3 months until relapse/progression or until 1 year, whenever comes first. At this point, patients will be followed semi-annually for up to 5 years and then annually for long term follow-up for monitoring for delayed adverse events until 15 years after receiving the genetically modified T cells, in accordance with FDA Guidelines.

CT Antigen TCR-Engineered T Cells for Myeloma

A Phase I/IIa, Open Label, Multiple Site Clinical Trial Evaluating the Safety and Activity of Engineered Autologous T Cells Expressing an Affinity-enhanced TCR Specific for NY-ESO-1 and LAGE-1 in Patients With Relapsed or Progressive Disease in Multiple Myeloma

Number of Participants with NCI CTCAE Version 4.0 Adverse Events related to study treatment greater than or equal to Grade 3

Number of participants with response post-infusion as assessed by international uniform response criteria

Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood (copies of WPRE per µg of genomic PBMC DNA)

Adaptimmune

Participants who received NY-ESO-1ᶜ²⁵⁹T

Participants who received cytoreductive chemotherapy followed by infusion of lentivirus-mediated genetically engineered NY-ESO-1ᶜ²⁵⁹T (Target dose: 1-10 billion cells)

NY-ESO-1ᶜ²⁵⁹T Cells Administered IV

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Clinical Trials Management

Adverse Events Related to Study Treatment

Evaluate the Direct Anti-tumor Activity of NY-ESO-1ᶜ²⁵⁹T

Participants who received cytoreductive chemotherapy followed by infusion of NY-ESO-1ᶜ²⁵⁹T with persistence data

Peak Persistence of Modified T-cells in the Peripheral Blood

Overall Study

Muromonab-CD3

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.

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.

Autologous Genetically modified T cells

GSK Clinical Trials

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.

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.

Redirected Auto T Cells for Advanced Myeloma

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

IPD for this study will be made available via the Clinical Study Data Request site.

Number of Participants with Adverse Events related to study treatment

Objective Response Rate (ORR) of sCR (stringent complete response), CR (complete response), VGPR (very good partial response), PR (partial response)

Number of participants with Best Objective Response of sCR, CR, VGPR, or PR

Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood

Number of participants with NY-ESO-1 and LAGE or LAGE-1a expression in the marrow post-infusion

Number of participants with engraftment in blood and bone marrow

GlaxoSmithKline

Participants who received NY-ESO-1ᶜ²⁵⁹T following ASCT

Participants who received NYESO-1ᶜ²⁵⁹T following ASCT

NYESO-1ᶜ²⁵⁹T Cells

GSK Response Center

Day 42

Day 100

Day 180

Day 270

Year 1

Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria

Prior to Initiation of Lenalidomide : sCR

Prior to Initiation of Lenalidomide : CR

Prior to Initiation of Lenalidomide : VGPR

Prior to Initiation of Lenalidomide : PR

Year 1 : sCR

Year 1 : CR

Year 1 : VGPR

Year 1 : PR

Participants who received NYESO-1ᶜ²⁵⁹T following ASCT with Best Objective Response (BOR) data.

Best Objective Response (BOR)

Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS)

Day 100 : NY-ESO-1

Day 100 : LAGE or LAGE-1a

Day 180 : NY-ESO-1

Day 180 : LAGE or LAGE-1a

Participants who received NYESO-1ᶜ²⁵⁹T following ASCT with data at pre-and post-infusion time points

Participants who received NYESO-1ᶜ²⁵⁹T following ASCT with expression data at all points.

Marrow Antigen Expression Pre-and Post-infusion

CD4+ : Blood

CD4+ : Bone Marrow

CD8+ : Blood

CD8+ : Bone Marrow

Participants who received NYESO-1ᶜ²⁵⁹T following ASCT with engraftment data.

Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells

Participants who received lentivirus-mediated genetically engineered NYESO-1ᶜ²⁵⁹T following autologous stem cell transplantation (ASCT)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CT Antigen TCR-Engineered T Cells for Myeloma	NCT01892293	Multiple Myelom...	Treatment with ...	18 Years - 80 Years	Adaptimmune
Redirected Auto T Cells for Advanced Myeloma	NCT01352286	Multiple Myelom...	Autologous Gene...	18 Years - 80 Years	GlaxoSmithKline
Redirected Auto T Cells for Advanced Myeloma	NCT01352286	Multiple Myelom...	Autologous Gene...	18 Years - 80 Years	GlaxoSmithKline

Spots Global Cancer Trial Database for received initial treatment previously