Multiple Myeloma
Conditions
Keywords
Multiple myeloma, Received initial treatment previously, Autologous stem cell transplantation
Brief summary
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
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.
Interventions
GENETICAutologous Genetically modified T cells
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.
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events Related to Study Treatment | Day -40 to Year 1 post-treatment | Number of Participants with Adverse Events related to study treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Objective Response (BOR) | Best Objective Response prior to initiation of lenalidomide and at Year 1 | Number of participants with Best Objective Response of sCR, CR, VGPR, or PR |
| Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (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. | Calculated median DOR, PFS, OS |
| Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria | Change from Baseline at Day 42, 100, 180, 270 and Year 1 | Objective Response Rate (ORR) of sCR (stringent complete response), CR (complete response), VGPR (very good partial response), PR (partial response) |
| Marrow Antigen Expression Pre-and Post-infusion | Pre- and post-infusion | Number of participants with NY-ESO-1 and LAGE or LAGE-1a expression in the marrow post-infusion |
| Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells | Post Treatment | Number of participants with engraftment in blood and bone marrow |
| Peak Persistence of Modified T-cells in the Peripheral Blood | Post-infusion through Day 42 | Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NYESO-1ᶜ²⁵⁹T Cells Participants who received NYESO-1ᶜ²⁵⁹T following ASCT | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | NYESO-1ᶜ²⁵⁹T Cells |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 25 |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 17 / 25 |
Outcome results
Primary
Adverse Events Related to Study Treatment
Number of Participants with Adverse Events related to study treatment
Time frame: Day -40 to Year 1 post-treatment
Population: Participants who received NYESO-1ᶜ²⁵⁹T following ASCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells | Adverse Events Related to Study Treatment | 24 participants |
Secondary
Best Objective Response (BOR)
Number of participants with Best Objective Response of sCR, CR, VGPR, or PR
Time frame: Best Objective Response prior to initiation of lenalidomide and at Year 1
Population: Participants who received NYESO-1ᶜ²⁵⁹T following ASCT with Best Objective Response (BOR) data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells | Best Objective Response (BOR) | Prior to Initiation of Lenalidomide : sCR | 1 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Best Objective Response (BOR) | Prior to Initiation of Lenalidomide : CR | 0 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Best Objective Response (BOR) | Prior to Initiation of Lenalidomide : VGPR | 12 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Best Objective Response (BOR) | Prior to Initiation of Lenalidomide : PR | 7 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Best Objective Response (BOR) | Year 1 : sCR | 2 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Best Objective Response (BOR) | Year 1 : CR | 1 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Best Objective Response (BOR) | Year 1 : VGPR | 13 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Best Objective Response (BOR) | Year 1 : PR | 5 Participants |
Secondary
Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS)
Calculated median DOR, PFS, OS
Time frame: 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.
Population: Participants who received NYESO-1ᶜ²⁵⁹T following ASCT
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells | Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) | DOR | 12.2 median months |
| NYESO-1ᶜ²⁵⁹T Cells | Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) | PFS | 13.5 median months |
| NYESO-1ᶜ²⁵⁹T Cells | Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) | OS | 35.1 median months |
Secondary
Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells
Number of participants with engraftment in blood and bone marrow
Time frame: Post Treatment
Population: Participants who received NYESO-1ᶜ²⁵⁹T following ASCT with engraftment data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells | Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells | CD4+ : Blood | 11 participants |
| NYESO-1ᶜ²⁵⁹T Cells | Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells | CD4+ : Bone Marrow | 11 participants |
| NYESO-1ᶜ²⁵⁹T Cells | Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells | CD8+ : Blood | 11 participants |
| NYESO-1ᶜ²⁵⁹T Cells | Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells | CD8+ : Bone Marrow | 11 participants |
Secondary
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
Time frame: Pre- and post-infusion
Population: Participants who received NYESO-1ᶜ²⁵⁹T following ASCT with expression data at all points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells | Marrow Antigen Expression Pre-and Post-infusion | Day 100 : NY-ESO-1 | 16 participants |
| NYESO-1ᶜ²⁵⁹T Cells | Marrow Antigen Expression Pre-and Post-infusion | Day 100 : LAGE or LAGE-1a | 16 participants |
| NYESO-1ᶜ²⁵⁹T Cells | Marrow Antigen Expression Pre-and Post-infusion | Day 180 : NY-ESO-1 | 14 participants |
| NYESO-1ᶜ²⁵⁹T Cells | Marrow Antigen Expression Pre-and Post-infusion | Day 180 : LAGE or LAGE-1a | 14 participants |
Secondary
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)
Time frame: Change from Baseline at Day 42, 100, 180, 270 and Year 1
Population: Participants who received NYESO-1ᶜ²⁵⁹T following ASCT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells | Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria | Day 42 | 20 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria | Day 100 | 19 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria | Year 1 | 11 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria | Day 180 | 16 Participants |
| NYESO-1ᶜ²⁵⁹T Cells | Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria | Day 270 | 13 Participants |
Secondary
Peak Persistence of Modified T-cells in the Peripheral Blood
Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood
Time frame: Post-infusion through Day 42
Population: Participants who received NYESO-1ᶜ²⁵⁹T following ASCT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NYESO-1ᶜ²⁵⁹T Cells | Peak Persistence of Modified T-cells in the Peripheral Blood | 143728.793 copies per μg of DNA |