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Redirected Auto T Cells for Advanced Myeloma

Primary Purpose

Multiple Myeloma

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Autologous Genetically modified T cells

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring Multiple myeloma, Received initial treatment previously, Autologous stem cell transplantation

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

GSK Investigational Site
GSK Investigational Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Autologous Genetically modified T cells

Arm Description

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.

Outcomes

Primary Outcome Measures

Adverse Events Related to Study Treatment

Number of Participants with Adverse Events related to study treatment

Secondary Outcome Measures

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)

Best Objective Response (BOR)

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

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

Calculated median DOR, PFS, OS

Peak Persistence of Modified T-cells in the Peripheral Blood

Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood

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

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

Number of participants with engraftment in blood and bone marrow

Full Information

NCT ID

NCT01352286

First Posted

May 4, 2011

Last Updated

November 19, 2019

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT01352286

Brief Title

Redirected Auto T Cells for Advanced Myeloma

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2019

Overall Recruitment Status

Completed

Study Start Date

May 13, 2011 (Actual)

Primary Completion Date

August 25, 2017 (Actual)

Study Completion Date

July 8, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Myeloma

Keywords

Multiple myeloma, Received initial treatment previously, Autologous stem cell transplantation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

25 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Autologous Genetically modified T cells

Arm Type

Experimental

Arm Description

Intervention Type

Genetic

Intervention Name(s)

Autologous Genetically modified T cells

Intervention Description

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.

Primary Outcome Measure Information:

Title

Adverse Events Related to Study Treatment

Description

Number of Participants with Adverse Events related to study treatment

Time Frame

Day -40 to Year 1 post-treatment

Secondary Outcome Measure Information:

Title

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

Description

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

Title

Best Objective Response (BOR)

Description

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

Title

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

Description

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.

Title

Peak Persistence of Modified T-cells in the Peripheral Blood

Description

Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood

Time Frame

Post-infusion through Day 42

Title

Marrow Antigen Expression Pre-and Post-infusion

Description

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

Time Frame

Pre- and post-infusion

Title

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

Description

Number of participants with engraftment in blood and bone marrow

Time Frame

Post Treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21201

Country

United States

Facility Name

GSK Investigational Site

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

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

IPD Sharing Time Frame

IPD is available via the Clinical Study Data Request site (click on the link provided below)

IPD Sharing Access Criteria

Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

IPD Sharing URL

https://clinicalstudydatarequest.com/Posting.aspx?ID=20063

Citations:

PubMed Identifier

31289029

Citation

Stadtmauer EA, Faitg TH, Lowther DE, Badros AZ, Chagin K, Dengel K, Iyengar M, Melchiori L, Navenot JM, Norry E, Trivedi T, Wang R, Binder GK, Amado R, Rapoport AP. Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma. Blood Adv. 2019 Jul 9;3(13):2022-2034. doi: 10.1182/bloodadvances.2019000194.

Results Reference

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Redirected Auto T Cells for Advanced Myeloma

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