Clinical trial NCT01352286: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple myeloma
Received initial treatment previously
Autologous stem cell transplantation
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-05-11
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Adverse Events Related to Study Treatment
timeFrame: Day -40 to Year 1 post-treatment
Secondary outcomes:
measure: Number of Participants With Response Per International Myeloma Working Group (IMWG) 2011 Criteria
timeFrame: Change from Baseline at Day 42, 100, 180, 270 and Year 1
measure: Best Objective Response (BOR)
timeFrame: Best Objective Response prior to initiation of lenalidomide and at Year 1
measure: Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS)
timeFrame: 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.
measure: Peak Persistence of Modified T-cells in the Peripheral Blood
timeFrame: Post-infusion through Day 42
measure: Marrow Antigen Expression Pre-and Post-infusion
timeFrame: Pre- and post-infusion
measure: Engraftment of Gene-modified Pentamer+ CD4+ T Cells and CD8+ T Cells
timeFrame: Post Treatment
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
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.