NY-ESO-1ᶜ²⁵⁹T Alone and in Combination With Pembrolizumab for Multiple Myeloma
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|ClinicalTrials.gov Identifier: NCT03168438|
Recruitment Status : Recruiting
First Posted : May 30, 2017
Last Update Posted : October 27, 2017
This study is intended for men and women at least 18 years of age who have relapsed and/or refractory multiple myeloma. This 2-arm randomized pilot study will test the safety, tolerability and efficacy of NY-ESO-1ᶜ²⁵⁹T alone (Arm 1) or in combination with pembrolizumab (Arm 2) in subjects who have the appropriate HLA-A2 marker, and whose bone marrow expresses the NY-ESO-1 and/or LAGE-1a protein.
This study will take a subject's T cells and give them a T cell receptor protein that recognizes and attacks the tumors.
|Condition or disease||Intervention/treatment||Phase|
|Multiple Myeloma Refractory Multiple Myeloma||Genetic: NY-ESO-1ᶜ²⁵⁹T cells Drug: NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumab||Early Phase 1|
This is a randomized pilot study of the efficacy and safety of NY-ESO-1ᶜ²⁵⁹T alone or in combination with pembrolizumab in patients with relapsed or refractory multiple myeloma, who are HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive, and whose plasma cells from a bone marrow (BM) aspirate test positive for NY-ESO-1 and/or LAGE-1a antigen.
Subjects meeting all eligibility criteria will be randomly assigned to a treatment Arm: NY-ESO-1ᶜ²⁵⁹T alone (Arm 1) or NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumab (Arm 2).
Leukapheresis is performed to obtain cells for the manufacture of autologous NY-ESO-1ᶜ²⁵⁹T cells. When the manufactured NY-ESO-1ᶜ²⁵⁹T cells are available, subjects will undergo lymphodepleting chemotherapy with cyclophosphamide and fludarabine on Day -7, Day 6, and Day -5, followed by a single infusion of NY-ESO-1ᶜ²⁵⁹T (transduced cell range: 1 to 8 billion cells) that will be administered on Day 1.
In Arm 2, three (3) weeks after the infusion of NY-ESO-1ᶜ²⁵⁹T, an initial dose of pembrolizumab will be administered on Day 22. If toxicities preclude Week 3 treatment, the first dose of pembrolizumab may be given at Week 6 (Day 43). The second dose of pembrolizumab will be administered 3 weeks later, at Week 6 (or Week 9), and subsequent doses of pembrolizumab will be administered every 3 weeks thereafter up to Week 108 post T-cell infusion.
Treatment Limiting Toxicities (TLTs) will be evaluated for subjects in the combination arm (Arm 2).
A complete safety review of the first 3 subjects dosed with T-cells and pembrolizumab on Arm 2 will be conducted before enrolling any further subject. The study may be paused to evaluate safety at any time or if at an interim assessment the predictive probability that the TLT rate at the end of the trial exceeds 33%, is greater than 50%.
Efficacy will be assessed using International Myeloma Working Group (IMWG) Uniform Response Criteria.
Upon confirmation of their disease progression, subjects will be considered completing for the primary analysis. Subjects will complete the study once they have met the criteria to be transferred into a Long-Term Follow-Up protocol, where they will continue to be followed for up to 15 years from the date of their T-cell infusion.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||20 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Open-Label Randomized Pilot Study to Assess the Safety, Tolerability and Antitumor Activity of Genetically Engineered NY-ESO-1 Specific (c259) T Cells Alone or in Combination With Pembrolizumab in HLA-A2+ Subjects With NY-ESO-1 and/or LAGE 1A Positive Relapsed and Refractory Multiple Myeloma (rrMM) (ADP-0011-008) (KEYNOTE-487)|
|Actual Study Start Date :||May 24, 2017|
|Estimated Primary Completion Date :||April 9, 2021|
|Estimated Study Completion Date :||September 20, 2024|
Experimental: Arm 1: NY-ESO-1ᶜ²⁵⁹T cells
Subjects will receive one infusion of NY-ESO-1ᶜ²⁵⁹T cells on Day 1.
Genetic: NY-ESO-1ᶜ²⁵⁹T cells
NY-ESO-1ᶜ²⁵⁹T cells administered by infusion on Day 1
Experimental: Arm 2: NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumab
NY-ESO-1ᶜ²⁵⁹T cells administered on Day 1, then pembrolizumab administered on Day 22 (3 weeks after initial infusion of NY-ESO-1ᶜ²⁵⁹T)
Drug: NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumab
NY-ESO-1ᶜ²⁵⁹T cells administered on Day 1, then pembrolizumab administered on Day 22 (3 weeks after initial infusion of NY-ESO-1ᶜ²⁵⁹T cells)
- Number of subjects with Treatment Limiting Toxicities (TLT), adverse events (AE), including serious adverse events (SAE). [ Time Frame: 3.5 years ]Adverse events (AEs), including serious adverse event (SAEs) and treatment limiting toxicities (TLTs with combination only); laboratory assessments including chemistry, hematology and coagulation; and cardiac assessments by electrocardiogram (ECG).
- Proportion of subjects with a positive response : Partial Response (PR), Very Good Partial response (VGPR), Complete Response (CR) or stringent CR (sCR) [ Time Frame: 3.5 years ]Evaluation of the efficacy of the treatment by assessment of the Overall Response rate (ORR) according to International Myeloma Working Group (IMWG) Uniform Response Criteria.
- Interval between the date of T-cell infusion and first documented evidence of positive response (PR, VGPR, CR, sCR) [ Time Frame: 3.5 years ]Evaluation of the efficacy of the treatment by assessment of time to first response (Time to Response (TTR))
- Interval between the date of first documented evidence of response (PR, VGPR, CR, sCR) until first documented disease progression (PD) or death due to any cause [ Time Frame: 5 years ]Evaluation of the efficacy of the treatment by assessment of duration of response.
- Interval between the date of T cell infusion and the earliest date of disease progression or death due to any cause [ Time Frame: 5 years ]Evaluation of the efficacy of the treatment by assessment of progression-free survival (PFS).
- Interval between the date of T cell infusion and the earliest date of death due to any cause [ Time Frame: 7 years ]Evaluation of the efficacy of the treatment by assessment of overall survival (OS).
- Assessment of response by correlating Minimal Residual Disease (MRD) with PFS and OS [ Time Frame: 4.5 years ]Molecular identification and quantification of the clonotypic sequence will be performed by Next-Gen Sequencing on bone marrow samples collected before and 100 days after T cell infusion.
- Correlation of NY-ESO-1ᶜ²⁵⁹T persistence, phenotype and functionality with response to treatment [ Time Frame: 4.5 years ]Flow cytometry will be used to assess the phenotype of transduced T cells in the manufactured product and in post-infusion samples.
- Assessment of loss of antigen expression as resistance mechanism [ Time Frame: 4.5 years ]Expression of NY-ESO-1, LAGE-1a and CD138 (marker of plasma cells) in bone marrow aspirates will be assessed by qRT-PCR at different time points after T cell infusion in order to assess tumor burden and antigen expression.
- Evaluation of potential antigenicity of NY-ESO-1ᶜ²⁵⁹T cell receptor [ Time Frame: 4.5 years ]The presence of antibodies directed against the NY-ESO-1ᶜ²⁵⁹T cell receptor in serum ("anti-drug antibodies") will be measured by ELISA using a custom assay and will be analyzed in relation to persistence of transduced T cells in peripheral blood.
- Evaluation of the role of expression of PD-1 and PD-L1 in bone marrow in response to treatment [ Time Frame: 4.5 years ]Expression of PD-1 and PD-L1 in Bone Marrow Mononuclear Cells (BMMC) isolated from BM aspirates will be measured by flow cytometry. When BM biopsies are collected, IHC will be used to assess expression of PD-L1 on plasma cells and in the microenvironment.
- Investigation of cellular and molecular biomarkers of response in BM samples [ Time Frame: 4.5 years ]BM aspirates will be analyzed at the cellular level (flow cytometry) and at the molecular level (gene expression profiling) to identify markers of immune response (immune cell subsets, immune-modulatory molecules, etc.)
- Correlation of clonal outgrowth of T-cell populations with response following T-cell infusion [ Time Frame: 4.5 years ]Assessment of the polyclonality status of the T cell population in peripheral blood and BM aspirates will be performed by TCR sequencing (NGS)
- Measurement of cytokines in relation to CRS [ Time Frame: 4.5 years ]Cytokines will be quantified in peripheral blood and BM serum before and after T-cell infusion using a multiplex assay (e.g. Luminex)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03168438
|United States, California|
|City of Hope||Recruiting|
|Duarte, California, United States, 91010|
|Contact: Hormoz Babaei Mirshkarlo 626-256-4673 ext 69074 firstname.lastname@example.org|
|Contact: Cara Nolan|
|Principal Investigator: Myo Htut, MD|
|United States, Florida|
|H. Lee Moffitt Cancer Center||Recruiting|
|Tampa, Florida, United States, 33612|
|Contact: Jeffrey Edelman, M.S. 813-745-1040 Jeffrey.Edelman@moffitt.org|
|Contact: Ani Suwarno|
|Principal Investigator: Taiga Nishihori, MD|
|United States, Maryland|
|University of Maryland, Greenebaum Cancer Center||Recruiting|
|Baltimore, Maryland, United States, 21201|
|Contact: Sunita Philip, MPH, CCRP 410-328-8199 email@example.com|
|Principal Investigator: Aaron Rapoport, MD|
|Principal Investigator:||Taiga Nishihori, MD||H. Lee Moffitt Cancer Center|