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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
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
Brief Summary:

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

Detailed Description:

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 Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
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)


Outcome Measures

Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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))

  3. 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.

  4. 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).

  5. 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).


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.)

  7. 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)

  8. 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)


Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject has voluntarily agreed to participate by giving written informed consent in accordance with ICH GCP Guidelines and applicable local regulations.
  2. Subject has voluntarily agreed to abide by all protocol required procedures including study related assessments, and management by the treating institution for the duration of the study and long-term follow-up.
  3. Subjects must be 18 years of age or older at the date of consent.
  4. Histologically confirmed diagnosis of secretory multiple myeloma (must have measurable M protein in serum or urine) with at least one of the following:

    1. Serum M- protein ≥0.5 g/dL for IgG, IgM, IgA, or ≥0.05 g/dL for IgD; or
    2. Urine M-protein ≥200 mg/24 hours ; or
    3. Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL and an abnormal serum FLC ratio (<0.26 or >1.65).
  5. Subject must have documented diagnosis of either:

    1. primary refractory myeloma (PRMM): subjects who have never achieved the minimal response or better to prior therapy OR
    2. relapsed and refractory multiple myeloma (RRMM): subjects who have received at least 2 prior regimen, were responsive to at least 1 prior regimen (as defined by IMWG criteria) and then are refractory to their most recent therapy (≤ 25% response or progression during therapy or within 60 days after completion of therapy).

    Prior therapies for subjects with PRMM or RRMM must include an immunomodulatory drug (IMiD) and a proteasome inhibitor as separate lines or a combined line of therapy.

    If prior therapy includes autologous stem cell transplantation (ASCT), then induction/ASCT/maintenance therapies will be considered as one line of therapy altogether.

    Subjects who have relapsed after ASCT or are unable to receive ASCT are eligible. The interval from ASCT to entry in the study must be ≥12 weeks.

  6. Subject is HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive as determined by a central laboratory. (This determination will be made under a pre enrollment screening informed consent form [ICF]. There are no restrictions on the timing of HLA typing for screening and data can be taken from subjects' records).
  7. Subject has confirmed sufficient expression of NY-ESO-1 and/or LAGE-1a by reverse transcription polymerase chain reaction (RT-PCR) as determined by a central laboratory contracted by the Sponsor (this determination will also be made under a pre-enrollment screening ICF).
  8. Left ventricular ejection fraction (LVEF) ≥50%. A lower LVEF (≥40%) is permissible if a formal cardiologic evaluation reveals no evidence for clinically significant functional impairment, otherwise the subject may not enter the study.
  9. Subject is fit for leukapheresis and has adequate venous access for the cell collection.
  10. Subject has adequate vital organ function, as per protocol-defined laboratory values for Absolute Neutrophil count (ANC), platelets, hemoglobin, Prothrombin Time (PT) or International Normalized Ratio (INR), Partial Thromboplastin Time (PTT), measured or calculated creatinine clearance, serum total bilirubin, Aspartate aminotransferase (AST)/ Serum Glutamic Oxaloacetic Transaminase (SGOT), and Alanine aminotransferase (ALT)/ Serum Glutamic Pyruvic Transaminase (SGPT).
  11. For subjects who have received prior checkpoint inhibitors:

    1. Subjects with endocrine AE of any grade are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
    2. Must not have experienced any ≥ Grade 3 AE nor any neurologic or ocular AE of any grade while receiving prior checkpoint inhibitors.
    3. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE related to checkpoint inhibitors, not have experienced recurrence of an AE related to checkpoint inhibitors if re challenged, and not currently require maintenance doses of corticosteroids.
  12. Subject has Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
  13. Female subjects of reproductive potential (FSRP) must have a negative urine or serum pregnancy test. NOTE: FSRP is defined as premenopausal and not surgically sterilized. FSRP must agree to use maximally effective birth control or to abstain from heterosexual activity throughout the study, starting at the first dose of chemotherapy for at least 12 months after receiving the T-cell infusion, or 4 months after there is no evidence of persistence/ gene modified cells in the subject's blood, whichever is longer. FSRP randomized to Arm 2 must use effective contraception for at least 4 months after the last dose of pembrolizumab if this time frame is longer than the duration of contraception required in the context of chemotherapy and gene modified cells.

Or Male subjects must be surgically sterile or agree to use a double barrier contraception method or abstain from heterosexual activity starting at the first dose of chemotherapy and for at least 4 months after the last dose of study treatment.

Exclusion Criteria:

  1. Subjects with only plasmacytomas, plasma cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), non-secretory myeloma or primarily amyloidosis.
  2. Subject has already received one of the following therapy/treatment: anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitor.
  3. Subject has received or plans to receive the following excluded therapy/treatment prior to leukapheresis or lymphodepleting chemotherapy.

    Required Wash-out periods:

    1. Cytotoxic chemotherapy -2 weeks
    2. Immune therapy (including monoclonal antibody therapy) -6 weeks
    3. Immunomodulator therapy (IMiD e.g. lenalidomide or thalidomide) -1 week
    4. Proteasome inhibitor therapy (e.g. bortezomib or carfilzomib) -2 weeks
    5. Anticancer Vaccine -2 months NOTE: The subject should be excluded if the Investigator considers their disease is responding to an experimental vaccine given within 6 months
    6. Live-virus vaccination -4 weeks NOTE: Seasonal flu vaccines that do not contain live virus are not an exclusion.
    7. Gene therapy using an integrating vector Allogeneic hematopoietic stem cell transplant at any time not permitted
    8. Corticosteroids or any other immunosuppressive therapy -2 weeks NOTE: Use of inhaled or topical steroids is not an exclusion
    9. Investigational treatment - 4 weeks
    10. Radiotherapy - 2 weeks NOTE: Duration of any other anticancer therapies must be discussed with the Sponsor Study Physician
  4. Subjects who have previously participated in Merck pivotal trial NCT02576977: Study of Pomalidomide and Low Dose Dexamethasone With or Without Pembrolizumab (MK-3475) in Refractory or Relapsed and Refractory Multiple Myeloma (RRMM) (MK-3475-183/KEYNOTE-183).
  5. Subject has toxicity from previous anticancer therapy that has not recovered to ≤ Grade 1 or to their baseline level of organ function prior to enrollment (except for non-clinically significant toxicities, e.g., alopecia, vitiligo).
  6. Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g. peripheral neuropathy) can be enrolled on a case-by-case basis with prior consultation and agreement with the Sponsor Study Physician.
  7. Subject had major surgery within 4 weeks prior to randomization (kyphoplasty is not considered major surgery); subjects should have been fully recovered from any surgical related toxicities.
  8. Subject has history of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide or other agents used in the study.
  9. Known history of myelodysplasia.
  10. Known history of chronic active hepatitis or liver cirrhosis (if suspected by laboratory studies, should be confirmed by liver biopsy).
  11. Subject has an active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or human T-lymphotropic virus (HTLV) as defined below:

    1. Positive serology for HIV.
    2. Active hepatitis B infection as demonstrated by test for hepatitis B surface antigen. Subjects who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable hepatitis B DNA and receive prophylaxis against viral reactivation. Prophylaxis should be initiated prior to lymphodepleting therapy and continued for 6 months.
    3. Active hepatitis C subjects as demonstrated by test for hepatitis C ribonucleic acid (RNA). Subjects who are HCV antibody positive will be screened for HCV RNA by any RT-PCR or by DNA assay. If HCV antibody is positive, eligibility will be determined based on a negative screening RNA value.
    4. Positive serology for HTLV 1 or 2. Re-screening for infection disease markers is not required at baseline (prior to lymphodepleting chemotherapy)
  12. History of severe immune disease, including non-infectious pneumonitis, requiring steroids or other immunosuppressive treatments.
  13. Active immune-mediated diseases including: connective tissue diseases, uveitis, sarcoidosis, inflammatory bowel disease, multiple sclerosis, (non-infectious) pneumonitis.
  14. Evidence or history of significant cardiac disease (such as, but not limited to, unstable angina pectoris, myocardial infarction within the prior 6 months, heart failure within 6 months, symptomatic congestive heart failure, symptomatic or uncontrolled arrhythmias, severe aortic stenosis, symptomatic mitral stenosis).
  15. Subjects showing an average QTc interval over 3 consecutive electrocardiograms (ECG) >450 msec in males and >470 msec in females at screening (≥ 480 msec for subjects with bundle branch block (BBB) are not eligible.
  16. Evidence or history of other significant, hepatic, renal, ophthalmologic, psychiatric, or gastrointestinal disease which would likely increase the risks of participating in the study.
  17. Subjects with concomitant second malignancies (except adequately treated nonmelanomatous skin cancers, carcinoma in situ of the breast, treated superficial bladder cancer or prostate cancer, or in situ cervical cancers) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period. Long-term adjuvant therapy (example: breast cancer) is acceptable.
  18. Active bacterial or systemic viral or fungal infections
  19. Pregnant or breastfeeding.
Contacts and Locations

Information from the National Library of Medicine

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


Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Hormoz Babaei Mirshkarlo    626-256-4673 ext 69074    hmirshkarlo@coh.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    sphilip1@umm.edu   
Principal Investigator: Aaron Rapoport, MD         
Sponsors and Collaborators
Adaptimmune
Merck Sharp & Dohme Corp.
GlaxoSmithKline
Investigators
Principal Investigator: Taiga Nishihori, MD H. Lee Moffitt Cancer Center
More Information

Responsible Party: Adaptimmune
ClinicalTrials.gov Identifier: NCT03168438     History of Changes
Other Study ID Numbers: ADP-0011-008
KEYNOTE-487 ( Other Identifier: Merck )
First Posted: May 30, 2017    Key Record Dates
Last Update Posted: October 27, 2017
Last Verified: October 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Adaptimmune:
Cell Therapy
Multiple Myeloma
Immuno-oncology
T Cell Therapy
Metastatic
SPEAR T Cell
T Cell Receptor
Previously Treated
NY-ESO-1

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Pembrolizumab
Antineoplastic Agents