Clinical Trials /

NY-ESO-1ᶜ²⁵⁹T Alone and in Combination With Pembrolizumab for Multiple Myeloma

NCT03168438

Description:

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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: NY-ESO-1ᶜ²⁵⁹T Alone and in Combination With Pembrolizumab for Multiple Myeloma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 208470
  • SECONDARY ID: ADP-0011-008
  • SECONDARY ID: KEYNOTE-487
  • NCT ID: NCT03168438

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumabArm 2: NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumab

Purpose

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.

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, 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1: NY-ESO-1ᶜ²⁵⁹T cellsExperimentalSubjects will receive one infusion of NY-ESO-1ᶜ²⁵⁹T cells on Day 1.
    Arm 2: NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumabExperimentalNY-ESO-1ᶜ²⁵⁹T cells administered on Day 1, then pembrolizumab administered on Day 22 (3 weeks after initial infusion of NY-ESO-1ᶜ²⁵⁹T)
    • NY-ESO-1ᶜ²⁵⁹T in combination with pembrolizumab

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Subject has voluntarily agreed to participate by giving written informed consent in
                 accordance with International Council on Harmonisation (ICH) Good Clinical Practice
                 (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: a. Serum M- protein
                 ≥0.5 g/dL (≥5 g/L) for IgG, IgM, IgA, or ≥0.05 g/dL for IgD; or b. Urine M-protein
                 ≥200 mg/24 hours ; or c. Serum free light chain (FLC) assay: involved FLC level ≥10
                 mg/dL (100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65).
    
              5. Subject must have documented diagnosis of either: a. primary refractory myeloma
                 (PRMM): subjects who have never achieved the minimal response or better to prior
                 therapy OR b. 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 the
                 succession of 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: a. Subjects with endocrine
                 AE of any grade are permitted to enroll if they are stably maintained on appropriate
                 replacement therapy and are asymptomatic. b. Must not have experienced any ≥ Grade 3
                 AE nor any neurologic or ocular AE of any grade while receiving prior checkpoint
                 inhibitors. c. 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. Male or Female subjects can participate. Contraceptive use by men or women should be
                 consistent with local regulations regarding the methods of contraception for those
                 participating in clinical studies. Male subjects are eligible to participate if they
                 agree to the following during the period 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. If 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. Males
                 should Refrain from donating sperm or either be abstinent from heterosexual or
                 homosexual intercourse as their preferred and usual lifestyle (abstinent on a long
                 term and persistent basis) and agree to remain abstinent OR must agree to use
                 contraception/barrier as follows: Agree to use a male condom and should also be
                 advised of the benefit for a female partner to use a highly effective method of
                 contraception as a condom may break or leak when having sexual intercourse with a
                 woman of childbearing (WOCBP) potential who is not currently pregnant, or agree to use
                 male condom when engaging in any activity that allows for passage of ejaculate to
                 another person. Female participant is eligible to participate if she is not pregnant
                 or breastfeeding, and at least one of the following conditions applies: she is not a
                 WOCBP OR she is a WOCBP who will agree to use a barrier method (male condom) and use a
                 contraceptive method that is highly effective (with a failure rate of <1% per year),
                 during the period 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. If
                 randomized to Arm 2 must use a barrier method (male condom) and a highly effective
                 contraception (with a failure rate of <1% per year) 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. WOCBP
                 should also agree not to donate eggs (ova, oocytes) for the purpose of reproduction
                 during this period. The investigator should evaluate the effectiveness of the
                 contraceptive method in relationship to the first dose of study intervention. A WOCBP
                 must have a negative highly sensitive pregnancy test (urine or serum as required by
                 local regulations) within 24 hours before the first dose of study intervention. If a
                 urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum
                 pregnancy test is required. In such cases, the subject must be excluded from
                 participation if the serum pregnancy result is positive. The investigator is
                 responsible for review of medical history, menstrual history, and recent sexual
                 activity to decrease the risk for inclusion of a woman with an early undetected
                 pregnancy.
    
            Exclusion Criteria:
    
              1. Subjects with only plasmacytomas, plasma cell leukemia, monoclonal gammopathy of
                 undetermined significance (MGUS), smoldering multiple myeloma (SMM), nonsecretory
                 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
                 within specified time frames prior to leukapheresis or lymphodepleting chemotherapy.
                 Required Wash-out periods: a. Cytotoxic chemotherapy -2 weeks b. Immune therapy
                 (including monoclonal antibody therapy) -6 weeks c. Immunomodulator therapy (IMiD e.g.
                 lenalidomide or thalidomide) -1 week d. Proteasome inhibitor therapy (e.g. bortezomib
                 or carfilzomib) -2 weeks e. 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 f. Live-virus vaccination -4 weeks NOTE: Seasonal flu
                 vaccines that do not contain live virus are not an exclusion. g. Gene therapy using an
                 integrating vector Allogeneic hematopoietic stem cell transplant at any time not
                 permitted h. Corticosteroids or any other immunosuppressive therapy -2 weeks NOTE: Use
                 of inhaled or topical steroids is not an exclusion i. Investigational treatment - 4
                 weeks j. 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). 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.
    
              6. 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.
    
              7. 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.
    
              8. Known history of myelodysplasia.
    
              9. Current active liver or biliary disease (with the exception of Gilbert's syndrome or
                 asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
                 per investigator assessment). NOTE: Stable chronic liver disease should generally be
                 defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia,
                 oesophageal or gastric varices, persistent jaundice or cirrhosis.
    
             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: a. Positive serology for HIV. b. Presence of hepatitis B surface antigen
                 (HBsAg), positive hepatitis C antibody test result at screening or within 3 months
                 prior to first dose of chemotherapy. c. 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. d.
                 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. QTc > 450 msec or QTc > 480 msec for subjects with bundle branch block. Note: The QTc
                 is the QT interval corrected for heart rate according to Bazett's formula (QTcB),
                 Fridericia's formula (QTcF), and/or another method, machine-read or manually
                 over-read. The specific formula that will be used to determine eligibility and
                 discontinuation for an individual subject should be determined prior to initiation of
                 the study. In other words, several different formulae cannot be used to calculate the
                 QTc for an individual subject and then the lowest QTc value used to include or
                 discontinue the subject from the trial. For purposes of data analysis, QTcB, QTcF,
                 another QT correction formula, or a composite of available values of QTc will be used.
    
             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. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
                 Subjects with previously treated brain metastases may participate provided they are
                 radiologically stable, i.e., without evidence of progression for at least 4 weeks by
                 repeat imaging (note that the repeat imaging should be performed during study
                 screening), clinically stable, and without requirement of steroid treatment for at
                 least 14 days prior to first dose of study treatment.
    
             19. Active bacterial or systemic viral or fungal infections.
    
             20. Pregnant or breastfeeding.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Number of subjects with Treatment Limiting Toxicities (TLT), adverse events (AE), including serious adverse events (SAE).
    Time Frame:Up to 3.8 years
    Safety Issue:
    Description: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

    Measure:Proportion of subjects with a positive response : Partial Response (PR), Very Good Partial response (VGPR), Complete Response (CR) or stringent CR (sCR)
    Time Frame:Up to 3.8 years
    Safety Issue:
    Description: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.
    Measure:Interval between the date of T-cell infusion and first documented evidence of positive response (PR, VGPR, CR, sCR)
    Time Frame:Up to 3.8 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of time to first response (Time to Response (TTR))
    Measure: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:Up to 3.8 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of duration of response.
    Measure:Interval between the date of T cell infusion and the earliest date of disease progression or death due to any cause
    Time Frame:Up to 3.8 years
    Safety Issue:
    Description:Evaluation of the efficacy of the treatment by assessment of progression-free survival (PFS).

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:GlaxoSmithKline

    Trial Keywords

    • Metastatic
    • Multiple Myeloma
    • Previously Treated
    • T Cell Receptor
    • Cell Therapy
    • Immuno-oncology
    • SPEAR T Cell
    • T Cell Therapy
    • NY-ESO-1

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