NY-ESO-1C259T Alone and in Combination With Pembrolizumab for Multiple Myeloma

Overview

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.

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.

SparkCures ID 888
Trial Phase Phase 2
Enrollment 20 Patients
Treatments
Trial Sponsors
  • Adaptimmune
Trial Collaborators
  • Merck Sharp & Dohme Corp.
  • GlaxoSmithKline
NCT Identifier

NCT03168438

Am I Eligible?

The following criteria is a partial list of reasons why patients may or may not be eligible to participate in this clinical trial. Further evaluation with a medical professional will be required to determine full eligibility.

The following criteria is provided for health care professionals.

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.

US Trial Locations

Accepting Patients

The following is a listing of trial locations that are open and accepting patients.

California
Florida
Georgia
Verified Winship Cancer Institute of Emory University

SparkCures Verified Accurate, up-to-date information. Learn more

Maryland

Resources

There are no resources, links or videos to display for this clinical trial.