Clinical Trial 19093

Cancer Type: Malignant Hematology
Interventions:NY-ESO-1c259T; Pembrolizumab (Keytruda); cyclophosphamide; cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate)

Study Type: Treatment
Phase of Study: Pilot
Investigators:

  • Taiga Nishihori

Overview

Study 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

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 participants 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 participant's T cells and give them a T cell receptor protein that recognizes and attacks the tumors.

Objective

Safety: To describe the safety and tolerability of autologous genetically modified T cells NY-ESO-1c259T) alone (Arm 1) or in combination with pembrolizumab (Arm 2) in subjects who are human leukocyte antigen HLA-A*02:01,HLA-A*02:05, and/or HLA-A*02:06 positive and have NY-ESO-1 and/or LAGE-1a positive relapsed refractory or primary refractory multiple myeloma. Efficacy: To describe the antitumor activity of autologous genetically modified T cells (NY-ESO-1c259T) alone (Arm 1) or in combination with pembrolizumab (Arm 2) in subjects who are HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive and have NY-ESO-1 and/or LAGE-1a positive relapsed refractory or primary refractory multiple myeloma. Exploratory: To evaluate minimal residual disease MRD) at 4 months post T-cell infusion(Week 15). To evaluate the persistence, phenotype,and functionality of NY-ESO-1c259 positive T cells. To understand mechanisms of resistance to NY-ESO-1c259T. To evaluate antigen spreading as a mechanism of response. To evaluate cytokine levels pre- and post-infusion on cytokine release syndrome (CRS). To evaluate the impact of germline polymorphisms in IL-6, TNF-alpha, IL-10, INF-gamma, and TGF-beta on CRS.

Inclusion Criteria

  • Have voluntarily agreed to participate by giving written informed consent in accordance with ICH GCP Guidelines and applicable local regulations; and 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.
  • 18 years of age or older at the date of consent.
  • Histologically confirmed diagnosis of secretory multiple myeloma (must have measurable M protein in serum or urine) with at least one of the following: Serum M- protein ≥0.5 g/dL for IgG, IgM, IgA, or ≥0.05 g/dL for IgD; or Urine M-protein ≥200 mg/24 hours; or Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL and an abnormal serum FLC ratio (1.65).
  • Documented diagnosis of either: primary refractory myeloma (PRMM): subjects who have never achieved the minimal response or better to prior therapy OR - 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 those 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. Those 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.
  • Is HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive as determined by a central laboratory.
  • 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.
  • 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.
  • Is fit for leukapheresis and has adequate venous access for the cell collection.
  • Adequate vital organ function, as per protocol-defined laboratory values.
  • If have received prior checkpoint inhibitors: Those with endocrine Adverse Event (AE) of any grade are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. Must not have experienced any ≥ Grade 3 AE nor any neurologic or ocular AE of any grade while receiving prior checkpoint inhibitors. 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.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
  • Females of reproductive potential (FSRP) must have a negative urine or serum pregnancy test. FSRP and males must follow birth control guidelines outlined in the study documentation.

  • Exclusion Criteria

  • Have only plasmacytomas, plasma cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), non-secretory myeloma or primarily amyloidosis.
  • Has received one of the following: anti-PD-1, anti-PD-L1, or anti-PD-L2 inhibitor.
  • Received or plan to receive the following excluded therapy/treatment prior to leukapheresis or lymphodepleting chemotherapy. Required Wash-out periods: Cytotoxic chemotherapy -2 weeks; Immune therapy -6 weeks; Immunomodulator therapy (IMiD) -1 week; Proteasome inhibitor therapy -2 weeks; Anticancer Vaccine -2 months (Should be excluded if the Investigator considers their disease is responding to an experimental vaccine given within 6 months); Live-virus vaccination -4 weeks (Seasonal flu vaccines that do not contain live virus are not excluded); Gene therapy using an integrating vector Allogeneic hematopoietic stem cell transplant at any time not permitted; Corticosteroids or any other immunosuppressive therapy -2 weeks NOTE: Use of inhaled or topical steroids is not excluded; Investigational treatment - 4 weeks; Radiotherapy - 2 weeks.
  • 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).
  • Toxicity from previous anticancer therapy, not recovered to ≤ Grade 1 or to their baseline level of organ function prior to enrollment (except non-clinically significant toxicities).
  • Grade 2 toxicities deemed stable or irreversible can be enrolled on a case-by-case basis with prior consultation and agreement with the Sponsor Study Physician.
  • Major surgery within 4 weeks prior to randomization (kyphoplasty is not considered major surgery); should have been fully recovered from any surgical related toxicities.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide or other agents used in the study.
  • Known history of myelodysplasia.
  • Known history of chronic active hepatitis or liver cirrhosis (if suspected, should be confirmed).
  • Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or human T-lymphotropic virus (HTLV)
  • History of severe immune disease requiring steroids or other immunosuppressive treatments.
  • Active immune-mediated diseases including: connective tissue diseases, uveitis, sarcoidosis, inflammatory bowel disease, multiple sclerosis, (non-infectious) pneumonitis.
  • Evidence or history of significant cardiac disease.
  • Average QTc interval over 3 consecutive electrocardiograms (ECG) >450 msec in males; >470 msec in females at screening (≥ 480 msec for those with bundle branch block (BBB) are not eligible).
  • Evidence or history of other significant, hepatic, renal, ophthalmologic, psychiatric, or gastrointestinal disease which would likely increase the risks of participating in the study.
  • 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 complete remission was achieved at >= 2 years prior to study entry and no additional therapy required or anticipated during study period. Long-term adjuvant therapy is acceptable.
  • Active bacterial or systemic viral or fungal infections
  • Pregnant or breastfeeding.