A Randomized, Placebo Controlled Study to Evaluate the Safety and Potential Efficacy of MS-20 in Combination with Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer

Inclusion criteria

• Male or female subjects who are over 20 years old (inclusive) at the time of signing the informed consent form.
• The subject is diagnosed pathologically or cytologically with non-small cell lung cancer (NSCLC).
• According to the 8th edition of the American Joint Committee on Cancer [AJCC], staging is metastatic III.B-IV NSCLC that cannot be surgically removed.
• The subject with metastatic non-squamous carcinoma whose EGFR/ALK/ROS 1 tumor gene is the original type, or subject with squamous cell carcinoma whose EGFR/ALK tumor gene is the original type.
• At least one measurable lesion per RECIST v 1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• The subject whose biomarker performance: The PD L1 performance detected by Dako 22C3 or Ventana SP263 and other third-level in vitro diagnostic medical devices (class III) must meet tumor proportion scores (TPS) ≥ 50%.
• The life expectancy is not less than 3 months.
• The subject whose liver and kidney functions must meet all of the following conditions:

• Liver function: aspartate aminotransferase (AST) value < 2.5 x ULN, alanine aminotransferase (ALT) value < 2.5 x ULN and total bilirubin (T-bilirubin) value < 1.5 x ULN. For the subjects who have liver metastases, total bilirubin value should be < 5 x ULN.
• Kidney function: Serum creatinine value < 1.5 ULN. If subject's serum creatinine value is ≥ 1.5 x ULN, his/her creatinine clearance value should be > 40 mL/min based on Cockcroft and Gault formula.
• Subject, if female of child-bearing potential, must agree to avoid sexual intercourse or be willing to use 2 medically accepted methods of contraception (e.g., Intra-uterine device or contraceptives) during the study. 【The definition of infertile：(1) Being menopause for more than 1 year；(2) Surgery for permanent contraception (e.g., abdominal tubal sterilization, bilateral Salpingooophorectomy, and tubectomy)；(3) Congenital structural abnormalities.】
• Subject, if male, agrees not to donate sperm, be willing to avoid sexual intercourse or use appropriate contraception method (e.g., using condom) during the study treatment period.
• Subject is active and capable to communicate with site staff, willing to be in compliance with the following two items based on investigator's judgment.

• To complete return visits and study examination per the study protocol.
• To collect stool specimens at home, refrigerate and deliver the sample.

Exclusion criteria

• Presence of any symptomatic central nervous system metastasis or leptomeningeal metastasis.
• Presence of any other malignant tumor. Unless the subject had completed radical treatment without any disease recurrence for at least 3 years. (Those who have successfully undergone radical resection or have received possible curative treatments for basal cell carcinoma, superficial bladder cancer, squamous-cell carcinoma, cervical intraepithelial neoplasia or other carcinoma in situ are not limited)
• Presence of any autoimmune disease which requires systemic treatment within the past 2 years. Hormone replacement therapy (for example, insulin or physiological replacement of corticosteroid due to adrenal or pituitary disorders… etc.) is allowed and not considered as systemic treatment.
• Have had any transplantation of allogeneic cell, tissue or solid organ.
• History of known human immunodeficiency virus (HIV) infection.
• Hepatitis B surface antigen (HBsAg) is positive or hepatitis B virus (HBV) DNA viral load is ≥ 500 IU/mL.Or Hepatitis C virus (HCV) antibody is positive and hepatitis C virus (HCV) ribonucleic acid (RNA) is also positive.
• Subject has non-infectious pneumonia history which requires systemic steroids. Subject who currently have interstitial pneumonia or interstitial pneumonitis can join this study if investigator confirms subject's clinical condition is stable.
• Presence of any severe cardiac dysfunction, Class III-IV of chronic heart failure based on New York Heart Association (NYHA) Functional Classification, which includes symptomatic coronary artery disease and severe ventricular arrhythmia; Presence of any myocardial infarction, unstable or poorly controlled angina within 6 months before subject screening visit (V0).
• Have any gastrointestinal history or surgery which investigator believes may affect the absorption of the oral investigational product.
• Enterocutaneous or non- enterocutaneous fistula which is defined as Grade 3 or above based on Common Terminology Criteria for Adverse Events (CTCAE, also known as Common Toxicity Criteria).
• Currently presence of inflammatory bowel disease or gastric ulcer.
• Have not yet recovered from major surgery or complications before subject screening visit(V0).
• History of active tuberculosis (TB, Mycobacterium tuberculosis).
• Presence of any mental disease or drug abuse disorder which may interfere with subject's ability for being compliant with study requirements.
• Active infection which requires systemic treatment.
• Allergies to soy products, severe allergies to antibody therapy, or known allergies or intolerances to any component of pembrolizumab.
• Have received any biologic therapy within 3 weeks prior to the first dose of trial therapy.
• Have received anti-PD-1, anti-PD-L1, or anti-PD-L2 drug therapy within 3 years before the screening visit (V0) or act on another drug treatment that stimulates signals or synergistically inhibits T cell receptors (e.g. CTLA-4 , OX 40, CD137).
• Received radiotherapy within the 14 days before receiving the investigational drug, or received pulmonary radiotherapy> 30 Gy within 6 months before receiving the investigational drug (the subject must recover from all radiation-related toxicities to grade 1 or below, without corticosteroid therapy and radiation pneumonia has never occurred).
• Diagnosed with immunodeficiency or are receiving any form of immunosuppressive therapy, systemic steroids (allowed to use up to 10 mg Prednisone or equivalent steroids per day) within 7 days before receiving the investigational drug.
• Those who have received live-virus vaccines within 30 days before receiving the investigational drug or are expected to receive live-virus vaccines during the study period.
• Have used antibacterial drugs including antibiotics and synthetic drugs (such as sulfonamides, quinolones), antifungal or antiviral drugs (not including topical medication) within the 14 days before receiving the investigational drug.
• Use probiotics and probiotic-related products within 14 days before receiving this test drug (e.g. yogurt, yogurt, Yakult, probiotic fermented beverages, Wakamoto tablets, Shin Biofermin S tablets, inulin, oligosaccharide products).
• Have used laxatives (such as MgO, Bisacodyl, Sennoside, Lactulose) within the 14 days before receiving the investigational drug.
• Those who have had gastrointestinal infection and diarrhea within the 14 days before receiving the investigational drug (soft or watery stools more than three times within 24 hours).
• Women who are pregnant, breastfeeding or expect to breastfeed during the study period.
• Currently participating in clinical trials of other investigational product treatments, medical devices, health foods, or cosmetics.
• Subjects who judged by the investigator to be unsuitable to participate in the trial.