Safety and Potential Efficacy of MS-20 In Combination With Pembrolizumab for the Treatment of NSCLC

Study Overview
=================
Brief Summary
-----------------
MS-20 was approved as the first oral cancer adjuvant new drug indicated for ameliorating fatigue and appetite loss associated with cancer chemotherapy via reshaping human gut ecosystem and restoring immunity. MS-20 has also been shown to be anti-PD-1 booster by activating tumor-infiltrating lymphocytes (TILs) in mice cancer models, particularly promoting migration of TILs into tumors and increasing the amount of TILs inside tumors. Therefore, this study is designed to explore the safety and relationship between gut microbiome and potential clinical outcomes in NSCLC patients under combination therapy with pembrolizumab and MS-20.

Official Title
-----------------
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

Conditions
-----------------
NSCLC Stage IV

Intervention / Treatment
-----------------
* Drug: MS-20
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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], it is classified as metastatic stage IV NSCLC. The subject with metastatic non-small cell lung cancer whose EGFR/ALK/ROS 1 tumor gene is wild 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 x 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 a female of child-bearing potential, must agree to completely abstain from sexual intercourse or be willing to use appropriate 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 Salpingo-Oophorectomy, 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 a 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. (1) To complete return visits and study examination per the study protocol. (2) To collect stool specimens at home, refrigerate and deliver the sample. Exclusion Criteria: Presence of any symptomatic central nervous system metastasis or leptomeningeal metastasis which has not been treated or is under disease progression. For subjects with brain metastasis who have been treated and confirmed as stable per radiology diagnosis, which means no evidence of disease progression based on repeated CT scan with at least a 4-week window period (Note: The repeated angiography should be within the study screening period and before receiving the investigational drug), could be enrolled if his/her clinical condition is stable and not using steroid treatment for at least 14 days before study treatment. 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 cells, 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. 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 or who currently have interstitial pneumonia or interstitial pneumonitis. 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 6months before subject screening visit (V0). Have any gastrointestinal history or surgery which the 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 that 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 previously received systemic chemotherapy or other targeted or biological anti-tumor treatments for metastatic NSCLC. 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 prebiotics-related products within 14 days before receiving the investigational drug. (e.g., yogurt drink, yogurt, Yakult, probiotic fermented beverages, Wakamoto tablets, Shin Biofermin S tablets, inulin, oligosaccharide products, etc.) 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.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MS-20 oral solution<br>Oral Solution 8 c.c per day divided twice daily (BID) for 48 weeks. | Drug: MS-20<br>* Fermented soybean extract MicrSoy-20(MS-20), which uses a variety of lactic acid bacteria and yeasts to metabolize organic soybeans<br>* Other names: Chemo young;|
| Placebo Comparator: Placebo<br>Oral Solution 8 c.c per day divided twice daily (BID) for 48 weeks. | Drug: Placebo<br>* Oral solution without active ingredients<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of treatment-emergent adverse event (TEAE) |  | Up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Assessed according to RECIST v1.1 | 48 week | 
| Progression Free Survival (PFS) | Assessed according to RECIST v1.1 | 48 week | 
| Disease Control Rate (DCR) | Assessed according to RECIST v1.1 | 48 week | 
| Duration of Response (DOR) | Assessed according to RECIST v1.1 | 48 week | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NSCLC, MS-20, Add-on, pembrolizumab, metastatic, microbiome, microbiota