• Time to progression (TTP) [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]
  TTP is defined as the period elapsing between the date of randomization and the date of disease progression.
• Overall survival (OS) [ Time Frame: at randomization, then at the end of every two cycle (i.e. approximately every 8 weeks), until death from any cause. Assessed up to 24 months. ]
  OS is defined as the interval between time of randomization and the date of death from any cause.
• Objective response rate (ORR) in each arm [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]
  The Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) will be used to establish disease response or progression
• Disease control rate (DCR) in each arm [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]
  DCR will be defined as the proportion of patients achieving either partial response (PR) or complete response (CR) or stable disease (SD).
• The safety and tolerability of the combination of YIV-906 plus sorafenib as measured by the rate and severity of AEs [ Time Frame: Continuously throughout the study until 28 days after treatment discontinuation ]
  All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 5.0 (CTCAE).
• Change of quality of life (QoL) in each arm with HCC18 [ Time Frame: At the beginning of every course (4 weeks) until the end of study. Assessed up to 24 months. ]
  Each of the domains in the HCC18 will be scored per the assessment's scoring algorithm and summarized using descriptive statistics at baseline
• Change of quality of life (QoL) in each arm with EORTC-C30 [ Time Frame: At the beginning of every course (4 weeks) until the end of study. Assessed up to 24 months. ]
  Each of the domains in the EORTC QLQ-C30 will be scored per the assessment' scoring algorithm and summarized using descriptive statistics at baseline
• Effects of YIV-906 on mean Cmax (mg/mL) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1 (4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
• Effects of YIV-906 on mean Tmax (Hr) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
• Effects of YIV-906 on mean AUC0-24(mg*h/L) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
• Effects of YIV-906 on mean AUC from time 0 to the end of the dosing period AUC0-tau (mg*h/L) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
• Effects of YIV-906 on mean t½ (Hr) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites.

• Time to progression (TTP) [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]
  TTP is defined as the period elapsing between the date of randomization and the date of disease progression.
• Overall survival (OS) [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]
  OS is defined as the interval between time of randomization and the date of death from any cause.
• Objective response rate (ORR) in each arm [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]
  The modified Response Evaluation Criteria in Solid Tumors (mRECIST) will be used to establish disease response or progression
• Disease control rate (DCR) in each arm [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]
  DCR will be defined as the proportion of patients achieving either partial response (PR) or complete response (CR) or stable disease (SD).
• The safety and tolerability of the combination of YIV-906 plus sorafenib as measured by the rate and severity of AEs [ Time Frame: Continuously throughout the study until 28 days after treatment discontinuation ]
  All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 4.0 (CTCAE).
• Change of quality of life (QoL) in each arm with HCC18 [ Time Frame: At baseline and then at end of every course (4 weeks) until the end of study. Assessed up to 24 months. ]
  Each of the domains in the HCC18 will be scored per the assessment's scoring algorithm and summarized using descriptive statistics at baseline
• Change of quality of life (QoL) in each arm with EORTC-C30 [ Time Frame: At baseline, and then at the end of every course (4 weeks) until the end of study. Assessed up to 24 months. ]
  Each of the domains in the EORTC QLQ-C30 will be scored per the assessment' scoring algorithm and summarized using descriptive statistics at baseline
• Correlation of cytokines levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
  Using a series of biomarker analysis for cytokines, including G-CSF and MCP1 proteins in the plasma
• Correlation of circulating mutated DNA levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
  Using a series of biomarker analysis for circulating mutated DNA
• Correlation of chemokines levels (pg/mL) with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
  Using a series of biomarker analysis for chemokines, including: IL-2, IL-4, IL-5, IL-10, TNF-α, IFN-γ
• Correlation of Alpha-feto-protein levels(ng/mL) with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
  Using a series of biomarker analysis for alpha-feto-protein
• Correlation of HBV serologic markers levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
  Using a series of biomarker analysis for HBV serologic markers
• Correlation of HBV viral load (IU/mL) levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
  Using a series of biomarker analysis for HBV viral load
• Correlation of plasma metabolomics levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
  Using a series of biomarker analysis for plasma metabolomics
• Effects of YIV-906 on mean Cmax (mg/mL) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1 (4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
• Effects of YIV-906 on mean Tmax (Hr) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
• Effects of YIV-906 on mean AUC0-24(mg*h/L) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
• Effects of YIV-906 on mean AUC from time 0 to the end of the dosing period AUC0-tau (mg*h/L) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio).
• Effects of YIV-906 on mean t½ (Hr) of sorafenib in blood [ Time Frame: On Day 1 of Cycle 1(4 week/28 days), PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration. ]
  PK is optional and limited to the first 15 male and 15 female patients from China study sites.
• The amounts of E.coli of the human gastrointestinal tract in comparison with efficacy and toxicity in each arm, both pre-, post-treatments and control arm [ Time Frame: At baseline, and then at the end of every course (4 weeks) until the end of study. Assessed up to 24 months. ]
  Samples will be collected from patients' buccal mucosa, and upper gingival; and analyzed by NGS and RT-PCR

The aim of this study is to compare the efficacy and safety of YIV-906 plus standard-of-care sorafenib versus those of sorafenib alone as a first-line systemic treatment for patients with Hepatitis B (+) associated advanced hepatocellular carcinoma.

YIV-906 (PHY906, KD018) is an immune system modulator. Clinical and preclinical research suggests that YIV-906 could act to enhance the body's immune response to fight cancer and increase the anti-tumor activity of sorafenib and protect and repair the gastrointestinal tract by reducing inflammation and promoting tissue regeneration.

Inspired by a 1,800-year-old traditional medicine still in use today, YIV-906 is a botanical drug candidate, composed of an extract of four herbs and administered in oral capsule form.

The CALM (Combination of YIV-906 and Sorafenib to treat Advanced Liver cancer in a Multi-center study) trial is a multi-regional, randomized, placebo-controlled study.

HCC patients with chronic HBV (+) (HBsAg(+) and IgM anti-HBc (-)), and Child-Pugh A status will be randomized to either the study arm (YIV-906 plus sorafenib) or control arm (placebo plus sorafenib) at ratio of 2:1. Patients will be stratified according to metastatic status (extrahepatic/vascular invasion vs. none), and their ECOG performance status (0 vs. 1) at randomization.

• ARM I: Patients receive Placebo + Sorafenib
• ARM II: Patients receive YIV-906+ Sorafenib

Patients in the study arm will be treated orally each 28-day course with YIV-906 (600 mg (3 capsules) BID) + sorafenib (400 mg BID) according to the following schedule: sorafenib BID daily treatment for 28 days, and YIV-906 BID 4 days on and 3 days off weekly in each course.

All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 5.0 (CTCAE). The Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) will be used to establish disease response or progression.

Patients will be evaluated for PFS, TTP, OS, antitumor response every two cycles, and QoL and safety at the beginning of each cycle. Biomarkers are mandatory and will be studied prior to drug administration on day 1 of each cycle. Gut and oral microbiota studies as well as TCM Syndrome Research are optional.

PK is only optional in China study sites, and limited to the first 15 male and 15 female patients. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio). PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration on Day 1 of Cycles 1.

• Drug: YIV-906+Sorafenib
  Patients will be treated orally for 28-day courses with YIV-906 (600 mg (3 capsules) BID) + sorafenib (400 mg BID) according to the following schedule: sorafenib BID daily treatment for 28 days, and YIV-906 BID 4 days on and 3 days off weekly in each course.
• Drug: Placebo+Sorafenib
  Patients will be given sorafenib (400 mg BID) daily for 28-day course with placebo (3 capsules, BID) 4 days on and 3 days off weekly in each course.

• Experimental: Sorafenib + YIV-906
  Patients in the study arm will be treated orally for 28-day courses with YIV-906 + sorafenib
  Intervention: Drug: YIV-906+Sorafenib
• Active Comparator: Sorafenib + Placebo
  Patients in the placebo arm will be given sorafenib with placebo
  Intervention: Drug: Placebo+Sorafenib

• Lam W, Ren Y, Guan F, Jiang Z, Cheng W, Xu CH, Liu SH, Cheng YC. Mechanism Based Quality Control (MBQC) of Herbal Products: A Case Study YIV-906 (PHY906). Front Pharmacol. 2018 Nov 19;9:1324. doi: 10.3389/fphar.2018.01324. eCollection 2018.
• Chu E. Wedding Rigorous Scientific Methodology and Ancient Herbal Wisdom to Benefit Cancer Patients: The Development of PHY906. Oncology (Williston Park). 2018 Feb 15;32(2):e20-e27. Review.
• Lam W, Jiang Z, Guan F, Huang X, Hu R, Wang J, Bussom S, Liu SH, Zhao H, Yen Y, Cheng YC. PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment. Sci Rep. 2015 Mar 30;5:9384. doi: 10.1038/srep09384.
• Rockwell S, Grove TA, Liu Y, Cheng YC, Higgins SA, Booth CJ. Preclinical studies of the Chinese Herbal Medicine formulation PHY906 (KD018) as a potential adjunct to radiation therapy. Int J Radiat Biol. 2013 Jan;89(1):16-25. doi: 10.3109/09553002.2012.717733. Epub 2012 Sep 3.
• Liu SH, Cheng YC. Old formula, new Rx: the journey of PHY906 as cancer adjuvant therapy. J Ethnopharmacol. 2012 Apr 10;140(3):614-23. doi: 10.1016/j.jep.2012.01.047. Epub 2012 Feb 3. Review.
• Wang E, Bussom S, Chen J, Quinn C, Bedognetti D, Lam W, Guan F, Jiang Z, Mark Y, Zhao Y, Stroncek DF, White J, Marincola FM, Cheng YC. Interaction of a traditional Chinese Medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment. BMC Med Genomics. 2011 May 11;4:38. doi: 10.1186/1755-8794-4-38.
• Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, Liu SH, Cheng YC. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med. 2010 Aug 18;2(45):45ra59. doi: 10.1126/scitranslmed.3001270.
• Saif MW, Li J, Lamb L, Kaley K, Elligers K, Jiang Z, Bussom S, Liu SH, Cheng YC. First-in-human phase II trial of the botanical formulation PHY906 with capecitabine as second-line therapy in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol. 2014 Feb;73(2):373-80. doi: 10.1007/s00280-013-2359-7. Epub 2013 Dec 3.
• Kummar S, Copur MS, Rose M, Wadler S, Stephenson J, O'Rourke M, Brenckman W, Tilton R, Liu SH, Jiang Z, Su T, Cheng YC, Chu E. A phase I study of the chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer. Clin Colorectal Cancer. 2011 Jun;10(2):85-96. doi: 10.1016/j.clcc.2011.03.003. Epub 2011 Apr 22.
• Saif MW, Lansigan F, Ruta S, Lamb L, Mezes M, Elligers K, Grant N, Jiang ZL, Liu SH, Cheng YC. Phase I study of the botanical formulation PHY906 with capecitabine in advanced pancreatic and other gastrointestinal malignancies. Phytomedicine. 2010 Mar;17(3-4):161-9. doi: 10.1016/j.phymed.2009.12.016. Epub 2010 Jan 22.
• Yen Y, So S, Rose M, Saif MW, Chu E, Liu SH, Foo A, Jiang Z, Su T, Cheng YC. Phase I/II study of PHY906/capecitabine in advanced hepatocellular carcinoma. Anticancer Res. 2009 Oct;29(10):4083-92.
• Farrell MP, Kummar S. Phase I/IIA randomized study of PHY906, a novel herbal agent, as a modulator of chemotherapy in patients with advanced colorectal cancer. Clin Colorectal Cancer. 2003 Feb;2(4):253-6.

Inclusion Criteria:

• Male or females ≥ 18 years old with the ability to take oral drugs
• Diagnosis of advanced HCC according to the American Association for the Study of Liver Diseases (AASLD) Guidelines (Heimbach et al. 2018) or diagnosis by tissue pathology
• Life expectancy of at least 3 months
• Presence of chronic hepatitis B (HBsAg (+) and IgM anti-HBc (-))
• Never received systemic antitumor therapy

• Patients must have at least one tumor lesion that meets both of the following criteria:

  • "Measurable disease" according to RECIST 1.1 , i.e. at least one measurable lesion.
  • Advanced unresectable HCC that have liver limited disease who have failed or not candidates to local therapies including surgery and local-regional therapies; or patients with extrahepatic disease.
• Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• Cirrhotic status of current Child-Pugh class A. Child-Pugh status should be calculated based on clinical findings and laboratory results during the screening period
• For patients with positive HBV-DNA and/or positive HBsAg results, they must be treated with antivirals (per local standard of care), as prophylaxis starting at least 1-2 weeks prior to receiving study drug and willingness to continue treatment for the length of the study.

• Patients with adequate organ reserve, such as laboratory parameters:

  • Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L
  • Platelets ≥ 60000 x 10^6/L
  • Hemoglobin (Hgb) ≥ 9 g/dL
  • Serum alanine amino-transferase (ALT) ≤ 5 x ULN

• Adequate renal function, based upon meeting the following laboratory criteria within 7 days before randomization:

  • Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40mL/min (using the Cockroft-Gault equation: (140-age) x weight (kg)/(serum creatinine x 72 [mg/dL] for males. (For females multiply by 0.85) AND
  • 24-hour urine protein <1 g
• Ability to understand and willingness to sign a written informed consent and to be able to follow the visit schedule

Exclusion Criteria:

• Patients who ever have HCV infection
• Patients who have received systemic chemo-therapies or immunotherapy or molecular target therapies
• Patients who have received any local anti-cancer therapy within 4 weeks prior to Cycle 1 treatment
• Active bleeding (including gastrointestinal bleeding, encephalopathy, and ascites) during the last 4 weeks prior to Cycle 1 treatment
• Patients with a history of allergy to the known components of YIV-906
• Known history of human immunodeficiency virus (HIV) seropositivity
• Known central nervous system metastasis including brain metastasis and meningeal carcinomatosis
• Hepatocholangiocarcinoma, fibrolamellar cell carcinoma and mixed hepatocellular carcinoma
• Active malignancy (except for definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 5 years

• Any severe and/or uncontrolled medical conditions including but not limiting to:

  • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to Cycle 1 treatment, serious uncontrolled cardiac arrhythmia, uncontrolled hypertension
  • Previous transient ischemic attack (TIA), cerebral vascular accident (CVA), symptomatic peripheral vascular disease (PVD) within last 6 months of Cycle 1 treatment
  • Congenital long QT syndrome
  • Alcoholic patients
  • Acute and chronic, active infectious disorders and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study therapy, in the opinion of the investigator, except chronic HBV
  • Impairment of gastrointestinal function or who have a gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
  • Patients who have had organ transplantation
• Patients receiving chronic treatment with corticosteroids (except for intermittent topical or local injection or aldosterone) or other immunosuppressive agent Subjects receive any blood transfusion, albumin transfusion, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), TPO or other medical supportive treatment prior to Cycle 1 treatment
• Patients treated with drugs known to be strong inducers of isoenzyme CYP3A within 7 days of Cycle 1 treatment
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from surgery
• Patients who have received an investigational drug or therapy within the last 4 weeks prior to Cycle 1 treatment.
• Pregnant and/or breastfeeding women
• Men and women of childbearing age and potential, who are not willing to use effective contraception
• Unwilling or unable to follow protocol requirements or to give informed consent
• An ongoing or recent history of autoimmune, uncontrolled psychiatric disorders and drug abuse
• Uncontrolled hereditary or acquired thrombotic or bleeding disorder
• Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection
• Therapeutic dose anticoagulation with warfarin or similar agents
• Chronic therapy with nonsteroidal anti-inflammatory agents or other antiplatelet agents. Aspirin at doses up to 100 milligrams/day is permitted
• Patients with an estimated or calculated baseline creatinine clearance of less than 40 mL/min should not be enrolled in this trial
• No patient, however, may enroll in this trial if they are taking phenytoin (Dilantin)
• Patients taking traditional Chinese medicines within 14 days prior to taking first dose of study treatment