YIV-906 (Formerly PHY906/KD018) With Sorafenib in HBV(+) Hepatocellular Carcinoma (HCC)

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 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.

The RECIST 1.1 and mRECIST will be used in a blinded independent central review (BICR) to determine the study endpoints.

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. TCM Syndrome Research is optional.

PK is only applicable in China study sites and limited to the first 15 male and 15 female patients. Patients will be randomized to either the study drug arm or the 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.

Eligibility Criteria:
Inclusion Criteria:

1. Male or females ≥18 years old with ability to take oral drugs
2. Diagnosis of advanced (locally advanced or metastatic) unresectable/inoperable HCC according to the American Association for the Study of Liver Diseases (AASLD) Guidelines (Heimbach et al. 2018) or diagnosis by tissue pathology
3. Participants categorized to stage B or C based on Barcelona Clinic Liver Cancer (BCLC) staging system
4. Life expectancy of at least 3 months
5. Presence of chronic hepatitis B (HBsAg (+))
6. Never received systemic antitumor therapy
7. Patients must have at least one tumor lesion that meets both of the following criteria:

   1. "Measurable disease" according to RECIST1.1, i.e. at least one measurable lesion.
   2. Advanced unresectable HCC that have liver limited disease who have failed and are not candidates to local therapies; or patients with extrahepatic disease.
8. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
9. 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
10. For patients with positive HBV-DNA and positive HBsAg, they must be treated with anti-HBV treatment (per local standard of care), as prophylaxis starting at least 1-2 weeks prior to receiving study drug and willing to continue treatment for the length of the study
11. Patients with adequate organ reserve, such as laboratory parameters:

    1. Absolute Neutrophil Count (ANC) ≥ 1.5 x 10\^9/L
    2. Platelets ≥ 60000 x 10\^6/L
    3. Hemoglobin (Hgb) ≥ 9 g/dL
    4. Serum alanine amino-transferase (ALT) ≤ 5 x ULN
    5. Serum Aspartate transaminase (AST) ≤ 5 x ULN
12. Adequate renal function, based upon meeting the following laboratory criteria within 7 days before randomization:

    1. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40mL/min (using the Cockcroft-Gault equation: (140-age) x weight (kg)/ (serum creatinine x 72 \[mg/dL\] for males. (For females multiply by 0.85) AND
    2. Urine protein/creatine ratio (UPCR) ≤ 1 mg/mg (≤113.1 mg/mmol) or 24-hour urine protein \<1 g
13. Ability to understand and willingness to sign a written informed consent and to be able to follow the visit schedule

Exclusion Criteria:

Patient who has any of the following criteria will be excluded from the trial:

1. Patients who ever have HCV infection
2. Patients who have received systemic chemotherapies or immunotherapy or molecular target therapies or anticancer Chinese medicine Cinobufacini
3. Patients who have received any local anti-cancer therapy within 4 weeks prior to Cycle 1 treatment
4. Active bleeding (including gastrointestinal bleeding) during the last 4 weeks prior to Cycle 1 treatment
5. Patients with a history of allergy to the known components of YIV-906
6. Known history of human immunodeficiency virus (HIV) seropositivity
7. Known central nervous system metastasis including brain metastasis and meningeal carcinomatosis
8. Hepatocholangiocarcinoma, fibrolamellar cell carcinoma and mixed hepatocellular carcinoma
9. 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
10. Any severe and/or uncontrolled medical conditions including but not limiting:

    1. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to Cycle 1 treatment, serious uncontrolled cardiac arrhythmia, uncontrolled hypertension
    2. Previous transient ischemic attack (TIA), cerebral vascular accident (CVA), symptomatic peripheral vascular disease (PVD) within last 6 months of Cycle 1 treatment
    3. Congenital long QT syndrome
    4. Alcoholic patients
    5. Acute and chronic, active infectious disorders and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy, in the opinion of the investigator, except chronic HBV
    6. Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
    7. Patients who have had organ transplantation
11. Patients receiving chronic treatment with corticosteroids (except for intermittent topical or local injection of aldosterone) or other immunosuppressive agents (oral prednisone or equivalent 10 mg/day is allowed to screen).
12. Patients received any blood transfusion, albumin transfusion, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), TPO or other medical supportive treatment within 4 weeks of Cycle 1 treatment
13. Patients treated with drugs known to be strong inducers of isoenzyme CYP3A within 7 days of Cycle 1 treatment
14. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from surgery
15. Patients who have received an investigative drug or therapy within the last 4 weeks prior to Cycle 1 treatment
16. Pregnant and/or breastfeeding women
17. Men and women of childbearing age and potential, who are not willing to use effective contraception
18. Unwilling or unable to follow protocol requirements or to give informed consent
19. Ongoing or recent history of autoimmune, uncontrolled psychiatric disorders and drug abuse
20. Uncontrolled hereditary or acquired thrombotic or bleeding disorder
21. Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection
22. Therapeutic dose anticoagulation with warfarin, or similar agents
23. Chronic therapy with nonsteroidal anti-inflammatory agents or other anti-platelet agents. Aspirin at doses up to 100 milligrams/day is permitted
24. No patient, however, may enroll in this trial if they are taking phenytoin (Dilantin)
25. Patients taking traditional Chinese medicines within 14 days prior to taking first dose of study treatment