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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Randomized Placebo-Controlled Study Investigating The Combination Of YIV-906 And Sorafenib (Nexavar®) In HBV (+) Patients With Advanced Hepatocellular Carcinoma

Conditions
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Advanced Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: YIV-906+Sorafenib
* Drug: Placebo+Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or females ≥18 years old with ability to take oral drugs 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 Participants categorized to stage B or C based on Barcelona Clinic Liver Cancer (BCLC) staging system Life expectancy of at least 3 months Presence of chronic hepatitis B (HBsAg (+)) Never received systemic antitumor therapy Patients must have at least one tumor lesion that meets both of the following criteria: Measurable disease according to RECIST1.1, i.e. at least one measurable lesion. Advanced unresectable HCC that have liver limited disease who have failed and are not candidates to local 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 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 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 Serum Aspartate transaminase (AST) ≤ 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 Cockcroft-Gault equation: (140-age) x weight (kg)/ (serum creatinine x 72 [mg/dL] for males. (For females multiply by 0.85) AND Urine protein/creatine ratio (UPCR) ≤ 1 mg/mg (≤113.1 mg/mmol) or 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: Patient who has any of the following criteria will be excluded from the trial: Patients who ever have HCV infection Patients who have received systemic chemotherapies or immunotherapy or molecular target therapies or anticancer Chinese medicine Cinobufacini Patients who have received any local anti-cancer therapy within 4 weeks prior to Cycle 1 treatment Active bleeding (including gastrointestinal bleeding) 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: 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 the complications of this study therapy, in the opinion of the investigator, except chronic HBV 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) Patients who have had organ transplantation 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). 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 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 investigative 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 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 anti-platelet agents. Aspirin at doses up to 100 milligrams/day is permitted 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib + YIV-906<br>Patients in the study arm will be treated orally for 28-day courses with YIV-906 + sorafenib | Drug: YIV-906+Sorafenib<br>* Patients will be given sorafenib (400 mg BID) daily for a 28-day course with YIV-906 (3 capsules, BID) 4 days on and 3 days off weekly in each course.<br>|
| Active Comparator: Sorafenib + Placebo<br>Patients in the placebo arm will be given sorafenib with placebo | Drug: Placebo+Sorafenib<br>* Patients will be given sorafenib (400 mg BID) daily for a 28-day course with placebo (3 capsules, BID) 4 days on and 3 days off weekly in each course.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | PFS is defined as the period elapsing between the date of date of randomization and the date of either disease progression or date of death, whichever is earlier. | 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. | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Advanced Adult Hepatocellular Carcinoma, BCLC Stage B Adult Hepatocellular Carcinoma, BCLC Stage C Adult Hepatocellular Carcinoma, Hepatitis B (+) Associated Advanced Hepatocellular Carcinoma, Child-Plough A Hepatocellular Carcinoma