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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
62
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.
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.
Calvin Pan. MD Gastroenterology & Hepatology Clinic
Flushing, New York, United States
Northwell Monter Cancer Institute
Lake Success, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
University Hospitals Cleveland Medical Center
Cleveland, Ohio, United States
Beijing You'An Hospital, Capital Medical University
Beijing, Beijing Municipality, China
Cancer Hospital Chinese Academy of Medical Sciences
Beijing, Beijing Municipality, China
China-Japan Friendship Hospital
Beijing, Beijing Municipality, China
Foshan Hospital of Traditional Chinese Medicine
Foshan, Guangdong, China
Guangdong Provincial Hospital of Traditional Chinese Medicine
Guangzhou, Guangdong, China
The First Affiliated Hospital, Sun Yat-Sen University
Guangzhou, Guangdong, China
...and 14 more locations
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.
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.
Time to progression (TTP)
TTP is defined as the period elapsing between the date of randomization and the date of disease progression.
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.
Overall survival (OS)
OS is defined as the interval between time of randomization and the date of death from any cause.
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.
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
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.
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).
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 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).
Time frame: 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
Time frame: 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
Time frame: 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).
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.
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).
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.
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).
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.
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).
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.
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.
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.
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