Advanced Hepatocellular CarcinomaPhase 2NCT04000737
YIV-906 (Formerly PHY906/KD018) With Sorafenib in HBV(+) Hepatocellular Carcinoma (HCC)
A Phase 2 study testing Sorafenib+YIV-906 in people with Advanced Hepatocellular Carcinoma, run by Yiviva Inc. at 24 sites in 4 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Hepatocellular Carcinoma
- What is being tested?
- Sorafenib+YIV-906
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 62 participants
- Where
- 24 sitesin 4 countries
- Study dates
- 10 Jan 2020to 19 Nov 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 22Show fewer
- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
24 sites in 4 countries.
24 sites in 4 countries
China12 sites
Beijing You'An Hospital, Capital Medical University
Beijing, Beijing Municipality
Cancer Hospital Chinese Academy of Medical Sciences
Beijing, Beijing Municipality
China-Japan Friendship Hospital
Beijing, Beijing Municipality
Hunan Cancer Hospital
Changsha, Hunan
Foshan Hospital of Traditional Chinese Medicine
Foshan, Guangdong
Guangdong Provincial Hospital of Traditional Chinese Medicine
Guangzhou, Guangdong
The First Affiliated Hospital, Sun Yat-Sen University
Guangzhou, Guangdong
The First Affiliated Hospital of Guangxi Medical University
Nanning, Guangxi
LongHua Hospital Shanghai University of Traditional Chinese Medicine
Shanghai, Shanghai Municipality
Shanghai Eastern Hepatobiliary Hospital
Shanghai, Shanghai Municipality
Shanghai University of Traditional Chinese Medicine Shuguang Hospital
Shanghai, Shanghai Municipality
Shenzhen People's Hospital
Shenzhen, Guangdong
Taiwan7 sites
China Medical University Hospital
Taichung
National Cheng Kung University Hospital
Tainan
Cancer Research Center, Taipei Municipal Wanfang Hospital
Taipei
Taipei Medical University -Shuang Ho Hospital, Ministry of Health and Welfare
Taipei
Taipei Medical University Cancer Center
Taipei
Taipei Veterans General Hospital
Taipei
Chang Gung Memorial Hospital, Linkou
Taoyuan
United States4 sites
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
Calvin Pan. MD Gastroenterology & Hepatology Clinic
Flushing, New York, 11355
Northwell Monter Cancer Institute
Lake Success, New York, 11042
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
About this study
Official title: A Phase II Randomized Placebo-Controlled Study Investigating The Combination Of YIV-906 And Sorafenib (Nexavar®) In HBV (+) Patients With Advanced Hepatocellular Carcinoma
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.
Read more
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.
Read the detailed description
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.
- Conditions
- Advanced Hepatocellular Carcinoma
- Being tested
- Sorafenib+YIV-906, Sorafenib+placebo
- Keywords
- 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
- Medical subject headings
- Carcinoma, Hepatocellular, Hepatitis B
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sorafenib+YIV-906Drug
Also called PHY906, KD018
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.
Sorafenib+placeboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Sorafenib + YIV-906 | Experimental | Patients in the study arm will be treated orally for 28-day courses with YIV-906 + sorafenib Receives: Drug: Sorafenib+YIV-906 |
| Sorafenib + Placebo | Active comparator | Patients in the placebo arm will be given sorafenib with placebo Receives: Drug: Sorafenib+placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 outcomes (12)
Time to progression (TTP)
TTP is defined as the period elapsing between the date of randomization and the date of disease progression.
Measured: 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.
Measured: 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
Measured: 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).
Measured: 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).
Measured: 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
Measured: 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
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2019
- Study start10 Jan 2020
- Primary completion22 Mar 2024
- Study completion19 Nov 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Advanced Hepatocellular CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yiviva Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Yun Yen, MD/PhD, Study chair, Taipei Medical UniversityGhassan Abou-Alfa, MD/MBA, Study chair, Memorial Sloan Kettering Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04000737
- Sponsor's protocol ID
- YIV-906-2018L1
- Status last verified
- Apr 2025
- First submitted
- 13 Jun 2019
- Last updated
- 13 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
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.
PubMed 30510512Chu 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.
PubMed 29492950Lam 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.
PubMed 25819872Rockwell 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.
PubMed 22856538Liu 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.
PubMed 22326673Wang 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.
PubMed 21569348Lam 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.
PubMed 20720216Saif 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.
PubMed 24297682Kummar 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.
PubMed 21859559Saif 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.
PubMed 20092990Yen 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.
PubMed 19846955Farrell 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. doi: 10.3816/CCC.2003.n.007. No abstract available.
PubMed 12620148
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Randomized Placebo-Controlled Study Investigating The Combination Of YIV-906 And Sorafenib (Nexavar®) In HBV (+) Patients With Advanced Hepatocellular Carcinoma
- ClinicalTrials.gov ID
- NCT04000737
- Acronym / sponsor ID
- YIV-906-2018L1
- Conditions
- Advanced Hepatocellular Carcinoma
- Keywords
- 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
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- Yiviva Inc.Industry (pharma, biotech, devices)
- Study start
- 10 Jan 2020 (actual)
- Primary completion
- 22 Mar 2024 (actual)
- Study completion
- 19 Nov 2024 (actual)
- First posted
- 27 Jun 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sorafenib + YIV-906 | Experimental | Drug: Sorafenib+YIV-906Patients in the study arm will be treated orally for 28-day courses with YIV-906 + sorafenib |
| Sorafenib + Placebo | Active comparator | Drug: Sorafenib+placeboPatients in the placebo arm will be given sorafenib with placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- 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 (+))
Key exclusion criteria (33 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sorafenib+YIV-906Also: PHY906, KD018Patients 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. | Drug | Sorafenib + YIV-906 |
| Sorafenib+placeboPatients 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. | Drug | Sorafenib + Placebo |
Primary outcome
Progression free survival (PFS)
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.
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.
12 secondary outcomes
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2025.
- Background: PubMed 30510512Lam 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.
- Background: PubMed 29492950Chu 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.
- Background: PubMed 25819872Lam 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.
- Background: PubMed 22856538Rockwell 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.
- Background: PubMed 22326673Liu 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.
- Background: PubMed 21569348Wang 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.
- Background: PubMed 20720216Lam 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.
- Results publication: PubMed 24297682Saif 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.
- Results publication: PubMed 21859559Kummar 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.
- Results publication: PubMed 20092990Saif 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.
- Results publication: PubMed 19846955Yen 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.
- Results publication: PubMed 12620148Farrell 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. doi: 10.3816/CCC.2003.n.007. No abstract available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yun Yen, MD/PhD study chair
Taipei Medical University
Ghassan Abou-Alfa, MD/MBA study chair
Memorial Sloan Kettering Cancer Center
24 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sorafenib+YIV-906 in people with Advanced Hepatocellular Carcinoma, run by Yiviva Inc. at 24 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 24 sites in China, Taiwan, United States, Hong Kong. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression free survival (PFS) (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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04000737, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2025.