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

Advanced Hepatocellular Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04000737
• Other study ID #: YIV-906-2018L1
• Status: Recruiting
• Phase: Phase 2
• Start date: January 10, 2020
• Est. completion date: May 19, 2024

Study information

• Verified date: November 2021
• Source: Yiviva Inc.
• Contact: Shwu-huey Liu, PhD
• Phone: +1 (646) 883-3906
• Email: Clinical.Trials[@]Yiviva.com
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 125
• Est. completion date: May 19, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Hepatocellular Carcinoma
• Carcinoma
• Carcinoma, Hepatocellular

Intervention

Drug:
• YIV-906+Sorafenib
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.
• Placebo+Sorafenib
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.

Locations

Country	Name	City	State
China	Beijing You'An Hospital, Capital Medical University	Beijing	Beijing
China	Cancer Hospital Chinese Academy of Medical Sciences	Beijing	Beijing
China	China-Japan Friendship Hospital	Beijing	Beijing
China	Hunan Cancer Hospital	Changsha	Hunan
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	The First Affiliated Hospital of Guangxi Medical University	Nanning	Guangxi
China	LongHua Hospital Shanghai University of Traditional Chinese Medicine	Shanghai	Shanghai
China	Shanghai Eastern Hepatobiliary Hospital	Shanghai	Shanghai
China	Shanghai University of Traditional Chinese Medicine Shuguang Hospital	Shanghai	Shanghai
China	Shenzhen People's Hospital	Shenzhen	Guangdong
Hong Kong	Queen Mary Hospital	Hongkong
Taiwan	China Medical University Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Cancer Research Center, Taipei Municipal Wanfang Hospital	Taipei
Taiwan	Taipei Medical University -Shuang Ho Hospital, Ministry of Health and Welfare	Taipei
Taiwan	Taipei Medical University Cancer Center	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital, Linkou	Taoyuan
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	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

Sponsors (1)

Lead Sponsor	Collaborator
Yiviva Inc.

Countries where clinical trial is conducted

United States,  China,  Hong Kong,  Taiwan, 

References & Publications (12)

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. — View Citation

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. — View Citation

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 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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 Pharm — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.