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

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ClinicalTrials.gov Identifier: NCT04000737
Recruitment Status : Not yet recruiting
First Posted : June 27, 2019
Last Update Posted : June 27, 2019
Sponsor:
Information provided by (Responsible Party):
Yiviva Inc.

Brief Summary:
YIV-960 (PHY906, KD018) is an oral form of a spray dried aqueous extract of four herbs, which have been used in the Orient for more than 1800 years for a variety of gastrointestinal symptoms including diarrhea, nausea, and vomiting. Extensive clinical and pre-clinical research has been done indicated that YIV-906 may have synergistic anticancer activities as well as GI toxicity reduction to cancer treatments, including sorafenib. The proposed plan will investigate the efficacy and mechanisms of YIV-906 as an adjuvant to sorafenib in the treatment of patients with Hepatitis B(+)-associated advanced hepatocellular carcinoma.

Condition or disease Intervention/treatment Phase
Advanced Hepatocellular Carcinoma Drug: YIV-906+Sorafenib Drug: Placebo+Sorafenib Phase 2

Detailed Description:

HCC patients with chronic HBV (+) (HBsAg(+) and IgM anti-HBc (-)), and Child-Pugh A status will be randomized to either the study arm (YIV-906 plus sorafenib) or control arm (placebo plus sorafenib). 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 4.0 (CTCAE). The modified Response Evaluation Criteria in Solid Tumors (mRECIST) will be used to establish disease response or progression.

Patients will be evaluated for PFS, TTP, OS, antitumor response, QoL and safety every two courses. Biomarkers are mandatory and will be studied prior to drug administration and day 1 of every other cycle. Gut and oral microbiota studies as well as TCM Syndrome Research are optional.

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 125 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Estimated Study Start Date : August 15, 2019
Estimated Primary Completion Date : November 2, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sorafenib + YIV-906
Patients in the study arm will be treated orally for two 28-day courses with YIV-906 + sorafenib
Drug: YIV-906+Sorafenib
Patients will be treated orally for two 28-day courses 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.

Active Comparator: Sorafenib + Placebo
Patients in the placebo arm will be given sorafenib with placebo
Drug: Placebo+Sorafenib
Patients will be given sorafenib (400 mg BID) daily for two 28-day course with placebo (3 capsules, BID) 4 days on and 3 days off weekly in each course.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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. ]
    TTP is defined as the period elapsing between the date of randomization and the date of disease progression.

  2. Overall survival (OS) [ 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. ]
    OS is defined as the interval between time of randomization and the date of death from any cause.

  3. 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. ]
    The modified Response Evaluation Criteria in Solid Tumors (mRECIST) will be used to establish disease response or progression

  4. 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. ]
    DCR will be defined as the proportion of patients achieving either partial response (PR) or complete response (CR) or stable disease (SD).

  5. 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 ]
    All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 4.0 (CTCAE).

  6. Change of quality of life (QoL) in each arm with HCC18 [ Time Frame: At baseline and then at end of every course (4 weeks) until the end of study. Assessed up to 24 months. ]
    Each of the domains in the HCC18 will be scored per the assessment's scoring algorithm and summarized using descriptive statistics at baseline

  7. Change of quality of life (QoL) in each arm with EORTC-C30 [ Time Frame: At baseline, and then at the end of every course (4 weeks) until the end of study. Assessed up to 24 months. ]
    Each of the domains in the EORTC QLQ-C30 will be scored per the assessment's scoring algorithm and summarized using descriptive statistics at baseline

  8. Correlation of cytokines levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
    Using a series of biomarker analysis for cytokines, including G-CSF and MCP1 proteins in the plasma

  9. Correlation of circulating mutated DNA levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
    Using a series of biomarker analysis for circulating mutated DNA

  10. Correlation of chemokines levels (pg/mL) with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
    Using a series of biomarker analysis for chemokines, including: IL-2, IL-4, IL-5, IL-10, TNF-α, IFN-γ

  11. Correlation of Alpha-feto-protein levels(ng/mL) with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
    Using a series of biomarker analysis for alpha-feto-protein

  12. Correlation of HBV serologic markers levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
    Using a series of biomarker analysis for HBV serologic markers

  13. Correlation of HBV viral load (IU/mL) levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
    Using a series of biomarker analysis for HBV viral load

  14. Correlation of plasma metabolomics levels with clinical outcomes [ Time Frame: At the end of every 1 cycle (4 week/28 days) through the study completion or 24 months, whichever is longer. ]
    Using a series of biomarker analysis for plasma metabolomics

  15. 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. ]
    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).

  16. 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. ]
    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).

  17. 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. ]
    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).

  18. 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. ]
    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).

  19. 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. ]
    PK is optional and limited to the first 15 male and 15 female patients from China study sites.

  20. The amounts of E.coli of the human gastrointestinal tract in comparison with efficacy and toxicity in each arm, both pre-, post-treatments and control arm [ Time Frame: At baseline, and then at the end of every course (4 weeks) until the end of study. Assessed up to 24 months. ]
    Samples will be collected from patients' buccal mucosa, and upper gingival; and analyzed by NGS and RT-PCR



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or females ≥ 18 years old with the ability to take oral drugs
  • Diagnosis of advanced HCC according to the American Association for the Study of Liver Diseases (AASLD) Guidelines (Heimbach et al. 2016) or diagnosis by tissue pathology
  • Life expectancy of at least 3 months
  • Presence of chronic hepatitis B (HBsAg (+), anti-HBc (+), IgM anti-HBc (-) and anti-HBs(-))
  • Never received systemic antitumor therapy
  • Patients must have at least one tumor lesion that meets both of the following criteria:

    • "Measurable disease" according to mRECIST, i.e. at least one measurable lesion.
    • The lesion has not been previously treated with local therapy
  • 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/or positive HBsAg results, they must be treated with antivirals, as prophylaxis starting at least 1-2 weeks prior to receiving study drug
  • 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
  • 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 Cockroft-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:

  • Patients who have received systemic chemo-therapies or immunotherapy or molecular target therapies
  • Patients who have received any local anti-cancer therapy within 4 weeks
  • Active bleeding (including gastrointestinal bleeding, encephalopathy, and ascites) during the last 4 weeks prior to Cycle 1
  • 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
  • Hepatocholangial carcinoma, 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:

    • 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
    • Patients with active alcohol intake
    • 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 or HCV
    • Impairment of gastrointestinal function or who have a 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 or aldosterone) or other immunosuppressive agent
  • Patients treated with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A
  • 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 investigational 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
  • An ongoing or recent history of autoimmune, 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, low molecular-weight heparin, or similar agents
  • Chronic therapy with nonsteroidal anti-inflammatory agents or other antiplatelet agents. Aspirin at doses up to 100 milligrams/day is permitted
  • Patients with an estimated or calculated baseline creatinine clearance of less than 30 mL/min should not be enrolled in this trial
  • No patient, however, may enroll in this trial if they are taking phenytoin (Dilantin)
  • Patients taking traditional Chinese medicines within 14 days prior to enrollment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04000737


Contacts
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Contact: Shwu-huey Liu, PhD +1-203-676-7255 Shwuhuey@yiviva.com

Locations
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United States, New York
Northwell Monter Cancer Institute Not yet recruiting
Lake Success, New York, United States, 11042
New York University School of Medicine Not yet recruiting
New York, New York, United States, 10016
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Ohio
Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106
China, Beijing
302 Military Hospital Not yet recruiting
Beijing, Beijing, China
Beijing YouAn Hospital Not yet recruiting
Beijing, Beijing, China
Chinese Academy of Medical Sciences Cancer Hospital Not yet recruiting
Beijing, Beijing, China
Sino-Japanese Friendship Hospital Not yet recruiting
Beijing, Beijing, China
China, Guangdong
Guangdong Provincial Hospital of Traditional Chinese Medicine Not yet recruiting
Guangzhou, Guangdong, China
Sun Yat-Sen University Affiliated Cancer Hospital Not yet recruiting
Guangzhou, Guangdong, China
The First Affiliated Hospital, Sun Yat-Sen University Not yet recruiting
Guangzhou, Guangdong, China
China, Guangxi
Guangxi Medical University Affiliated Tumor Hospital
Nanning, Guangxi, China
China, Hunan
Hunan Provincial Cancer Hospital Not yet recruiting
Changsha, Hunan, China
China, Shanghai
Shanghai University of Traditional Chinese Medicine Shuguang Hospital Not yet recruiting
Shanghai, Shanghai, China
Shanghai Zhongshan Hospital Not yet recruiting
Shanghai, Shanghai, China
The Third Affiliated Hospital of Naval Military Medical University; Not yet recruiting
Shanghai, Shanghai, China
Hong Kong
Queen Mary Hospital Not yet recruiting
Hongkong, Hong Kong
Taiwan
Taipei Medical University Cancer Center at Shuang Ho Hospital Not yet recruiting
Taipei, Taiwan
Taipei Medical University Cancer Center at Wan Fang Hospital Not yet recruiting
Taipei, Taiwan
Taipei Medical University Hospital Cancer Center Not yet recruiting
Taipei, Taiwan
Sponsors and Collaborators
Yiviva Inc.
Investigators
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Study Chair: Yun Yen, MD/PhD Taipei Medical University
Principal Investigator: Ghassan Abou-Alfa, MD/MBA Memorial Sloan Kettering Cancer Center

Publications of Results:
Other Publications:

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Responsible Party: Yiviva Inc.
ClinicalTrials.gov Identifier: NCT04000737     History of Changes
Other Study ID Numbers: YIV-906-2018L1
First Posted: June 27, 2019    Key Record Dates
Last Update Posted: June 27, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Yiviva Inc.:
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
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Sorafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action