Neoplasms

All Conditions

Digestive System Diseases

Rare Diseases

Carcinoma

Carcinoma, Hepatocellular

Liver Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Primary Liver Cancer

Hematinics

All Drugs and Chemicals

Antineoplastic Agents

Liver Extracts

Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive Chinese herbal formulation PHY906 PO BID on days 1-4, 8-11, 15-18, 21-24 and sorafenib tosylate PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Chinese herbal formulation PHY906

sorafenib tosylate

laboratory biomarker analysis

pharmacological study

Joseph Chao, MD

This phase I trial studies the side effects and best dose of Chinese herbal formulation PHY906 when given together with sorafenib tosylate in treating patients with advanced liver cancer. Biological therapies, such as Chinese herbal formulation PHY906, may interfere with the growth of tumor cells and slow the growth of tumors. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib tosylate may also stop the growth of liver cancer by blocking blood flow to the tumor. Giving Chinese herbal formulation PHY906 together with sorafenib tosylate may work better in treating advanced liver cancer.

PRIMARY OBJECTIVES:

I. To characterize the safety and tolerability of KD018 (Chinese herbal formulation PHY906) in combination with daily sorafenib (sorafenib tosylate) and to determine the maximum tolerated dose (MTD) of the combination of KD018 plus sorafenib to bring forward into phase 2.

SECONDARY OBJECTIVES:

I. To describe the efficacy of the combination of KD018 plus sorafenib at the explored dose-levels in terms of best overall response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.

II. To assess the safety and tolerability of the combination of KD018 plus sorafenib as measured by the rate and severity of adverse events (AEs).

III. To determine the steady state of sorafenib after KD018 exposure at pre-dose and 1 hour and 2 hours post-dose at the explored combination dose-levels using concentrations at pre-dose (Cmin) and at 1 hour (C1h) and 2 hours (C2h) post-dose.

TERTIARY OBJECTIVES:

I. To assess the effect of treatment on soluble markers of angiogenesis, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), placental growth factor (PLGF), soluble vascular endothelial growth factor receptor 1 (sVEGFR1), sVEGFR2, apoptosis (i.e. M30 monoclonal antibody \[M30\] and M65) and on the insulin-like growth factor (IGF) axis including molecules such as IGF-binding protein 2 (IGFII).

II. To correlate the above soluble biomarker measurements with clinical endpoints.

III. To examine the correlation between the soluble biomarkers.

IV. To examine the predictive relationship of immunohistochemical tumor biomarkers at baseline, i.e. phosphorylated ribosomal protein S6 kinase (pS6), p-protein kinase B (pAKT), p-mitogen-activated protein kinase 1 (ERK), p-mitogen-activated protein kinase kinase (pMEK), hypoxia-inducible factor 2, alpha subunit (HIF2a), phosphatase and tensin homolog gene (PTEN), signal transducer and activator of transcription 3 (acute-phase response factor) (STAT3) and tumor protein p53 (p53), as well as of mutational status, i.e. p53, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and PTEN, with efficacy endpoints (time to progression \[TTP\]).

V. To determine if soluble apoptosis markers (M30/M65) correlate with proliferative markers at baseline (proliferation-related Ki-67 antigen \[Ki67\] and p53) in archival tumor samples.

VI. To examine the relationship of immunohistochemical and/or soluble biomarkers with subgroup classification namely, patients with hepatitis B virus (HBV), patients with hepatitis C virus (HCV) and patients with other etiologies.

VII. To explore potential biomarker differences within patient subgroups, namely, patients with HBV, patients with HCV and patients with other etiologies.

VIII. To determine the effect of KD018 on cytokine/chemokine levels including interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, VEGF, FGF-basic (b), sargramostim (GM-CSF), filgrastim (G-CSF).

IX. To explore potential relationships between efficacy and Cmin of sorafenib after co-administration with KD018 and between occurrence of adverse events and C1h/C2h endpoints (efficacy, safety, pharmacokinetics \[PK\]).

OUTLINE: This is a phase I, dose-escalation study of Chinese herbal formulation PHY906.

Patients receive Chinese herbal formulation PHY906 orally (PO) twice daily (BID) on days 1-4, 8-11, 15-18, 21-24 and sorafenib tosylate PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Chinese Herbal Formulation PHY906 and Sorafenib Tosylate in Treating Patients With Advanced Liver Cancer

A Phase I Open Label Study Investigating the Combination of KD018 and Sorafenib (Nexavar) in Patients With Advanced Hepatocellular Carcinoma

National Cancer Institute (NCI)

City of Hope Medical Center

Infections

Hepatitis A

Hepatitis

Hepatitis B

Patients in the study arm will be treated orally for 28-day courses with YIV-906 + sorafenib

Patients in the placebo arm will be given sorafenib with placebo

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.

YIV-906+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.

Placebo+Sorafenib

Shwu-huey Liu, PhD

Calvin Pan, MD

James Harding, MD

Ghassan Abou-Alfa, MD

Xiuhui Li, MD

Yuankai Shi, MD

Liqun Jia, MD

Kaiping Jing, MD

Kaiping Jiang, MD

Shunqin Long, MD

Jianyong Yang, MD

Ruilian Xu, MD

Jian Kong, MD

Xiaohua Hu, MD

Shanzhi Gu, MD

Yingjie Zhu, MD

Kui Wang, MD

Chenghai Liu, MD

Man-Fung Yuen, MD

Long-Bin Jeng, MD

Chia-Jui Yen, MD

Jacqueline Whang-Peng, MD

Tzu-Yi Chao, MD

Huey-En Tzeng, MD

Yee Chao, MD

Chia-Hsun Hsieh, MD

Yun Yen, MD/PhD

Ghassan Abou-Alfa, MD/MBA

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.

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

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

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.

TTP is defined as the period elapsing between the date of randomization and the date of disease progression.

OS is defined as the interval between time of randomization and the date of death from any cause.

The Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) will be used to establish disease response or progression

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

All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 5.0 (CTCAE).

Each of the domains in the HCC18 will be scored per the assessment's scoring algorithm and summarized using descriptive statistics at baseline

Each of the domains in the EORTC QLQ-C30 will be scored per the assessment' scoring algorithm and summarized using descriptive statistics at baseline

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).

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

Yiviva Inc.

Anticoagulants

Micronutrients

Bone Density Conservation Agents

Edetic Acid

Pentetic Acid

Antidotes

Protective Agents

Chelating Agents

Iron

Iron Chelating Agents

Calcium

Calcium, Dietary

Patients receive gadoxetate disodium IV and then undergo enhanced liver MRI.

Gadoxetate Disodium

Magnetic Resonance Imaging

Gilbert Whang

This pilot clinical trial studies magnetic resonance imaging (MRI) with gadoxetate disodium in measuring tumors in patients with liver cancer. Diagnostic procedures, such as MRI with gadoxetate disodium, may help find and diagnose liver cancer and find out how far the disease has spread. It is not yet known whether MRI with gadoxetate disodium provides a more precise measurement of liver tumors than standard computed tomography (CT).

PRIMARY OBJECTIVES:

I. To evaluate the precision of gadoxetate (gadoxetate disodium)-enhanced MRI in evaluating lesion size.

II. To evaluate if there is a subjective improvement in the delineation of hepatocellular carcinoma (HCC) in the hepatocellular phase of contrast administration.

III. To further assess the sensitivity of gadoxetate-enhanced MRI for the detection of HCC.

SECONDARY OBJECTIVES:

I. To evaluate the reproducibility of various tumor measurement techniques in the evaluation of HCC.

II. To further evaluate how administration of gadoxetate affects diffusion weighted imaging.

OUTLINE:

Patients receive gadoxetate disodium intravenously (IV) and then undergo enhanced liver MRI.

After completion of study, patients are followed up at 2, 4, 8, and 12 months.

MRI With Gadoxetate Disodium in Measuring Tumors in Patients With Liver Cancer

MR Techniques in the Evaluation of Hepatocellular Carcinoma: Gadoxetate

Initially, a random effects analysis of variance (ANOVA) will be performed for each type of image (CT vs. MRI), for each phase (4 for CT and 5 for MRI) and for each method of measuring "size" (1-, 2-, and 3-dimensional) - for a total of 27 ANOVAs. Lesion, radiologist, and replication (for the 20 target lesions measured twice) will all be random effects; the inter-reader and the intra-reader variability will be estimated from these models and 95% confidence intervals will be constructed.

ADC values will be recorded for uninvolved liver parenchyma and for tumors before and after administration of gadoxetate disodium.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chinese Herbal Formulation PHY906 and Sorafenib Tosylate in Treating Patients With Advanced Liver Cancer	NCT01666756	Adult Primary H... Advanced Adult ... Advanced Adult ... BCLC Stage B Ad... BCLC Stage C Ad...	Chinese herbal ... sorafenib tosyl... laboratory biom... pharmacological...	18 Years -	City of Hope Medical Center
YIV-906 (Formerly PHY906/KD018) With Sorafenib in HBV(+) Hepatocellular Carcinoma (HCC)	NCT04000737	Advanced Hepato...	YIV-906+Sorafen... Placebo+Sorafen...	18 Years -	Yiviva Inc.
MRI With Gadoxetate Disodium in Measuring Tumors in Patients With Liver Cancer	NCT02578602	Adult Hepatocel... Advanced Adult ... BCLC Stage 0 Ad... BCLC Stage A Ad... BCLC Stage B Ad... BCLC Stage C Ad... BCLC Stage D Ad... Localized Non-R... Localized Resec...	Gadoxetate Diso... Magnetic Resona...	18 Years -	University of Southern California

Spots Global Cancer Trial Database for bclc stage b adult hepatocellular carcinoma