A Phase I Open Label Study Investigating the Combination of KD018 and Sorafenib (Nexavar) in Patients With Advanced Hepatocellular Carcinoma
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
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.
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),
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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Recommended phase II dose, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4
City of Hope Medical Center
United States: Federal Government
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