Chinese Herbal Formulation PHY906 and Sorafenib Tosylate in Treating Patients With Advanced Liver Cancer
|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||Dietary Supplement: Chinese herbal formulation PHY906 Drug: sorafenib tosylate Other: laboratory biomarker analysis Other: pharmacological study||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Phase I Open Label Study Investigating the Combination of KD018 and Sorafenib (Nexavar) in Patients With Advanced Hepatocellular Carcinoma|
- 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 [ Time Frame: 28 days ]
- Adverse events as determined by NCI CTCAE version 4 [ Time Frame: Up to 4 weeks after completion of study treatment ]
- Serious adverse events as determined by NCI CTCAE version 4 [ Time Frame: Up to 4 weeks after completion of study treatment ]
- Discontinuation rate [ Time Frame: Up to 6 years ]
- Dose adjustment rate [ Time Frame: Up to 6 years ]
- Tumor response in terms of best overall response, assessed using RECIST [ Time Frame: Up to 6 years ]
- Sorafenib tosylate concentration after co-administration with Chinese herbal formulation PHY906 [ Time Frame: Baseline; 1 hour post-dose; 2 hours post-dose ]
- Change in cytokine/chemokine levels [ Time Frame: Baseline to up to 6 years ]
- Change in levels of soluble biomarkers [ Time Frame: Baseline to up to 6 years ]
|Actual Study Start Date:||May 6, 2013|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
Experimental: Treatment (Chinese herbal formulation PHY906 and sorafenib)
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.
Dietary Supplement: Chinese herbal formulation PHY906
Other Names:Drug: sorafenib tosylate
Other Names:Other: laboratory biomarker analysis
Correlative studiesOther: pharmacological study
Other Name: pharmacological studies
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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.
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), 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01666756
|United States, California|
|City of Hope Medical Center|
|Duarte, California, United States, 91010|
|Principal Investigator:||Joseph Chao, MD||City of Hope Medical Center|