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

• Adverse events as determined by NCI CTCAE version 4 [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: Yes ]
• Serious adverse events as determined by NCI CTCAE version 4 [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: Yes ]
• Discontinuation rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
• Dose adjustment rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
• Tumor response in terms of best overall response, assessed using RECIST [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
• Sorafenib tosylate concentration after co-administration with Chinese herbal formulation PHY906 [ Time Frame: Baseline; 1 hour post-dose; 2 hours post-dose ] [ Designated as safety issue: No ]

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 previously untreated 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 kill more tumor cells

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.

• Adult Primary Hepatocellular Carcinoma
• Advanced Adult Primary Liver Cancer

• Dietary Supplement: Chinese herbal formulation PHY906
  Given PO
  Other Name: PHY-906
• Drug: sorafenib tosylate
  Given PO
  Other Names:

  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
• Other: laboratory biomarker analysis
  Correlative studies
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies

Inclusion Criteria:

• Ability to take oral drugs
• Diagnosis of advanced hepatocellular carcinoma (HCC) according to the American Association for the Study of Liver Diseases (AASLD) guidelines
• HCC stage B or C according to the Barcelona Clinic Liver Cancer (BCLC)
• No previous systemic therapy for HCC (tamoxifen is allowed as previous systemic therapy)
• Measurable disease according to RECIST, i.e. at least one measurable lesion; this lesion should not have been previously treated with local therapy; a treated lesion may be used where these lesions are the only lesions available for evaluation and have shown definite progression since their last local treatment; local therapy must have been completed at least four weeks prior to baseline evaluation
• Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Cirrhotic status of current Child-Pugh class A only (5-6 points) with no encephalopathy and no ascites (ascites controlled by diuretics is also excluded in this study); Child-Pugh status should be calculated based on clinical findings and laboratory results during the screening period
• For patients with positive HBV-deoxyribonucleic acid (DNA) and/or positive of hepatitis B surface antigen (HbsAg) results, they must be treated with anti-virals, as prophylaxis at least 1-2 weeks prior to receiving study drug, cycle 1, day 1
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelets >= 100000 x 10^6/L
• Hemoglobin (Hgb) >= 9 g/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x upper limit of normal (ULN)
• Serum creatinine =< 1.5 x ULN
• Total bilirubin =< 3.0
• Ability to understand and willingness to sign a written informed consent and to be able to follow the visit schedule
• Life expectancy of approximately 6 months
• For female patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control, adequate contraceptives must be used throughout the trial and for 3 months after last study drug administration in both sexes; women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to administration of KD018 and/or sorafenib
• All subjects must have the ability to understand and the willingness to sign a written informed consent
• No previous systemic therapy for HCC is permitted, however, tamoxifen is allowed as previous systemic therapy

Exclusion Criteria:

• Patients currently receiving any anti-cancer therapy or who have received any local anti-cancer therapy =< 4 weeks prior to baseline computed tomography (CT)/magnetic resonance imaging (MRI) scan, prior to cycle 1 treatment
• Active bleeding during the last 30 days prior to cycle 1 treatment including variceal bleeding (esophageal varices should be treated according to standard practice e.g. ligation/banding and procedure completed 30 days prior to cycle 1 treatment
• Patients with a known hypersensitivity to KD018 or known hypersensitivity to sorafenib or contraindications to sorafenib based on the local sorafenib label
• Known previous/current malignancy requiring treatment within =< 3 years except for cervical carcinoma in situ, basal cell carcinoma, and superficial bladder carcinoma
• Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)
• Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to course 1 treatment, serious uncontrolled cardiac arrhythmia, uncontrolled hypertension
• Previous transient ischemic attack (TIA), cerebral vascular accident (CVA), symptomatic posterior vitreous detachment (PVD) within last 6 months of cycle 1 treatment
• Patients with active alcohol intake
• Uncontrolled diabetes as defined by glycosylated hemoglobin (HbA1c) > 8%
• Greater or equal grade 3 hypercholesterolemia/hypertriglyceridemia or >= grade 2 hypercholesterolemia/hypertriglyceridemia with history of coronary artery disease (despite lipid-lowering treatment if given)
• 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

• Significant deterioration of lung function, defined as any of the following:

  • 30% decrease in predicted lung volumes, and/or 30% decrease in diffusion capacity of the lung for carbon monoxide (DLCO), and/or =< 88% oxygen (O2) saturation at rest on room air
• Patients receiving chronic treatment with corticosteroids (except for intermittent topical or local injection or aldosterone) or another immunosuppressive agent
• Patients treated with drugs known to be strong inhibitors or inducers of isoenzyme cytochrome P450 3A unless the drugs are medically necessary and no substitutes are available
• 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 investigative drug or therapy within the last 30 days prior to cycle 1 treatment