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

Phase 1
18 Years
Open (Enrolling)
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer

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Trial Information

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),
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.

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

- 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

- 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 mg/dL

- 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

- The effects of KD018 and sorafenib on the developing fetus are unknown. For this
reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control or abstinence) prior to
study entry and for three months following duration of study participation. Should a
woman become pregnant, or suspect that she is pregnant while participating on the
trial, she should inform her treating physician immediately

- 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

- Congenital long QT syndrome

- 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

- Impairment of gastrointestinal function or who have gastrointestinal disease that may
significantly alter the absorption of study drug (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)

- 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

- 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

- Pregnant and/or breastfeeding women

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Yun Yen

Investigator Role:

Principal Investigator

Investigator Affiliation:

City of Hope Medical Center


United States: Federal Government

Study ID:




Start Date:

May 2013

Completion Date:

Related Keywords:

  • Adult Primary Hepatocellular Carcinoma
  • Advanced Adult Primary Liver Cancer
  • Carcinoma
  • Liver Neoplasms
  • Carcinoma, Hepatocellular



City of Hope Medical Center Duarte, California  91010