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Phase II Study of Bevacizumab Plus Erlotinib in Patients With Advanced Hepatocellular Cancer (HCC)

Phase 2
18 Years
Not Enrolling
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

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Trial Information

Phase II Study of Bevacizumab Plus Erlotinib in Patients With Advanced Hepatocellular Cancer (HCC)


I. Evaluate the objective response rate in patients with advanced hepatocellular carcinoma
treated with bevacizumab and erlotinib.


I. Evaluate the time to progression in patients treated with this regimen. II. Evaluate the
overall and progression-free survival of patients treated with this regimen.

III. Evaluate the adverse events in patients treated with this regimen.


I. Determine the presence of epidermal growth factor receptor (EGFR) mutations in tumor
tissue and correlate this with response rate, progression, and survival in patients treated
with this regimen.

II. Evaluate the expression of molecules involved in EGFR signal transduction, including
EGFR, phosphorylated-EGFR, Akt, phosphorylated-Akt, mitogen-activated protein kinase (MAPK),
phosphorylated-MAPK, and HER2/neu by immunohistochemistry (from tumor tissue) and correlate
these with patient outcome measures.

III. Determine the levels of vascular endothelial growth factor (VEGF) and VEGF receptors in
tumor tissue as well as baseline plasma VEGF levels and correlate these with patient outcome

OUTLINE: This is a multicenter study.

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral erlotinib
hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of
disease progression or unacceptable toxicity. Patients undergo laboratory studies to
determine epidermal growth factor receptor (EGFR) and phosphorylated-EGFR protein levels
using initial diagnostic biopsy specimens by immunohistochemistry (IHC) for correlation with
clinical outcome. Levels of proteins through which EGFR signals, including Akt,
phosphorylated-Akt, mitogen-activated protein kinase (MAPK), and phosphorylated-MAPK, are
also determined using initial diagnostic biopsy specimens by IHC and correlated with
clinical outcome. Total and free serum vascular endothelial growth factor levels are
determined at the start of study and prior to course 3 by enzyme-linked immunosorbent assays

After completion of study treatment, patients are followed periodically for up to 3 years.

Inclusion Criteria:

- Absolute neutrophil count >= 1,500/mm^3

- Creatinine =< 2 mg/dL

- Albumin >= 2.5 g/dL

- Total bilirubin =< upper limit of normal (ULN)

- AST and ALT =< 2.5 times ULN

- Alkaline phosphatase =< 5 times ULN

- Urine protein:creatinine ratio < 1.0 OR 24-hour urine protein < 1,000 mg

- Not pregnant or nursing:

No nursing for >= 6 months after completion of study treatment

- Negative pregnancy test

- Fertile patients must use effective contraception during study and for >= 6 months
after completion of study treatment

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to bevacizumab or erlotinib hydrochloride

- No abnormalities of the cornea, including any of the following:

History of dry eye syndrome or Sjögren's syndrome; Congenital abnormality (e.g., Fuch's
dystrophy); Abnormal slit-lamp examination using a vital dye (e.g., fluorescein,
Bengal-Rose); Abnormal corneal sensitivity test (e.g., Schirmer test or similar tear
production test)

- No stroke or transient ischemic attack within the past 6 months

- No uncontrolled high blood pressure, history of labile hypertension, or history of
poor compliance with an antihypertensive regimen

- No unstable angina pectoris within the past 6 months

- No symptomatic congestive heart failure

- No myocardial infarction within the past 6 months

- No serious uncontrolled cardiac arrhythmias

- No uncontrolled diabetes mellitus

- No active or uncontrolled infection

- No impaired GI function or disease that may significantly alter the absorption of
erlotinib hydrochloride (e.g., ulcerative disease, uncontrolled nausea, vomiting, or
diarrhea, malabsorption syndrome, or bowel obstruction)

- Able to swallow tablets

- No psychiatric illness or social situation that would limit compliance with study

- No history of nephrotic-range protein

- No history of bleeding diathesis

- No encephalopathy

- No serious nonhealing wounds, skin ulcers, or bone fractures

- No clinically significant peripheral vascular disease

- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- No history of a GI bleed that required procedural intervention (e.g., variceal
banding, surgical shunt, transvenous intrahepatic porto-systemic shunt [TIPS]) within
the past 3 months

- No significant traumatic injury within the past 28 days

- No other prior malignancy within the past 5 years except for the following:

Adequately treated basal cell or squamous cell skin cancer; Adequately treated in situ
cervical cancer; Stage I or II cancer from which the patient is currently in complete
remission; Stage I chronic lymphocytic leukemia

- Recovered from all therapy-related toxicities

- No more than 1 prior systemic or liver directed drug therapy including transarterial
chemoembolization (TACE) (multiple TACEs will count as 1 prior regimen irrespective
of their total numbers) that were used for HCC

- No chemotherapy for HCC within the past 4 weeks (6 weeks for nitrosoureas or
mitomycin C)

- No biological therapy or immunotherapy for HCC within the past 4 weeks

- Prior surgery, regional therapy (e.g., transarterial embolization), liver
transplantation, or other liver-directed ablative therapies of discrete lesions
allowed provided any related progressive or recurrent disease is documented

- No cryotherapy, radiofrequency ablation, ethanol injection, or photodynamic therapy
within the past 6 weeks:

Indicator lesions must be outside the area of prior treatment OR if the lesion is inside
the area of prior treatment, there must be clear evidence of disease progression
associated with that lesion

- No core biopsy within the past 7 days

- No radiotherapy within the past 4 weeks

- No prior antiangiogenesis agent or antiepidermal growth factor receptor drug

- No prior treatment with hepatic arterial infusion with chemotherapy or yttrium Y
90-labeled microspheres

- No other concurrent investigational agents

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent anticancer therapy

- Concurrent full-dose anticoagulants (e.g., warfarin) with INR > 1.2 allowed provided
the following criteria are met:

An in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant (or on a
stable dose of low molecular weight heparin)

- AND (continued from above) No active bleeding or pathological condition that carries
a high risk of bleeding (e.g., tumor involving major vessels, gastrointestinal [GI]
ulceration, or known varices)

- No concurrent major surgical procedures

- Histologically confirmed hepatocellular carcinoma (HCC):

- No fibrolamellar subtype HCC

- Advanced disease

- Not a candidate for surgical resection or liver transplantation

- Measurable disease:

- Edges of the indicator lesion must be clearly distinct on CT scan

- Lesions that measure at least 1 cm but less than 2 cm only must use spiral CT
imaging for both pre- and post-treatment tumor assessments

- Child's Pugh classification A or B

- No primary brain tumor, brain metastasis, or other CNS diseases

- ECOG performance status 0-1

- Platelet count >= 75,000/mm^3

- No major surgery (e.g., laparotomy), open biopsy, or minor surgery (e.g., insertion
of a vascular access device) within the past 4 weeks

- No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the

- No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 28

- No concurrent prophylactic hematopoietic colony-stimulating factors

Type of Study:


Study Design:

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

Outcome Measure:

Proportion of confirmed tumor responses defined to be either a CR or PR

Outcome Description:

Estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. The largest success proportion where the proposed treatment regimen would be considered ineffective in this population is 10%, and the smallest proportion that would warrant subsequent studies with the proposed regimen in this patient population is 25%.

Outcome Time Frame:

Assessed up to 3 years

Safety Issue:


Principal Investigator

Philip Philip

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

August 2006

Completion Date:

Related Keywords:

  • Adult Primary Hepatocellular Carcinoma
  • Advanced Adult Primary Liver Cancer
  • Localized Unresectable Adult Primary Liver Cancer
  • Recurrent Adult Primary Liver Cancer
  • Carcinoma
  • Liver Neoplasms
  • Carcinoma, Hepatocellular



Mayo Clinic Rochester, Minnesota  55905