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A Randomized Open-Label Multi-Institution Phase II Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients With Advanced Hepatocellular Carcinoma (HCC)

Phase 2
18 Years
Open (Enrolling)
Liver Cancer

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Trial Information

A Randomized Open-Label Multi-Institution Phase II Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients With Advanced Hepatocellular Carcinoma (HCC)



- To estimate the overall survival in patients with advanced hepatocellular carcinoma
treated with bevacizumab and erlotinib hydrochloride vs sorafenib tosylate.


- To estimate the event-free survival and tumor response rate of these patients.

- To evaluate the safety and tolerability of these regimens in these patients.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral
erlotinib hydrochloride once daily on days 1-28.

- Arm II: Patients receive oral sorafenib tosylate twice daily on days 1-28. In both
arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed at 30 days and then every 3
months for 1 year.

Inclusion Criteria


- Pathologically confirmed advanced hepatocellular carcinoma (HCC)

- Childs-Pugh class A

- CLIP score ≤ 5

- Not a candidate for curative surgical resection or loco-regional therapy

- Measurable disease as per RECIST criteria, defined as ≥ 1 previously unirradiated,
bidimensionally measurable lesion ≥ 20 mm by CT scan or MRI (triphasic spiral CT scan
or MRI employing a "liver protocol" image capture technique required)

- Bone lesions, ascites, and pleural effusions are not considered measurable

- No fibrolamellar HCC

- No known brain metastases

- No prior organ transplantation


- ECOG performance status 0-2

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 75,000/mm³

- Hemoglobin ≥ 9 g/dL

- Transaminases ≤ 5 times upper limit of normal (ULN)

- Total bilirubin ≤ 3.0 times ULN

- Serum albumin > 2.5 g/dL

- PT ≤ 1.8 times ULN

- Prolonged INR allowed for patients who require full dose anticoagulation

- Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 45 mL/min

- Urine protein < 2+ by urine dipstick OR urine protein ≤ 1 g by 24-hour urine

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 12 weeks after
completion of study treatment

- Able to take and absorb oral medication

- No active infection requiring parenteral therapy

- No known HIV or AIDS

- No uncontrolled blood pressure (BP), defined as systolic BP ≥ 150 mm Hg and/or
diastolic BP ≥ 100 mm Hg

- No uncontrolled or significant cardiovascular disease, including any of the

- Myocardial infarction within the past 6 months

- Uncontrolled angina within the past 6 months

- New York Heart Association class II-IV congestive heart failure

- Grade 3 cardiac valve dysfunction

- Cardiac arrhythmia not controlled by medication

- Stroke or transient ischemic attack within the past 6 months

- Arterial thrombotic event of any type within the past 6 months

- No significant or symptomatic vascular disease (e.g., aortic aneurysm, aortic
dissection, or peripheral vascular disease) within the past 6 months

- No decompensated liver disease as evidenced by clinically significant ascites
refractory to diuretic therapy, hepatic encephalopathy, or coagulopathy not corrected
by conservative measures

- No grade 3 bleeding esophageal or gastric varices within the past 2 months

- Prior variceal bleeding allowed provided patient has undergone banding or
sclerotherapy and there has been no evidence of bleeding for 2 months

- No gastric varices ≥ grade 2

- No hemoptysis (i.e., ≥ ½ teaspoon of bright red blood per episode) within the past

- No evidence of bleeding diathesis or coagulopathy

- No concurrent uncontrolled illness, including, but not limited to, a history of or
current evidence of unexplained nephrotic syndrome or other severe illness/disease
that would preclude study participation

- No history of hypertensive crisis or hypertensive encephalopathy

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 6 months

- No serious, non-healing wound, active ulcer, or untreated bone fracture

- No significant traumatic injury within the past 28 days

- No history of allergy to bevacizumab, erlotinib hydrochloride, sorafenib tosylate, or
related compounds

- No other primary malignancy within the past 5 years, except carcinoma in situ of the
cervix or urinary bladder or nonmelanoma skin cancer

- No mental incapacitation or psychiatric illness that would preclude study

- Not incarcerated or compulsorily detained (i.e., involuntarily incarcerated) for
treatment of either a psychiatric or physical illness (e.g., infectious disease)


- Prior surgery, local ablation, trans-arterial hepatic artery embolization, or
trans-arterial chemoembolization are allowed provided the lesion(s) have progressed
since treatment OR there are additional measurable, untreated lesions present

- No prior systemic therapy for HCC

- No prior organ transplantation

- More than 7 days since prior minor surgical procedures, fine needle aspirations, or
core biopsies (excluding placement of a vascular access device)

- More than 28 days since any prior therapy

- More than 28 days since prior and no concurrent major surgical procedure or open

- More than 28 days since prior and no concurrent participation in another experimental
drug study

- No other concurrent anticancer or antitumor therapy, including chemotherapy,
radiotherapy, immunotherapy, or hormonal anticancer therapy

- No other concurrent investigational agents

- No concurrent warfarin (other types of anticoagulation allowed)

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

The primary objective of this study is to estimate clinical efficacy outcomes (based on OS) of patients treated with B+E and patients treated with S. Forty-five patients in each arm who are evaluable for response will be sufficient for this analysis. A patient is evaluable for response if one 28-day cycle of therapy is completed. Enrolled patients who are not evaluable will be replaced, so there will be 45 patients in each arm evaluable for response.

Outcome Time Frame:

28 day cycle

Safety Issue:


Principal Investigator

Melanie B. Thomas, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Medical University of South Carolina


United States: Food and Drug Administration

Study ID:




Start Date:

March 2009

Completion Date:

Related Keywords:

  • Liver Cancer
  • adult primary hepatocellular carcinoma
  • advanced adult primary liver cancer
  • recurrent adult primary liver cancer
  • Liver Neoplasms
  • Carcinoma, Hepatocellular



USC/Norris Comprehensive Cancer Center and Hospital Los Angeles, California  90033-0804
Hollings Cancer Center at Medical University of South Carolina Charleston, South Carolina  29425
California Pacific Medical Center San Francisco, California  94115
Tennessee Oncology, PLLC at Sarah Cannon Cancer Center Nashville, Tennessee  37203
Columbia University/ New York Presbyterian Hospital New York, New York  10032