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A Phase II Trial of Erlotinib Plus Bevacizumab in Advanced Hepatocellular Carcinoma as a Second-line Therapy in Patients Who Have Received First-line Sorafenib Therapy (AVF4572)

Phase 2
18 Years
Open (Enrolling)
Liver Cancer

Thank you

Trial Information

A Phase II Trial of Erlotinib Plus Bevacizumab in Advanced Hepatocellular Carcinoma as a Second-line Therapy in Patients Who Have Received First-line Sorafenib Therapy (AVF4572)

The Study Drugs:

Bevacizumab is designed to block the growth of blood vessels that supply nutrients necessary
for tumor growth. This may prevent or slow down the growth of cancer cells.

Erlotinib hydrochloride is designed to block the activity of a protein found on the surface
of many tumor cells that may control tumor growth and survival. This may stop tumors from
growing. There is a commercially available form of the drug (called Tarceva) that is
expected to be very similar to the erlotinib being used for this study, but it is possible
that there may be some differences between the 2 formulations.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive the study drugs
during 28-day "study cycles."

You will receive bevacizumab by vein on Days 1 and 15 of each cycle. The first dose of
bevacizumab will be given over about 90 minutes. If you do not have a reaction to the drug,
such as fever and/or chills, the next dose will be given over about 60 minutes. If you
still have no reaction after the second dose, each dose after that will be given over about
30 minutes. If you experience a reaction to the bevacizumab, you may be given Tylenol®
(acetaminophen) by mouth and/or an antihistamine by vein over 30 minutes before each dose to
help minimize the risk of further reactions.

You will take 1 erlotinib hydrochloride tablet by mouth every day. You should take
erlotinib hydrochloride in the morning with a full glass of water (6-8oz) at least 1 hour
before or 2 hours after any food, grapefruit juice, vitamins, iron supplements, or other
non-prescription drugs.

Study Visits:

On Day 1 of Cycle 2 and beyond:

- Blood (about 3 tablespoons) will be drawn for routine blood tests and to check how well
the blood clots.

- Urine will be collected for routine testing. A 24-hour urine sample may be collected
if needed. If a 24-hour urine sample is needed, you will be provided with a special
container to collect the sample.

- You will be asked questions about any side effects you may have had and about any drugs
you may be currently taking or have taken since you last saw the study doctor.

- You will have a complete physical exam, including measurements of weight and vital

- Your performance status will be recorded.

On Day 15 of Cycle 2 and beyond, your vital signs will be recorded.

At the end of Cycle 2, 4, and every 2 cycles after that (Cycles 6, 8, 10, and so on):

-You will have CT/MRI scans of the abdomen and pelvis and chest scan (if the doctor thinks
they are needed) to check the status of the disease.

Additional tests may be done during the study if the study doctor thinks it is necessary.

Length of Treatment:

You will receive bevacizumab and erlotinib hydrochloride for as long as you are benefitting.
There is no maximum number of cycles that you can receive. If you experience severe side
effects, the treatment on this study may be delayed, stopped, or the study doctor may give
you smaller doses of the study drugs. You will be taken off study if the disease gets
worse, the side effects are too severe, or your doctor thinks that it is in your best
interest to stop receiving treatment.

End-of-Treatment Visit:

After you stop receiving all of the study drugs, you will return for an end-of-treatment
visit. At this visit, the following tests and procedures will be performed:

- Blood (about 3 tablespoons) and urine will be collected for routine tests and to learn
how well the blood clots.

- You will be asked questions about any side effects you may have had and about any drugs
you may be currently taking or have taken since you last saw the study doctor.

- You will have a complete physical exam, including measurements of weight and vital

- Your performance status will be recorded.

- CT and/or MRI scans of the abdomen and pelvis will be performed to check the status of
the disease.


After the end-of-treatment visit, the study doctor will continue to review your medical
records every 3 months until the study analysis is complete. You will also be called every
3 months for as long as the study doctor thinks is needed. During these phone calls, you
will be asked about how you are doing and if you are experiencing any health problems. The
phone call should take about 15 minutes. During the follow-up period, if the study doctor
thinks it is necessary, you may be asked to come in for a clinic visit.

This is an investigational study. Bevacizumab is FDA approved and commercially available
for the treatment of metastatic colon and rectal cancer. Erlotinib hydrochloride is FDA
approved and commercially available for the treatment of lung cancer. The use of this drug
combination in patients with advanced liver cancer is investigational.

Up to 44 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients with histological or cytologically documented HCC not amenable to curative
resection (documentation of original biopsy for diagnosis is acceptable if tumor
tissue is unavailable) or clinical diagnosis by American Association for the Study of
Liver Diseases (AASLD) criteria in cirrhotic subjects is required. For subjects
without cirrhosis, histological or cytological confirmation is mandatory.

2. Patients must have measurable disease as per the modified RECIST criteria. Measurable
target lesions are defined at baseline as lesions that can be accurately measured in
at least one dimension (longest diameter to be recorded) >/= 20 mm using conventional
techniques (CT or MRI) or >/= 10 mm using spiral CT scan. Lesion must not be chosen
from a previously irradiated field, unless there has been documented disease
progression in that field after irradiation.

3. Patients who have progressed on, or were intolerant to, one prior systemic therapy
with sorafenib, completed ≥ 14 days prior to treatment day 1. Previous treatments
also allowed that do not count as systemic therapy include: surgical resection,
transarterial embolization/chemoembolization (TAE/TACE), radiofrequency ablation
(RFA), percutaneous ethanol injection (PEI), provided that the lesion(s) to be
evaluated in this study are separate from the previously treated lesions(s).

4. Eastern Cooperative Oncology Group (ECOG) performance status of
5. Childs-Pugh liver function status of A or B (only 7 points allowed).

6. Organ function: Absolute peripheral granulocyte count of >/= 1500 mm^3, platelet
count of >/= 40,000 mm^3, hemoglobin >/= 10 gm/dL. Total bilirubin serum albumin >/= 2.5 gm/dL; asparate aminotransferase (AST) and alanine
aminotransferase (ALT) up to 5 X the upper limit of institutional normal (AST - 46
and ALT - 56); and prothrombin time prolonged not more than 3 seconds greater than
institutional normal, once attempts to correct a prolonged PT have been made.

7. (Continuation of # 6) Patients who require full dose anticoagulation, who are
otherwise eligible for this trial, are allowed to have an appropriately prolonged
International Normalized Ratio (INR).

8. Negative serum pregnancy test in women with childbearing potential (those who are not
surgically sterilized or who are not amenorrheic for >/= 12 months), within one week
prior to initiation of treatment.

9. Men and women of childbearing potential must agree to use effective means of
contraception prior to study entry and for at least 180 days after the last dose of
study treatment. They must agree to use two forms of birth control, for example,
barrier methods (such as a diaphragm, cervical cap, contraceptive sponge, female
condom, or male condom), and an intrauterine device (IUD).

10. Age >/= 18 years. The agents bevacizumab and erlotinib have not been studied in
pediatric patients, thus the doses to be used in this study cannot be assumed to be
safe in children.

11. Radiographic evidence of disease progression during or following prior treatment with

12. Patients must have proteinuria < 2+ or a urine protein:creatinine (UPC) ratio < 1.0.
Patients who have proteinuria >/= 2+ and UPC ratio >/= 1.0 must undergo a 24 hour
urine collection and must demonstrate
Exclusion Criteria:

1. Patients who have had prior systemic therapy other than sorafenib. Patients may not
have received any systemic chemotherapy
2. Active malignancy other than superficial basal cell and superficial squamous (skin)
cell, or carcinoma in situ of the cervix within last five years.

3. Current, recent (within 4 weeks of Treatment Day 1) or planned participation in an
experimental drug study, other than this study.

4. Gastrointestinal disease resulting in an inability to take oral medication or a
requirement for intravenous hyperalimentation.

5. History of rupture of existing HCC lesion, or HCC lesion with large necrotic areas
seen on conventional imaging studies, as determined by the Principal Investigator, if
there is no measurable solid tumor area > 1.5 cm.

6. Inadequately controlled hypertension (defined as systolic blood pressure >140 and/or
diastolic blood pressure > 90).

7. Prior history of hypertensive crisis or hypertensive encephalopathy.

8. New York Heart Association Class II or greater congestive heart failure.

9. Cardiac arrhythmia not controlled by medication.

10. History of myocardial infarction or unstable angina within 6 months of Treatment Day

11. History of stroke or transient ischemic attack within 6 months prior to Day 1 of

12. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1.

13. Evidence of clinically significant [Common Terminology Criteria (CTC) Grade 3 or 4]
venous or arterial thrombotic disease within previous 6 months.

14. Radiographic evidence of major tumor thrombus in the vena cava.

15. History of hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) within 1
month prior to Day 1.

16. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation).

17. History of significant gastrointestinal bleeding requiring procedural intervention
(eg variceal banding, Transjugular Intrahepatic Portosystemic Shunts (TIPS)
procedure, arterial embolization) within three months prior to treatment day 1.
Patients at risk for varices (based on the following: known history of esophageal or
gastric varices; evidence of hepatic cirrhosis and/or portal hypertension including
biopsy-proven cirrhosis, radiographic evidence of cirrhosis, hypersplenism, or
radiographic findings of varices) will be screened for esophageal varices.

18. (Continuation of # 17) If varices are identified that require intervention (banding),
that patient will not be eligible for the trial until the varices have been
adequately treated.

19. Known CNS disease, except for treated brain metastases. Treated brain metastases are
defined as having no evidence of progression or hemorrhage after treatment and no
ongoing requirement for dexamethasone, as ascertained by clinical examination and
brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose)
are allowed. Treatment for brain metastases may include whole brain radiotherapy
(WBRT), radiosurgery (RS; Gamma Knife, linear accelerator (LINAC), or equivalent) or
a combination as deemed appropriate by the treating physician.

20. (Continuation of # 20) Patients with CNS metastases treated by neurosurgical
resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.

21. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1, or anticipation of need for major surgical procedure during the
course of the study.

22. Core biopsy, fine needle aspiration, or other minor surgical procedure, excluding
placement of a vascular access device, within 7 days prior to Day 1.

23. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to Day 1.

24. Serious, non-healing wound, active ulcer, or untreated bone fracture.

25. 0ngoing or active infection requiring parenteral therapy.

26. Known HIV disease.

27. Uncontrolled psychiatric illness.

28. Known hypersensitivity to any component of bevacizumab and erlotinib.

29. Pregnancy (positive pregnancy test) or lactation.

30. Inability to comply with study and/or follow-up procedures.

Type of Study:


Study Design:

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

Outcome Measure:

Number of Patients with Progression Free Survival (PFS) at 16 weeks

Outcome Description:

Progression-free survival is defined as time from initiation of therapy until documented disease progression or death.

Outcome Time Frame:

16 weeks

Safety Issue:


Principal Investigator

Ahmed Kaseb, MBBS

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

April 2011

Completion Date:

Related Keywords:

  • Liver Cancer
  • Advanced Liver Cancer
  • primary neoplasm of the liver
  • Erlotinib
  • Bevacizumab
  • Hepatocellular Carcinoma
  • HCC
  • Avastin
  • Anti-VEGF monoclonal antibody
  • rhuMAb-VEGF
  • OSI-774
  • Tarceva
  • Carcinoma
  • Liver Neoplasms
  • Carcinoma, Hepatocellular



UT MD Anderson Cancer Center Houston, Texas  77030