Efficacy and Safety Study of Bevacizumab and Erlotinib to Treat Primary Liver Cancer That Cannot be Removed By Surgery
Condition: Hepatocellular Carcinoma; Liver Cancer
MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms
Intervention: Bevacizumab (Avastin); Erlotinib
Intervention description: 10 mg/kg IV every 14 days, repeat cycle every 28 days; 150 mg orally every day continuous dosing, repeat cycle every 28 days
Intervention MeSH terms: Bevacizumab; Erlotinib Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatocellular Carcinoma; Liver Cancer; Bevacizumab; Anti-VEGF monoclonal antibody; rhuMAb-VEGF; Erlotinib Hydrochloride; OSI-774; Tarceva; Erlotinib; Avastin

Summary:

      The primary objective will be to assess progression-free survival (PFS) measured at 16 weeks
      following initiation of therapy with the combination of Avastin and erlotinib in patients
      with unresectable hepatocellular carcinoma (HCC). Progression-free survival is defined as the
      time from initiation of therapy until documented disease progression or death.

      Secondary objectives include: response rate, median and overall survival, toxicity and
      tolerability, and to ascertain whether there is any correlation of response with prior
      treatment status and underlying HCC risk factor(s).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have histologically confirmed hepatocellular carcinoma not amenable to
             curative resection.

          2. Patients must have measurable disease as per the Response Evaluation Criteria In Solid
             Tumors (RECIST) criteria.

          3. Patients are allowed to have had up to one prior systemic therapy, including
             chemotherapy or hormonal therapy. Previous treatments that are 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). Any prior therapy must have been
             completed >/= 30 days prior to study entry.

          4. Eastern Cooperative Oncology Group (ECOG) performance status of </= 2.

          5. Childs-Pugh status of A or B.

          6. Organ function: Absolute peripheral granulocyte count of >/= 1500 mm(3), platelet
             count of >/= 40,000 mm(3), hemoglobin >/= 10 gm/dL. Total bilirubin </= 2.0 gm/dL;
             serum albumin >/= 2.5 gm/dL; transaminases up to 5 times the upper limit of
             institutional normal; and prothrombin time prolonged not more than 3 seconds greater
             than institutional normal, once attempts to correct a prolonged PT have been made.
             Patients who require full dose anticoagulation, who are otherwise eligible for this
             trial, are allowed to have an appropriately prolonged International Normalized Ratio
             (INR).

          7. Negative 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.

          8. Fertile men and women must agree to use adequate contraception prior to study entry
             and for the duration of study participation.

          9. Age >/= 18 years. The agents Avastin 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.

        Exclusion Criteria:

          1. Patients who have had prior vascular endothelial growth factor (VEGF) - or epidermal
             growth factor receptor (EGFR)-targeted therapy.

          2. History of prior malignancy other than non-melanoma skin cancer or cervical dysplasia,
             within five years prior to protocol entry.

          3. History of ruptured Hepatocellular carcinoma (HCC) lesion, or HCC lesion with large
             necrotic areas seen on conventional imaging studies, as determined by the Principal
             Investigator.

          4. Abnormalities of the cornea based on history (eg dry eye syndrome, Sjogren's syndrome)
             or congenital abnormality (eg Fuch's dystrophy).

          5. Gastrointestinal disease resulting in an inability to take oral medication or a
             requirement for intravenous hyperalimentation.

          6. Uncontrolled intercurrent illness including but not limited to: ongoing or active
             infection requiring parenteral therapy; known HIV disease, New York Heart Association
             Class II or greater heart failure, cardiac arrhythmia not controlled by medication,
             uncontrolled psychiatric illness, a history of or current evidence of unexplained
             nephrotic syndrome, history of uncontrolled hypertension (defined as systolic blood
             pressure >140 and/or diastolic blood pressure > 90) that is refractory to medical
             management.

          7. Patients may not have received any other investigational agents nor have received any
             systemic chemotherapy </=30 days prior to enrollment.

          8. History of significant gastrointestinal bleeding requiring procedural intervention (eg
             variceal banding, TIPS procedure, arterial embolization) within 3 months prior to
             study enrollment. 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, hypersplenism, or radiographic
             findings of varices) will be screened for esophageal varices. If varices are
             identified that require intervention (banding),patient will not be eligible until
             varices adequately treated.

          9. History of myocardial infarction or unstable angina within 6 months.

         10. History of stroke within 6 months.

         11. Any prior history of hypertensive crisis or hypertensive encephalopathy.

         12. Significant or symptomatic vascular disease (e.g., aortic aneurysm, aortic dissection,
             or peripheral vascular disease).

         13. Evidence of clinically significant (Common Toxicity Criteria (CTC) Grade 3 or 4)
             venous or arterial thrombotic disease within previous 6 months.

         14. Current evidence of bleeding disorder or coagulopathy that is not controlled by
             conservative medical management.

         15. Known presence or clinical evidence of central nervous system or brain metastases.

         16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 0, or anticipation of need for major surgical procedure during the course
             of the study.

         17. Minor surgical procedures, fine needle aspirations or core biopsies, excluding
             placement of a vascular access device, within 7 days prior to Day 0.

         18. Pregnant (positive pregnancy test) or lactating.

         19. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months prior to Day 0.

         20. Serious, non-healing wound, ulcer, or bone fracture.

         21. Proteinuria at screening as demonstrated by either: Urine protein:creatinine (UPC)
             ratio >/= 1.0 at screening, or: Urine dipstick for proteinuria >/= 2+ (patients
             discovered to have >/= 2+ proteinuria on dipstick urinalysis at baseline should
             undergo a 24 hour urine collection and must demonstrate </= 1g of protein in 24 hours
             to be eligible).

         22. Known hypersensitivity to any component of Avastin

         23. Inability to comply with study and/or follow-up procedures.

         24. Radiographic evidence of major tumor thrombus in the vena cava.