Bevacizumab and Erlotinib in Treating Patients With Advanced Liver Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00365391
First received: August 16, 2006
Last updated: May 24, 2013
Last verified: March 2013
  Purpose

This phase II trial is studying how well giving bevacizumab together with erlotinib works in treating patients with advanced liver cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and erlotinib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with erlotinib may kill more tumor cells


Condition Intervention Phase
Adult Primary Hepatocellular Carcinoma
Advanced Adult Primary Liver Cancer
Localized Unresectable Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer
Biological: bevacizumab
Drug: erlotinib hydrochloride
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Bevacizumab Plus Erlotinib in Patients With Advanced Hepatocellular Cancer (HCC)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Number of Patients With Confirmed Tumor Response Defined to be Either a Complete Response (CR) or Partial Response (PR). [ Time Frame: Patients were able to continue treatment indefinitely and were evaluated every cycle until discontinued treatment. ] [ Designated as safety issue: No ]
    Responses to erlotinib and bevacizumab treatment were evaluated using RECIST Criteria. A Complete Response (CR) is defined as the disappearance of all target lesions. A Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of the longest diameters.


Secondary Outcome Measures:
  • Survival Time [ Time Frame: From registration to death due to any cause, patients are followed up to 3 years after treatment ] [ Designated as safety issue: No ]
    Survival time is defined as the time from registration to death due to any cause. Estimated using the method of Kaplan-Meier.

  • Time to Disease Progression [ Time Frame: From registration to documentation of disease progression ] [ Designated as safety issue: No ]
    Time to disease progression is defined as the time from registration to documentation of disease progression. Estimated using the method of Kaplan-Meier.

  • Duration of Response [ Time Frame: The date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented. ] [ Designated as safety issue: No ]
    Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented.

  • Time to Treatment Failure [ Time Frame: From the date of randomization to the date at which the patient is removed from treatment due to progression, toxicity, or refusal. ] [ Designated as safety issue: No ]
    Time to treatment failure is defined to be the time from the date of randomization to the date at which the patient is removed from treatment due to progression, toxicity, or refusal.


Enrollment: 27
Study Start Date: August 2006
Study Completion Date: August 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (monoclonal antibody, enzyme inhibitor)
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 EGFR and phosphorylated-EGFR protein levels using initial diagnostic biopsy specimens by IHC for correlation with clinical outcome. Levels of proteins through which EGFR signals, including Akt, phosphorylated-Akt, 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 ELISA.
Biological: bevacizumab
Given IV, 10 mg/kg, days 1 and 15 in every cycle
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Drug: erlotinib hydrochloride
Given orally, 150 mg, every day during each cycle.
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774

Detailed Description:

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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 measures.

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 (ELISA).

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 requirements
  • 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 lung
  • No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 28 days
  • No concurrent prophylactic hematopoietic colony-stimulating factors
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00365391

Locations
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Investigators
Principal Investigator: Philip Philip Mayo Clinic
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00365391     History of Changes
Obsolete Identifiers: NCT01649076
Other Study ID Numbers: NCI-2009-00136, MC044I, N01CM62205
Study First Received: August 16, 2006
Results First Received: March 22, 2013
Last Updated: May 24, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Liver Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Bevacizumab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Erlotinib
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Immunologic Factors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 19, 2014