Bevacizumab and Erlotinib Hydrochloride in Treating Patients With Metastatic or Unresectable Biliary Tumors

A Phase II Trial of Bevacizumab and Erlotinib in Patients With Advanced Biliary Tumors

This phase II trial is studying how well giving bevacizumab together with erlotinib hydrochloride works in treating patients with metastatic or unresectable biliary tumors. 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 hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and erlotinib hydrochloride may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with erlotinib hydrochloride may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder
• Intervention / Treatment: Drug: erlotinib hydrochloride; Biological: bevacizumab

Detailed Description

PRIMARY OBJECTIVES:

I. Evaluate the objective response rate in patients with metastatic or unresectable cholangiocarcinoma treated with bevacizumab and erlotinib hydrochloride.

SECONDARY OBJECTIVES:

I. Evaluate time to progression in these patients.

II. Evaluate overall and progression-free survival of these patients.

III. Evaluate the adverse events associated with this regimen. OUTLINE: This is an open-label, multicenter study.

Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15 and oral erlotinib hydrochloride daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

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

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Criteria:

• Absolute neutrophil count >= 1,500/mm3

• Histologically or cytologically confirmed cholangiocarcinoma or gallbladder carcinoma:

  • Metastatic or surgically unresectable disease

• Measurable disease, defined as >= 1 lesion whose longest diameter can be accurately measured as >= 2.0 cm with conventional techniques or as > 1.0 cm with spiral CT scan:

  • Spiral CT scan imaging must be used for pre- and post-treatment tumor measurements of lesions measuring >= 1.0 cm to < 2.0 cm

• Clinical lesions will only be considered measurable when they are superficial

  • Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung
• No ampulla of Vater tumors
• No evidence of CNS disease
• Life expectancy >= 3 months
• ECOG performance status 0-2
• Platelet count >= 75,000/mm3
• Total bilirubin =< 2 times ULN
• ALT and AST =< 2.5 times ULN
• Creatinine =< 2 mg/dL
• Albumin >= 2.5 g/dL
• Alkaline phosphatase =< 5 times ULN
• Urine protein:creatinine ratio < 1.0 OR 24-hour urine protein < 1000 mg

• No concurrent illness or medical condition, including any of the following:

  • Impairment of gastrointestinal (GI) function or disease that may significantly alter the absorption of erlotinib hydrochloride
  • Requirement for IV alimentation

• No concurrent illness or medical condition, including any of the following:

  • Active peptic ulcer disease;
  • Serious or nonhealing wound, ulcer, or bone fracture;
  • GI bleed that required procedural intervention within the past 3 months

• No concurrent illness or medical condition, including any of the following:

  • Abdominal fistula, GI perforation, or intra-abdominal abscess within the past 28 days
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Psychiatric illness or social situation that would limit study compliance
• No other malignancy within the past 3 years
• No abnormalities of the cornea
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No clinically significant cardiovascular disease
• More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
• No significant traumatic injury within the past 28 days
• No prior systemic anticancer therapy for metastatic gallbladder or bile duct cancer
• More than 28 days since prior major surgery [Note: Insertion of a vascular access device is not considered major/minor surgery]
• More than 2 weeks since prior minor surgery [Note: Insertion of a vascular access device is not considered major/minor surgery]
• More than 7 days since prior core biopsy
• No concurrent major surgery
• No other concurrent chemotherapy, immunotherapy, radiotherapy, or any other therapy or supportive care considered investigational
• No concurrent enzyme-inducing antiepileptic drugs or any other CYP3A4 inducer, such as rifampin or Hypericum perforatum
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents or other concurrent anticancer therapies
• No concurrent prophylactic hematopoietic colony-stimulating factors

• Concurrent full-dose anticoagulants allowed provided PT/INR is > 1.5 and both of the following criteria are met:

  • In-range INR 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 ulcerations, or known varices)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Bevacizumab and Erlotinib Hydrochloride; Patients receive 5 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15 and 150 mg oral erlotinib hydrochloride daily on days 1-28. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Tumor tissue and blood specimens are collected periodically for correlative studies. Specimens are examined by immunohistochemistry for epidermal growth factor receptor (EGFR) and P-EGFR protein levels; AKT p-AKT, mitogen-activated protein kinase (MAPK) and P-MAPK protein levels; and vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2 protein levels. EGFR mutations are detected by laser capture microdissection. Enzyme-linked immunosorbent assay is used to measure total and free serum VEGF levels.

Drug: erlotinib hydrochloride; Given orally, 150 mg, once daily.; Other Names: OSI-774; erlotinib; CP-358,774; Biological: bevacizumab; Given IV, 5mg/kg on days 1 and 15 every cycle; Other Names: Avastin; anti-VEGF humanized monoclonal antibody; anti-VEGF monoclonal antibody; rhuMAb VEGF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Confirmed Tumor Responses.	Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the target lesions. A confirmed tumor response is defined to be either a Complete Response or a Partial Response noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Confirmed tumor responses will be evaluated using the first 6 cycles of treatment. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment and had one post-baseline disease assessment will be evaluable for response. Forty-nine of the 53 eligible patients had at least one post-baseline disease assessment and were evaluable for this endpoint.	After 6 courses of treatment. Each course lasts 28 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival Time	Estimated using the method of Kaplan-Meier (1958).	From registration to death due to any cause, assessed up to 3 years
Time to Disease Progression	Estimated using the method of Kaplan-Meier (1958).	From registration to documentation of disease progression, assessed up to 3 years
Duration of Response	Point estimates and 95% confidence intervals were calculated using the method of Duffy and Santner (1987).	From 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, assessed up to 3 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: William Schelman, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: July 26, 2006
• First Submitted That Met QC Criteria: July 26, 2006
• First Posted (Estimate): July 27, 2006

Study Record Updates

• Last Update Posted (Estimate): May 28, 2014
• Last Update Submitted That Met QC Criteria: May 12, 2014
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Digestive System Neoplasms; Gastrointestinal Diseases; Gallbladder Diseases; Biliary Tract Diseases; Bile Duct Diseases; Biliary Tract Neoplasms; Recurrence; Gastrointestinal Neoplasms; Cholangiocarcinoma; Gallbladder Neoplasms; Bile Duct Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Antibodies; Erlotinib Hydrochloride; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological
• Other Study ID Numbers: NCI-2009-00115; N01CM17104 (U.S. NIH Grant/Contract); MC044G; CDR0000484566 (Registry Identifier: PDQ (Physician Data Query))