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

National Cancer Institute (NCI)

Status and phase: Completed; Phase 2

Conditions: Recurrent Extrahepatic Bile Duct Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Recurrent Gallbladder Cancer; Gastrointestinal Cancer; Unresectable Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Cholangiocarcinoma of the Gallbladder

Treatments: Biological: bevacizumab; Drug: erlotinib hydrochloride

Study type: Interventional

Funder types: NIH

Identifiers

NCT00356889

CDR0000484566 (Registry Identifier)

MC044G

N01CM17104 (U.S. NIH Grant/Contract)

NCI-2009-00115

Details and patient eligibility

About

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.

Full 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.

Enrollment: 56 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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)

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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56 participants in 1 patient group

Bevacizumab and Erlotinib Hydrochloride

Experimental group

Description:

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.

Treatment:

Drug: erlotinib hydrochloride

Biological: bevacizumab