Erlotinib in Treating Patients With Breast Cancer That Can Be Removed by Surgery

Phase II Trial of OSI-774 (Tarceva), a Human Epidermal Growth Factor (HER) (erbB, Also Known as Epidermal Growth Factor Receptor, EGFR) Tyrosine Kinase Inhibitor, in Treatment-Naïve Operable Breast Cancer

RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving erlotinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This phase II trial is studying how well erlotinib works in treating patients with breast cancer that can be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: erlotinib hydrochloride; Genetic: TUNEL assay; Genetic: protein expression analysis; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Other: liquid chromatography; Other: mass spectrometry; Other: matrix-assisted laser desorption ionization mass spectrometry; Procedure: therapeutic conventional surgery

Detailed Description

OBJECTIVES:

Primary

• To determine the in situ antitumor effect of neoadjuvant erlotinib hydrochloride as measured by a reduction in Ki67 and/or an increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-positive tumor cells in patients with treatment-naive, operable breast cancer.

Secondary

• To identify a molecular profile, based on measurements of Estrogen Receptor (ER), Epidermal Growth Factor Receptor (EGFR), and a Human Epithelial Growth Factor Receptor-2(HER2), and protein expression profiles in patients with treatment-naïve, operable breast cancer that is responsive to erlotinib hydrochloride.
• To correlate tumor concentrations of erlotinib hydrochloride with serum levels immediately before surgery.

OUTLINE: This is a multi-center study.

Patients receive oral erlotinib hydrochloride once daily for 5-14 days. Patients then undergo surgical resection within 24 hours after the last dose of erlotinib hydrochloride.

Tumor tissue samples are collected at baseline and during surgery for correlative laboratory studies. Tissue samples are stained for ER, HER2, and EGFR levels, proliferation (Ki67), and apoptosis (TUNEL) by immunohistochemistry. Levels of erlotinib hydrochloride in tissue samples are measured by matrix-assisted laser desorption/ionization mass spectrometry. Blood samples are collected on the day of surgery. Levels of erlotinib hydrochloride in blood samples are measured by liquid chromatography/mass spectrometry.

Patients are followed within 6 weeks after surgery.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama, Birmingham
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Lineberger Comprehensive Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
    • Nashville, Tennessee, United States, 37208
      • Meharry Medical College

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

Inclusion Criteria:

• Clinical stage I or II (T1 or T2, N0 or N1) invasive mammary carcinoma

  • Diagnosis may be made by fine needle aspiration cytology or core biopsy

    • A repeat core biopsy is not required for patients who have a paraffin embedded diagnostic core biopsy specimen available for immunohistochemical staining

Exclusion Criteria:

• Patients with locally advanced disease who are planning to undergo preoperative neoadjuvant therapy are not eligible*

  • Locally advanced disease includes any of the following:

    • Primary tumor ≥ 5 cm (T3)
    • Tumor of any size with direct extension to the chest wall or skin (T4a-c)
    • Inflammatory breast cancer (T4d)
    • Fixed axillary lymph node metastases (N2)
    • Metastasis to ipsilateral internal mammary node (N3) NOTE: *Patients with primary tumors ≥ 5 cm (T3) or tumors involving the chest wall or skin who are not candidates for preoperative chemotherapy or who decline preoperative chemotherapy are eligible

• Measurable residual tumor at the primary site

  • Measurable disease is defined as any mass that can be reproducibly measured by physical examination
• Planning to undergo surgical treatment with either segmental resection or total mastectomy
• Patients with a prior history of contralateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer
• No locally recurrent breast cancer
• No evidence of distant metastatic disease (i.e., lung, liver, bone, or brain metastases)
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• ANC ≥ 1,000/mm^3
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 times ULN
• Serum glutamic oxaloacetic transminase (SGOT) and serum glutamic pyruvic transminase (SGPT) ≤ 1.5 times ULN
• Must be at least 18 years old
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No serious medical illness that, in the judgement of the treating physician, places the patient at high risk of operative mortality

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy for this primary breast cancer
• At least 7 days since prior tamoxifen or raloxifene as a preventive agent

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: Tarceva

Drug: erlotinib hydrochloride; Tarceva will be given orally at a dose of 150 mg/day for 5-14 days. Patients are to undergo surgical resection of their tumor within 24 hours of the last dose of Tarceva.; Other Names: OSI-774; erlotonib; Genetic: TUNEL assay; Used to assess drug-induced changes in tumor cell proliferation and cell death in pre-therapy and surgical specimens; Genetic: protein expression analysis; Used to assess drug-induced changes in tumor cell proliferation and cell death in pre-therapy and surgical specimens; Other: immunohistochemistry staining method; Used to assess drug-induced changes in tumor cell proliferation and cell death in pre-therapy and surgical specimens; Other: laboratory biomarker analysis; Used to assess level of expression of genetic markers in pre-therapy and surgical specimens; Other: liquid chromatography; Used to determine blood plasma levels of Erlotinib on the day of surgery; Other Names: (LC/MS); Other: mass spectrometry; Used to determine blood plasma levels of Erlotinib on the day of surgery; Other Names: (LC/MS); Other: matrix-assisted laser desorption ionization mass spectrometry; After treatment and following surgery, intervention will be used to determine Tarceva levels in tissue; Other Names: MALDI MS; Procedure: therapeutic conventional surgery; Surgical treatment will occur within 24-hours following completion of therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing in Situ Anti-tumor Effect of Tarceva	In situ anti-tumor effect of Tarceva as measured by a minimum 75% reduction in Ki67 compared to pre-treatment tumor cells in patients with operable breast cancer.	5-14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular Profile of Participants Who Are Responsive to Tarceva	Determined by estrogen receptor status (ER) and human epidermal growth factor receptor 2 (HER2) status, which are measured by staining of 200-500 tumor cells and noting the number stained. Positive = > 10% of cell show staining, negative = < 10% of cells show staining	at 5-14 days
Average Post-treatment Plasma Level of Erlotinib Hydrochloride	Post-treatment plasma level in µmol/L of erlotinib hydrochloride	After last dose of Tarceva, at 5-14 days, and before surgery

Collaborators and Investigators

• Sponsor: Vanderbilt-Ingram Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Carlos L. Arteaga, MD, Vanderbilt-Ingram Cancer Center

Study record dates

Study Major Dates

• Study Start: August 1, 2002
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: March 11, 2008
• First Submitted That Met QC Criteria: March 11, 2008
• First Posted (Estimate): March 12, 2008

Study Record Updates

• Last Update Posted (Estimate): September 5, 2012
• Last Update Submitted That Met QC Criteria: August 2, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage I breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: VICC BRE 0222; P50CA098131 (U.S. NIH Grant/Contract); VU-VICC-BRE-0222; VU-VICC-020448; R01CA080195 (U.S. NIH Grant/Contract)