Cetuximab + / - Carboplatin for Estrogen Receptor-Negative, Progesterone Receptor-Negative Metastatic Breast Cancer

OBJECTIVES:

Primary

• Compare the overall response rate in women with estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor 2 (HER2)-nonoverexpressing metastatic breast cancer treated with cetuximab with vs without carboplatin.

Secondary

• Compare the time to disease progression in patients treated with these regimens.
• Correlate downstream effects of epidermal growth factor receptor (EGFR) inhibitor on Mitogen-activated protein kinases (MAPK), Protein kinase B (AKT), monoclonal antibody Ki-67 (Ki67), and EGFR-dependent signaling, proliferation, and apoptosis with toxicity and response in patients with accessible tumors treated with these regimens.
• Determine the changes in biomarkers and gene expression in circulating tumor cells during treatment.
• Compare the overall survival rate in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive cetuximab IV over 60-120 minutes once a week.
• Arm II: Patients receive cetuximab as in arm I and carboplatin IV on days 1, 8, and 15.

In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients not responding to treatment in arm I may cross over to arm II.

Blood samples are collected periodically throughout study for correlative biomarker analysis by Immunohistochemistry (IHC) and gene expression analysis.

After completion of study treatment, patients are followed every 4 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed breast cancer

• Metastatic (stage IV) disease
• Measurable disease by RECIST criteria

• Irradiated lesions are not considered measurable disease
• Central nervous system (CNS) metastases allowed if disease is stable (no evidence of progression) ≥ 3 months after local therapy
• No lesions identifiable only by positron emission tomography (PET) scan
• HER2 nonoverexpressing disease by IHC (0 or 1) or non-gene amplified by Fluorescence In Situ Hybridization (FISH)

• HER2 2+ by IHC allowed
• Hormone receptor status:

• Estrogen receptor-negative and progesterone receptor-negative tumor

Inclusion criteria

• At least 18 years of age
• Metastatic breast cancer (Stage IV) with measurable disease by RECIST criteria
• No more than three prior chemotherapy regimens either in the adjuvant or metastatic setting.
• Histologically documented (either primary or metastatic site) breast cancer that is estrogen receptor- (ER-) negative, PR-negative, and HER-2 nonoverexpressing by immunohistochemistry (0,1) or non-gene amplified by FISH performed upon the primary tumor or metastatic lesion. HER-2 2+ by immunohistochemistry is usually negative by FISH, and this confirmatory test should be performed when possible, however may participate if fulfill other criteria.
• Completion of prior chemotherapy at least 3 weeks prior to study entry.
• Patients may have received therapy (ies) in the adjuvant or metastatic setting, however must have discontinued prior to entry. Patients may receive concurrent bisphosphonates, however if taking bisphosphonates, bone lesions may not be used for progression or response.
• Radiation therapy must be completed at least 2 weeks prior to study entry, and radiated lesions may not serve as measurable disease.
• Patients may have CNS metastases if stable (no evidence of progression) > 3 months after local therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and life expectancy of at least 6 months.
• Adequate organ function defined as:absolute neutrophil count (ANC) > 1500/mm3, plts > 100,000/mm3, creatinine clearance >50 mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) (or ≤5 x ULN in case of liver metastases); total bilirubin ≤1.5 mg/dL.
• Tissue block available for EGFR studies is recommended, although will not exclude patients from participating.
• Pregnant or lactating women will be excluded. Women of child bearing potential must have documented negative pregnancy test within two weeks of study entry and agree to acceptable birth control during the duration of the study therapy.
• Signed written informed consent.

Exclusion criteria

• Lesions identifiable only by PET.
• More than three prior chemotherapy regimens (including adjuvant). Sequential regimens such as doxorubicin and cyclophosphamide followed by paclitaxel (AC-paclitaxel) are considered one regimen.
• Prior therapy which specifically and directly targets the EGFR pathway with therapeutic intent.
• Prior platinum agent for metastatic disease. If platinum agent was used adjuvantly, the patient must have had at least 12 months disease-free interval prior to relapse.
• Prior severe infusion reaction to a monoclonal antibody.
• Major medical conditions that might affect study participation (uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection).
• Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy that is either symptomatic or asymptomatic but with decreased ejection fraction <45%
• Other significant comorbid condition which the investigator feels might compromise effective and safe participation in the study.
• Inability to comply with the requirements of the study.