Phase II Trial of Cetuximab Alone and in Combination With Carboplatin in ER-Negative, PR-Negative, HER-2 Nonoverexpressing Metastatic Breast Cancers (LCCC 0403)

Primary Objectives

• Overall response rate to single agent cetuximab in triple negative metastatic breast cancer.
• Overall response rate to combination cetuximab plus carboplatin in triple negative metastatic breast cancer.

Secondary Objectives

• Time to disease progression on single agent cetuximab
• Time to disease progression on combination cetuximab/carboplatin.
• To correlate downstream effects of EGFR inhibitor on MAPK, AKT, Ki67 and EGFR-dependent signaling, proliferation, and apoptosis and correlate these with toxicity and response in patients with accessible tumors.
• To examine changes in above markers and gene expression in circulating tumor cells during therapy
• Overall survival.

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 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.
• ECOG performance status 0-2 and life expectancy of at least 6 months.
• Adequate organ function defined as: ANC > 1500/mm3, plts > 100,000/mm3, creatinine clearance >50mL/min, ALT and 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 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.