Patient case: 56-year-old female with breast cancer; genetic feature: ERBB2

Clinical trial: Phase II Neoadjuvant Doxorubicin and Cyclophosphamide -> Docetaxel With Lapatinib in Stage II/III Her2Neu+ Breast Cancer

Summary: This trial combines dose dense chemotherapy with Doxorubicin and Cyclophosphamide (AC) followed by standard every 3 week docetaxel and GW572016 for neoadjuvant treatment of her2neu positive stage II/III breast cancer. GW572016 or Lapatinib, the investigational agent, acts as a duel inhibitor of both epidermal growth factor receptor (EGFR) and ErbB-2 (Her2/neu) tyrosine kinase activity. EGFR and ErbB2 receptors are frequently over-expressed or altered in human cancers including breast cancer. This study plans to determine the antitumor activity of this regimen and its effectiveness of preventing tumor growth and spread.

Detailed description: This trial combines dose dense chemotherapy with Doxorubicin and Cyclophosphamide (AC) followed by standard every 3 week docetaxel and GW572016 for neoadjuvant treatment of her2neu positive stage II/III breast cancer. GW572016 or Lapatinib, the investigational agent, acts as a duel inhibitor of both epidermal growth factor receptor (EGFR) and ErbB-2 (Her2/neu) tyrosine kinase activity. EGFR and ErbB2 receptors are frequently over-expressed or altered in human cancers including breast cancer. This study plans to determine the antitumor activity of this regimen and its effectiveness of preventing tumor growth and spread.
  The primary objective of the study is to improve pathological complete response rates with the addition of dual EGFR blockade. Neoadjuvant chemotherapy which achieves pathologic complete responses (pCR) has been shown to predict improved long-term survival and serves as a surrogate for clinical outcome. By using this primary endpoint we can obtain statistical data with smaller patient numbers and at a lower overall cost. Additionally, we hope to correlate clinical and radiologic outcomes with gene expression data.

Eligibility: Inclusion Criteria:- Women with histologically confirmed Her2neu positive breast cancer. Patients are considered Her2Neu positive by either Immunohistochemistry (IHC) 3+ or Fluorescence In Situ Hybridization (FISH)+
  -  Stage II/III breast cancer including any large primary tumor (> 2 cm), tumors of any size associated with skin or chest wall involvement, tumors of any size with axillary lymph node involvement, (T2-T4, N0-N2) and those with ipsilateral subclavicular or supraclavicular lymph nodes).
  -  At least one bidimensional, measurable indicator lesion. All sites of disease should be noted and followed. Baseline measurements and evaluations of tumor must be done within 3 weeks prior to initiation of treatment.
  -  Patients must be between 18 and 70 years of age
  -  ECOG performance status 2/ Karnofsky > 60% at screening and on the first day of treatment.
  -  Informed consent must be obtained prior to registration.
  -  Cardiac ejection fraction within the institutional range of normal as measured by MUGA scan. Note that baseline and on treatment scans should be performed using the same modality and preferably at the same institutions
  -  Patients must have normal organ and marrow function as defined below:
  -  Hematologic (minimal values)
  1. Absolute neutrophil count > 1,500/mm3
  2. Hemoglobin > 8.0 g/dl
  3. Platelet count > 100,000/mm^3
  -  Creatinine within normal institutional limits
  -  Hepatic
  1. Total Bilirubin equal to or less than ULN
  2. AST and ALT and Alkaline Phosphatase must be within the range allowing for eligibility.
  3. In determining eligibility the more abnormal of the two values (AST or ALT) should be used.
  -  Eligibility of patients receiving medications or substances known to affect, or with the potential to affect the activity or pharmacokinetics of GW572016 will be determined following review of their use by the Principal Investigator
  -  Antacid use is prohibited 1 hour before and 1 hour after GW572016 dosing.
  -  All herbal (alternative) medicines are prohibited. In addition please see section 6.6 of the protocol regarding medications that are prohibited during the administration of GW572016 and for the duration of GW572016.
  -  The effects of GW572016 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Must have negative pregnancy test if of child bearing years.
  -  Peripheral neuropathy: must be < grade 1
  -  Able to swallow and retain oral medication
  Exclusion Criteria:- Evidence of disease outside the breast or chest wall, except for ipsilateral axillary , supraclavicular, or infraclavicular lymph nodes.
  -  Prior chemotherapy, immunotherapy, or hormonal therapy for breast cancer.
  -  More than 3 months between histologic diagnosis and registration on this study.
  -  History of other malignancy within the last five years, except curatively treated basal cell carcinoma of the skin or carcinoma in situ of the cervix.
  -  Psychological, familial, sociological or geographical conditions which do not permit weekly medical follow-up and compliance with the study protocol. Patients who are medically unstable, including but not limited to active infection, acute hepatitis, deep vein thrombosis requiring anticoagulant therapy, gastrointestinal bleeding, uncontrolled hypercalcemia, uncontrolled diabetes, dementia, seizures, superior vena cava syndrome, and patients whose circumstances do not permit completion of the study or the required follow-up.
  -  Patients who have congestive heart failure, abnormal LVEF, angina pectoris, uncontrolled cardiac arrhythmias, or other significant heart disease, or who have had a myocardial infarction within the past year.
  -  Pregnant or lactating females, or females of childbearing potential not employing adequate contraception.
  -  History of allergic reactions attributed to compounds of similar chemical or biologic composition to GW572016.
  -  HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with GW572016. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated.
  -  Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis).
  -  Patients with a history of severe hypersensitivity reaction to Taxotere® or other drugs formulated with polysorbate 80.

Relevance to patient case: definitely relevant