An Open-Label Randomized, Parallel, Two-Arm Phase II Study Comparing BMS-690514 + Letrozole with Lapatinib + Letrozole in Recurrent or Metastatic Breast Cancer Patients Who Are Hormone Receptor Positive Despite HER2 Status And Who Relapsed While Receiving or After Completing Adjuvant Antiendocrine TherapyRevised Protocol 02, incorporating Protocol Amendments 02 and 04+ Pharmacogenetics Blood Sample Amendment Number 01 - Site Specific (version 1.0 dated 20-Nov-09)

Conditions: ocally recurrent or metastatic hormone receptor positive (HR+) breast cancer and either:• HER2+ disease with progression while on adjuvant antiendocrine therapy or at any time after adjuvant antiendocrine therapy, or• HER2- disease with progression while on adjuvant antiendocrine therapy or within 6 months of completing adjuvant antiendocrine therapy.
MedDRA version: 12.1Level: LLTClassification code 10027475Term: Metastatic breast cancer

Registration Number: EUCTR2009-016622-13-DE

Lead Sponsor: Bristol-Myers Squibb International Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Female

Target Recruitment: 175

Inclusion Criteria

1) Signed Written Informed Consent

Target Population
2) Histologically documented invasive breast cancer, positive for ER+ and/or PgR+ in greater than or equal to 10% of tumor cells with tumor tissue from prior surgery available for analysis of ER/PR, EGFR, HER2, PTEN and PIK3CA
3) Patients must have previously received adjuvant treatment for their breast cancer using tamoxifen, anastrozole or exemestane. Sequential use of antihormonal agents is permitted.
a) Patients with HER2- disease must have developed disease progression or recurrence while receiving or within 6 months of completing adjuvant treatment prior to the first dose of randomized study medication
b) Patients with HER2+ disease must have developed disease progression or recurrence while receiving or at any time after receiving adjuvant treatment with prior to the first dose of randomized study medication
4) Patients who received cytotoxic chemotherapy (in the adjuvant, neoadjuvant or metastatic settings) are required to have completed therapy at least 4 weeks prior to the first dose of randomized study medication.
5) Patients who received adjuvant therapy using trastuzumab alone or in combination with either chemotherapy or an aromatase inhibitor are required to have completed therapy at least 2 weeks prior to the first dose of randomized study medication.
a) Patients with newly diagnosed metastatic breast cancer that is HER2+ and HR+ who do not receive treatment with trastuzumab plus aromatase inhibitor standard-of-care therapy (where this is considered an approved use of the combination) are eligible for this study with careful documentation of the reason why trastuzumab-based therapy was not used
6) Patients may have received radiotherapy to a limited area only within 2 weeks prior to the initiation of randomized therapy but this cannot be the sole site of disease and cannot be used as a target lesion
7) ECOG performance status of 0 or 1
8) Patients have disease that is either measurable or non-measurable, including bone only disease without a soft tissue component.
a) Measurable lesions include measurable lytic or lytic/blastic lesions as noted in the RECIST 1.1 criteria. See Appendix 6.
9) Adequate bone marrow function defined as:
a) Absolute neutrophil count > 1500/mm³.
b) Hemoglobin > 10 g/dL (The use of erythropoietin stimulating agents is permitted)
c) Platelet count > 100,000/mm³
10) Adequate renal parameters defined as:
a) Serum creatinine = 1.2 mg/dL or a 24-hour urinary creatinine clearance > 60 mL/min. For patients over the age of 70, a 24-hour urine collection for creatinine clearance must be performed and must indicate a creatinine clearance of > 60 mL/minute.
b) Serum magnesium > 1.5 mg/dL or > 0.5 mmol/L (supplementation to achieve this is acceptable).
c) Serum potassium > 3.5 mEq/L (supplementation to achieve this is acceptable).
11) Adequate hepatic parameters defined as:
a) AST = 2.5 times the institutional ULN
b) ALT = 2.5 times the institutional ULN
c) Alkaline phosphatase = 2 times the institutional ULN
d) Total bilirubin = 2 times the institutional ULN
12) In the presence of documented liver metastases, the hepatic parameters will be defined as:
a) AST = 3.5 times the institutional ULN
b) ALT = 3.5 times the institutional ULN
c) Alkaline phosphatase = 2.5 times the institutional ULN
d) Total bilirubin = 2.5 times the institutional ULN
13) Patients must be able to take oral medications on an empty stomach (1 hour before or 2 hours after a meal)
14

Exclusion Criteria

Target Disease Exceptions
18) Patients who have received prior hormonal therapy for metastatic disease
19) Patients who have received prior hormonal therapy with letrozole for adjuvant disease
20) Not Applicable - This criterion has been deleted per Amendment 02. Patients who present with blastic bony metastatic disease as their only manifestation of recurrent or metastatic breast cancer
21) Patients who have symptomatic brain metastases
22) Patients who have signs or symptoms suggestive of spinal cord compression or any other medical condition that requires immediate radiotherapy, surgery or high dose steroid therapy
23) Other concurrent chemotherapy, hormonal therapy, immunotherapy regimens or radiotherapy, standard or investigational
24) Any history of hemoptysis > 10mL/day within the last 10 days

Medical History and Concurrent Diseases
25) Concurrent or previous malignancies (except for non-melanoma skin cancers, in situ bladder cancer, cervical cancer/dysplasia or any other in situ malignancies) are excluded unless a complete remission was achieved at least 3 years prior to randomization and no additional therapy is required or anticipated to be required during the study period
26) Prior treatment with any tyrosine kinase inhibitor (marketed or investigational)
27) Uncontrolled or significant cardiovascular disease including:
a) Myocardial infarction within 6 months
b) Uncontrolled angina within 6 months
c) Class III-IV New York Heart Association (NYHA) congestive heart failure
d) Uncontrolled hypertension (systolic blood pressure of greater than 150 mmHg or diastolic blood pressure above 90 mmHg for 24 hours) despite optimized antihypertensive therapy.
28) Any history of uncontrolled diarrhea, Crohn’s disease or ulcerative colitis that may be exacerbated by EGFR tyrosine kinase inhibitors
29) Any serious or uncontrolled medical disorder or active infection that would impair the ability of the patient to receive protocol therapy (This includes any possible risks of interactions that may interfere with the control of the medical disorder that is
unrelated to the patient’s breast cancer.)
30) Any surgery within 4 weeks of initiation of randomized therapy
31) Any non-healing wounds or skin ulcers
32) Inability to swallow tablets, malabsorption syndrome or gastrointestinal surgery that results in inability to properly absorb protocol therapy
33) Patients with a documented diagnosis of HIV
34) Any psychiatric or other disorders such as dementia that would prohibit the patients from understanding or rendering informed consent or from fully complying with protocol treatment and follow-up
35) Inability to tolerate multiple blood sampling/or tolerate venous access
36) Any other medical, psychiatric, and/or social reason as determined by the investigator.

Physical and Laboratory Test Findings
37) Cardiac ejection fraction that is below the institutional range of normal as measured by echocardiogram or MUGA

Allergies and Adverse Drug Reaction
38) History of allergy to EGFR/HER2/VEGFR tyrosine kinase inhibitors

Sex and Reproductive Status
39) Women of child-bearing potential or have not undergone menopause
40) Men with breast cancer

Other Exclusion Criteria
41) Prisoners or subjects who are involuntarily incarcerated
42) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness