Study Evaluating Bosutinib-Letrozole Combination Versus Letrozole Alone In Post Menopausal Women With Breast Cancer

A PHASE 2, RANDOMIZED, OPEN-LABEL STUDY OF BOSUTINIB ADMINISTERED IN COMBINATION WITH LETROZOLE VS. LETROZOLE ALONE AS FIRST LINE THERAPY IN POST-MENOPAUSAL WOMEN WITH LOCALLY ADVANCED OR METASTATIC ER+/PR+/HER2- BREAST CANCER.

This is a phase 2 study of bosutinib administered in combination with letrozole versus letrozole alone in post-menopausal women with breast cancer. This is a 2-part study. Subjects in part 1 will receive bosutinib and letrozole daily, and will be closely monitored for 28 days. The second part will proceed with subjects receiving a dose that is determined to be safe based on the safety evaluation of the first part. Eligible subjects will be randomly assigned to receive either bosutinib daily combined with daily letrozole, or daily letrozole alone for a specified period of time. Subjects will be followed up for survival after study drug discontinuation.

This study was terminated on 19 April 2009 due to unfavorable risk benefit ratio of Bosutinib in combination with Letrozole including one confirmed Hy's law case. 37.5% of patients had treatment related liver events with the majority of severe events resulting in permanent study treatment discontinuation.

Inclusion Criteria:

• Surgically sterile or post-menopausal women.
• Confirmed pathologic diagnosis of breast cancer.
• Locally advanced or metastatic, or loco-regional recurrent breast cancer not amenable to curative treatment with surgery or radiotherapy.
• Documented ER+ and/or PgR+ and erbB2- tumor based on most recently analyzed biopsy, as documented by a local laboratory.
• At least 1 radiologically measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

Exclusion Criteria:

• Prior letrozole (except in adjuvant setting), prior bosutinib, or any other prior Src inhibitor.
• Prior endocrine treatment for locally advanced or metastatic breast cancer (up to one prior adjuvant Aromatase Inhibitor (AI) agent/regimen is permitted).
• More than 1 prior chemotherapy regimen in locally advanced or metastatic breast cancer.
• Adjuvant endocrine therapy <=12 months prior to day 1 of treatment.
• Disease refractory (ie, Progressive disease (PD) within 6 months from initiation of therapy) to previous adjuvant antiestrogen therapy.
• Bone or skin as the only site of disease.
• Extensive visceral disease or active Central Nervous System (CNS) disease.
• Any other cancer within 5 years of screening with the exception of ER+ contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.
• Major surgery or radiotherapy within 14 days of treatment day.
• Inadequate hepatic/renal/bone marrow function.
• History of clinically significant or uncontrolled cardiac disease.
• Serious concurrent illness.