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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Bosutinib
* Drug: Letrozole
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Combination of Bosutinib and Letrozole | Drug: Bosutinib<br>* 400mg (4x100)mg tablets once daily during the active phase of treatment until Disease Progression, unacceptable toxicity or withdraw of consents occurs<br>Drug: Letrozole<br>* 2.5 mg - one tablet per day- once daily during the active phase of treatment until Disease Progression, unacceptable toxicity or withdraw of consents occurs<br>|
| Active Comparator: 2<br>Letrozole | Drug: Letrozole<br>* 2.5 mg - one tablet per day- once daily during the active phase of treatment until Disease Progression, unacceptable toxicity or withdraw of consents occurs<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Based on Independent Radiologist | Time in weeks from date of randomization to first documentation of objective tumor progression or death due to any cause. PFS: calculated as (first event date minus the date of randomization plus 1) divided by 7. Tumor progression: determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was Death). PFS assessed by independent radiologist was to be reported. | Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Part 1 Baseline up to 28 days after the last dose | 
| Progression-Free Survival (PFS) Based on Investigator | Time in weeks from date of randomization to first documentation of objective tumor progression or death due to any cause. PFS: calculated as (first event date minus the date of randomization plus 1) divided by 7. Tumor progression: determined from oncologic assessment data (where data meet the criteria for PD), or from AE data (where the outcome was Death). PFS assessed by investigator was to be reported. | Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose | 
| Percentage of Participants With Objective Response | Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all target lesions. Confirmed PR defined as greater than or equal to >=30 percent (%) decrease in sum of the longest dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response. | Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose | 
| Overall Survival (OS) | Time in weeks from randomization to date of death due to any cause. OS was calculated as (the death date minus the date of randomization plus 1) divided by 7. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death). | Part 2 Baseline until death or up to 36 months | 
| Duration of Response (DR) | Time in weeks from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumor response. | Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose | 
| Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) | FACT-B is used for assessment of health-related quality of life (QoL) in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: physical (7 items), functional (7 items), social/family (7 items); all 3 ranged from 0 to 28, emotional (6 items) ranging from 0 to 24, and additional concerns on breast cancer subscale (9 items) ranging from 0 to 36; high subscale score represents a better QoL. All single-item measures ranges from 0='Not at all' to 4='Very much'. Total possible score ranged from 0 to 144. High scale score represents a better QoL. | Part 2 Baseline, Week 12, 24, 52, 2-6 weeks after the last dose | 
| Maximum Observed Plasma Concentration (Cmax) |  | 0 hour (pre-dose) on Day 1; 2, 3, 4, 6, 8, 24 hours post-dose on Day 29 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 0 hour (pre-dose) on Day 1; 2, 3, 4, 6, 8, 24 hours post-dose on Day 29 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] | AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). | 0 hour (pre-dose) on Day 1; 2, 3, 4, 6, 8, 24 hours post-dose on Day 29 |