Study Evaluating Bosutinib-Exemestane Combination Vs Exemestane 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, open-label, multicenter, 2-arm study of bosutinib administered in combination with exemestane versus exemestane alone. This is a 2-part study consisting of a safety lead-in phase and randomized phase 2 portion. Subjects in part 1 will receive bosutinib and exemestane daily, and will be closely monitored for 28 days. If no safety concerns arise, then future eligible subjects will be randomly assigned to the main phase of the study. They will either receive bosutinib daily combined with daily exemestane, or daily exemestane alone for a specified period of time. Subjects will be followed up for survival after treatment discontinuation.

Detailed Description
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This study was terminated on 19 Apr 2010 due to unfavorable risk benefit ratio which did not support continuation in part 2 of the study. Even if the safety profile of the combination of Bosutinib and Exemestane was acceptable 25% of subjects had treatment related liver events including 14% of severe liver events.

Official Title
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A Phase 2, Randomized, Open-Label Study Of Bosutinib Administered In Combination With Exemestane Versus Exemestane Alone As Second Line Therapy In Postmenopausal Women With Locally Advanced Or Metastatic ER+/PgR+/ErbB2- Breast Cancer

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: Bosutinib
* Drug: exemestane
* Drug: Exemestane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Woman aged 18 years or older. Confirmed pathologic diagnosis of breast cancer. Locally advanced, metastatic, or locoregional recurrent breast cancer not amenable to curative treatment with surgery or radiotherapy. Surgically sterile or postmenopausal woman. Documented ER+ and/or PgR+ and erbB2- tumor. Progression of locally advanced or metastatic disease during treatment with a nonsteroidal AI or tamoxifen, or progression during treatment with (or within 6 months of discontinuation of) an adjuvant nonsteroidal AI. Exclusion Criteria: Prior exemestane, prior bosutinib, or any other prior anti-Src therapy. More than 1 prior endocrine treatment for locally advanced or MBC. More than 1 prior cytotoxic chemotherapy regimen in metastatic setting. Bone or skin as the only site of disease.

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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>combination of bosutinib and exemestane | Drug: Bosutinib<br>* 300 mg =(3x100mg) tablets once daily during the active phase of treatment until disease progression, unacceptable toxicity or withdrawal of consent occurs<br>Drug: exemestane<br>* 25 mg tablet once daily<br>|
| Active Comparator: 2<br>exemestane | Drug: Exemestane<br>* 25 mg - 1 tablet per day- once daily daily during the active phase of treatment until disease progression, unacceptable toxicity or withdrawal of consent 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 randomization to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of randomization plus 1) divided by 7. Tumor progression was 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). | 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. | Baseline up to 28 days after the last dose | 
| Progression Free Survival (PFS) Based on Investigator | Time in weeks from randomization to first documentation of objective tumor progression or death due to any cause. PFS was calculated as (first event date minus the date of randomization plus 1) divided by 7. Tumor progression was 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). | 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 24 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, 2 to 6 weeks after last dose | 
| Euro Quality of Life (EQ-5D)- Health State Profile Utility Score | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. | Part 2 Baseline, Week 12, 2 to 6 weeks after last dose | 
| Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 millimeter (mm) = worst imaginable health state to 100 mm =best imaginable health state; higher scores indicate a better health state. | Part 2 Baseline, Week 12, 2 to 6 weeks after last dose | 
| Maximum Observed Plasma Concentration (Cmax) |  | 0 hour (pre-dose) on Day 1, 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, 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, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bosutinib, Exemestane, postmenopausal, breast cancer