Advanced Breast Cancer
Conditions
Keywords
Bosutinib, Exemestane, postmenopausal, breast cancer
Brief summary
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
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.
Interventions
DRUGBosutinib
300 mg =(3x100mg) tablets once daily during the active phase of treatment until disease progression, unacceptable toxicity or withdrawal of consent occurs
DRUGexemestane
25 mg tablet once daily
DRUGExemestane
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
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Based on Independent Radiologist | Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Based on Investigator | Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose | 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). |
| Percentage of Participants With Objective Response | Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose | 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. |
| Overall Survival (OS) | Part 2 Baseline until death or up to 24 months | 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). |
| Duration of Response (DR) | Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose | 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. |
| Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) | Part 2 Baseline, Week 12, 2 to 6 weeks after last dose | 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. |
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) | Baseline up to 28 days after the last dose | 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. |
| Euro Quality of Life (EQ-5D)- Visual Analog Scale (VAS) | Part 2 Baseline, Week 12, 2 to 6 weeks after last dose | 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. |
| 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)] | 0 hour (pre-dose) on Day 1, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 29 | AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). |
| Euro Quality of Life (EQ-5D)- Health State Profile Utility Score | Part 2 Baseline, Week 12, 2 to 6 weeks after last dose | 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. |
Countries
Australia, Belgium, Canada, China, Hong Kong, Hungary, India, Poland, South Africa, Spain, United States
Participant flow
Pre-assignment details
Study was pre-maturely terminated after part 1 (safety lead-in phase) of the study and hence, the planned treatments of part 2, bosutinib + exemestane (part 2) and exemestane (part 2), were not administered.
Participants by arm
| Arm | Count |
|---|---|
| Bosutinib 400 mg + Exemestane 25 mg (Part 1) Four bosutinib 100 milligram (mg) tablets (equivalent to 400 mg bosutinib) orally along with exemestane 25 mg tablet orally once daily up to 6 months or until disease progression, unacceptable toxicity, withdrawal of consent. | 14 |
| Bosutinib 300 mg + Exemestane 25 mg (Part 1) Three bosutinib 100 mg tablets (equivalent to 300 mg bosutinib) orally along with exemestane 25 mg tablet orally once daily up to 6 months or until disease progression, unacceptable toxicity, withdrawal of consent. | 28 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 8 | 27 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Bosutinib 400 mg + Exemestane 25 mg (Part 1) | Bosutinib 300 mg + Exemestane 25 mg (Part 1) | Total |
|---|---|---|---|
| Age Continuous | 64.1 years STANDARD_DEVIATION 8.16 | 58.2 years STANDARD_DEVIATION 10.02 | 60.2 years STANDARD_DEVIATION 9.75 |
| Sex: Female, Male Female | 14 Participants | 28 Participants | 42 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 14 | 27 / 28 |
| serious Total, serious adverse events | 4 / 14 | 5 / 28 |
Outcome results
Primary
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).
Time frame: Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
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).
Time frame: 0 hour (pre-dose) on Day 1, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 29
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
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.
Time frame: Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
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.
Time frame: Part 2 Baseline, Week 12, 2 to 6 weeks after last dose
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
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.
Time frame: Part 2 Baseline, Week 12, 2 to 6 weeks after last dose
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
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.
Time frame: Part 2 Baseline, Week 12, 2 to 6 weeks after last dose
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Maximum Observed Plasma Concentration (Cmax)
Time frame: 0 hour (pre-dose) on Day 1, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 29
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
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).
Time frame: Part 2 Baseline until death or up to 24 months
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
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.
Time frame: Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
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.
Time frame: Baseline up to 28 days after the last dose
Population: Safety population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib 300 mg + Exemestane 25 mg (Part 2) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) | AEs | 100 percentage of participants |
| Bosutinib 300 mg + Exemestane 25 mg (Part 2) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) | SAEs | 28.6 percentage of participants |
| Exemestane 25 mg (Part 2) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) | AEs | 96.4 percentage of participants |
| Exemestane 25 mg (Part 2) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) | SAEs | 17.9 percentage of participants |
Secondary
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).
Time frame: Part 2 Baseline, every 8 weeks up to 2 to 6 weeks after last dose
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: 0 hour (pre-dose) on Day 1, 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 29
Population: Data were not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.