Advanced Breast Cancer (Parts 1 and 2), Advanced Cholangiocarcinoma (Part 1), Advanced Colorectal Cancer (Part 1), Advanced Glioblastoma Multiforme (Part 1), Advanced Pancreatic Cancer (Part 1)
Conditions
Keywords
Phase 1/2, 2-part study, bosutinib and capecitabine
Brief summary
This is a research study in 2 parts assessing the following parameters of the combination of the study drug called bosutinib, and a drug called capecitabine: the safety, how well the subject's body handles the study drug, and preliminary anti-tumor activity as treatment for different types of cancers in part 1, and breast cancer only in part 2. In part 1, subjects will receive bosutinib and capecitabine daily at different dose levels of each drug in order to determine the highest tolerated dose of the combination study treatment. In part 2, subjects will receive bosutinib and capecitabine at this highest tolerated dose to see how well the study treatment works to treat breast cancer. In addition, genetic research testing (research analyses involving genes and gene products) will be performed on biological samples from subjects.
Detailed description
The study was prematurely discontinued following Part 1 evaluation, when the sponsor concluded that further translational biomarker analyses were needed to better define the breast tumor biomarkers that predict sensitivity to Src family kinase inhibitors. Thus the Sponsor made a determination to stop the study after Part 1 as communicated to investigators on 02Dec2010 . No subjects were enrolled into Part 2 of this study. The study was not terminated due to safety reasons.
Interventions
DRUGBosutinib
Doses in part 1 include bosutinib 200 mg QD; bosutinib 300 mg QD. Depending on safety bosutinib can be administered at 200 mg/m2 QD. The MTD of the combination treatment determined from part 1, will be administered in part 2 (phase 2).
DRUGCapecitabine
Doses in part 1 include capecitabine 750 mg/m2 BID on days 1-14; capecitabine 625 mg/m2 BID on days 1-14. Depending on safety, capecitabine can also be administered at 1000 mg/m2 BID. The MTD of the combination treatment determined from part 1, will be administered in part 2 (phase 2).
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part 1: * Ages eligible for study: 18 years or older. * Male and female. * Confirmed pathologic diagnosis of advanced breast cancer or pancreatic cancer or colorectal cancer or cholangiocarcinoma or glioblastoma not curable with available therapies, for whom bosutinib plus capecitabine is a reasonable treatment option. Part 2: * Ages eligible for study: 18 years or older. * Female. * Confirmed pathologic diagnosis of locally advanced or metastatic breast cancer, or loco-regional recurrent breast cancer that is not amenable to curative treatment with surgery or radiotherapy. * Documented ER+ and/or PgR+/erbB2- or ER-/PgR-/erbB2- tumor based upon recently analyzed biopsy.
Exclusion criteria
Part 1: * Prior bosutinib, or any other prior Src inhibitor. * Prior chemotherapy with capecitabine or 5-FU for the treatment of metastatic disease is allowed unless patient stopped therapy for toxicity. Part 2: * Prior bosutinib, or any other prior Src inhibitor prior chemotherapy with capecitabine or 5-FU for the treatment of metastatic disease. * Prior chemotherapy with capecitabine or 5-FU for adjuvant chemotherapy within the past 12 months. * erbB2+ breast cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) - Part 1 | Part 1 Baseline up to Day 21 | The MTD contour is defined as the dose combinations that achieve a toxicity rate (dose-limiting toxicity \[DLT\] rate) of less than (\<) 1/3. The observed toxicity rates for all the reporting groups (to which at least 1 cohort of participants was allocated) was estimated by calculating the proportion of DLTs observed in the first 21 days of treatment at those reporting groups. DLT includes grade (Gr) 3/4 nausea, vomiting, diarrhea, or asthenia more than 3 days, Gr 4 hematologic toxicities, delayed study treatment administration due to dose toxicities by more than 3 weeks. Pre-defined criterion for MTD: if a higher dose level of capecitabine existed such that the same dose level of bosutinib had a DLT rate of \<1/3, no MTD was recommended for that capecitabine dose and if even the lowest dose of bosutinib achieved a toxicity rate of greater than (\>) 1/3, no MTD was recommended for that capecitabine dose level. |
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | Part 1 Baseline up to 28 days after last dose of study treatment | 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. |
| Percentage of Participants With Objective Response - Part 2 | Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose | Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.0). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR is defined as the disappearance of all lesions (target and/or non target). PR are those with at least 30 percent (%) decrease in the sum of the longest dimensions (LDs) of the target lesions taking as a reference the baseline sum LDs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DR) - Part 2 | Part 2 Baseline, every 6 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. |
| Maximum Observed Plasma Concentration (Cmax) - Part 2 | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 2 | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | — |
| Apparent Volume of Distribution (Vz/F) - Part 2 | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. |
| Best Overall Response - Part 1 | Part 1 Baseline, every 6 weeks up to 6 months | Best overall response based on investigator's disease status assessment. CR: disappearance of all lesions. PR: at least 30% decrease in sum of LDs of target lesions taking as reference baseline sum LDs. Progressive disease (PD): at least 20% increase in sum of LD of target lesions taking as a reference smallest sum of the recorded LDs since treatment start, or the appearance of 1 or more new lesions. Stable disease (SD): neither sufficient shrinkage for PR nor sufficient increase for PD taking as reference smallest sum of LD since treatment started. |
| Apparent Oral Clearance (CL/F) - Part 2 | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Terminal-Phase Disposition Rate Constant (λz) - Part 2 | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | The terminal-phase disposition rate constant measured by a log-linear regression of the terminal mono exponential portion of the observed plasma concentrations. |
| Plasma Decay Half-Life (t1/2) - Part 2 | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Half-life was to be calculated as 0.693/λz. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] - Part 2 | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | AUC (0-24) = Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). |
| Progression Free Survival (PFS) - Part 2 | Part 2 Baseline, every 6 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 PD), or from adverse event (AE) data (where the outcome was Death). |
| Clinical Benefit Rate - Part 2 | Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose | Percent of participants with confirmed CR, PR or SD for at least 24 weeks on study according to RECIST. CR: disappearance of all lesions. PR: at least 30% decrease in sum of LDs of target lesions taking as reference baseline sum LDs. SD: neither sufficient shrinkage for PR nor sufficient increase for PD taking as reference smallest sum of LD since treatment started. |
Countries
Australia, Belgium, France, Hong Kong, Spain, United States
Participant flow
Pre-assignment details
Study was pre-maturely terminated after part 1 (safety lead-in phase) of study and hence, planned treatments of part 2, Bosutinib 300 milligram (mg) + Capecitabine 1000 mg/square meter (mg/m\^2) (Part 2): estrogen receptor positive (ER+) and Bosutinib 300 mg+Capecitabine 1000 mg/m\^2 (Part 2): estrogen receptor negative (ER-), were not administered.
Participants by arm
| Arm | Count |
|---|---|
| Bosutinib 200 mg + Capecitabine 625 mg/m^2 (Part 1) Bosutinib 200 mg tablet orally once daily in a 21-day cycle along with capecitabine 625 mg/m\^2 tablet orally twice daily from Day 1 to 14, followed by 7 days off treatment in a 21-day cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. | 2 |
| Bosutinib 200 mg + Capecitabine 750 mg/m^2 (Part 1) Bosutinib 200 mg tablet orally once daily in a 21-day cycle along with capecitabine 750 mg/m\^2 tablet orally twice daily from Day 1 to 14, followed by 7 days off treatment in a 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. | 4 |
| Bosutinib 200 mg + Capecitabine 1000 mg/m^2 (Part 1) Bosutinib 200 mg tablet orally once daily in a 21-day cycle along with capecitabine 1000 mg/m\^2 tablet orally twice daily from Day 1 to 14, followed by 7 days off treatment in a 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. | 4 |
| Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) Bosutinib 300 mg tablet orally once daily in a 21-day cycle along with capecitabine 625 mg/m\^2 tablet orally twice daily from Day 1 to 14, followed by 7 days off treatment in a 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. | 5 |
| Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) Bosutinib 300 mg tablet orally once daily in a 21-day cycle along with capecitabine 750 mg/m\^2 tablet orally twice daily from Day 1 to 14, followed by 7 days off treatment in a 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. | 4 |
| Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) Bosutinib 300 mg tablet orally once daily in a 21-day cycle along with capecitabine 1000 mg/m\^2 tablet orally twice daily from Day 1 to 14, followed by 7 days off treatment in a 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. | 9 |
| Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) Bosutinib 400 mg tablet orally once daily in a 21-day cycle along with capecitabine 750 mg/m\^2 tablet orally twice daily from Day 1 to 14, followed by 7 days off treatment in a 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. | 2 |
| Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) Bosutinib 400 mg tablet orally once daily in a 21-day cycle along with capecitabine 1000 mg/m\^2 tablet orally twice daily from Day 1 to 14, followed by 7 days off treatment in a 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. | 2 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Disease Progression | 2 | 4 | 2 | 4 | 4 | 6 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Bosutinib 200 mg + Capecitabine 625 mg/m^2 (Part 1) | Bosutinib 200 mg + Capecitabine 750 mg/m^2 (Part 1) | Bosutinib 200 mg + Capecitabine 1000 mg/m^2 (Part 1) | Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) | Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) | Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) | Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) | Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | 53.0 Years STANDARD_DEVIATION 4.24 | 56.8 Years STANDARD_DEVIATION 16.32 | 67.3 Years STANDARD_DEVIATION 10.05 | 63.0 Years STANDARD_DEVIATION 8.43 | 56.0 Years STANDARD_DEVIATION 8.45 | 63.8 Years STANDARD_DEVIATION 5.49 | 51.5 Years STANDARD_DEVIATION 6.36 | 61.5 Years STANDARD_DEVIATION 4.95 | 60.7 Years STANDARD_DEVIATION 9.24 |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 3 Participants | 4 Participants | 1 Participants | 1 Participants | 18 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 1 Participants | 5 Participants | 1 Participants | 1 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 4 / 4 | 3 / 4 | 5 / 5 | 4 / 4 | 9 / 9 | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 2 / 4 | 2 / 4 | 2 / 5 | 0 / 4 | 3 / 9 | 0 / 2 | 1 / 2 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) - Part 1
The MTD contour is defined as the dose combinations that achieve a toxicity rate (dose-limiting toxicity \[DLT\] rate) of less than (\<) 1/3. The observed toxicity rates for all the reporting groups (to which at least 1 cohort of participants was allocated) was estimated by calculating the proportion of DLTs observed in the first 21 days of treatment at those reporting groups. DLT includes grade (Gr) 3/4 nausea, vomiting, diarrhea, or asthenia more than 3 days, Gr 4 hematologic toxicities, delayed study treatment administration due to dose toxicities by more than 3 weeks. Pre-defined criterion for MTD: if a higher dose level of capecitabine existed such that the same dose level of bosutinib had a DLT rate of \<1/3, no MTD was recommended for that capecitabine dose and if even the lowest dose of bosutinib achieved a toxicity rate of greater than (\>) 1/3, no MTD was recommended for that capecitabine dose level.
Time frame: Part 1 Baseline up to Day 21
Population: DLT evaluable population included all participants who received at least 14 doses of bosutinib and at least 10 doses of capecitabine in the first 21 days of treatment or had experienced a DLT within the first 21 days of treatment. N (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib + Capecitabine 625 mg/m^2 | Maximum Tolerated Dose (MTD) - Part 1 | NA mg |
| Bosutinib + Capecitabine 750 mg/m^2 | Maximum Tolerated Dose (MTD) - Part 1 | NA mg |
| Bosutinib + Capecitabine 1000 mg/m^2 | Maximum Tolerated Dose (MTD) - Part 1 | 300 mg |
Primary
Percentage of Participants With Objective Response - Part 2
Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.0). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR is defined as the disappearance of all lesions (target and/or non target). PR are those with at least 30 percent (%) decrease in the sum of the longest dimensions (LDs) of the target lesions taking as a reference the baseline sum LDs.
Time frame: Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Primary
Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1
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: Part 1 Baseline up to 28 days after last dose of study treatment
Population: Safety population: included participants who received at least 1 dose of the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib + Capecitabine 625 mg/m^2 | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | AEs | 100.0 Percentage of Participants |
| Bosutinib + Capecitabine 625 mg/m^2 | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | SAEs | 0.0 Percentage of Participants |
| Bosutinib + Capecitabine 750 mg/m^2 | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | SAEs | 50.0 Percentage of Participants |
| Bosutinib + Capecitabine 750 mg/m^2 | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | AEs | 100.0 Percentage of Participants |
| Bosutinib + Capecitabine 1000 mg/m^2 | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | AEs | 100.0 Percentage of Participants |
| Bosutinib + Capecitabine 1000 mg/m^2 | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | SAEs | 50.0 Percentage of Participants |
| Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | AEs | 100.0 Percentage of Participants |
| Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | SAEs | 40.0 Percentage of Participants |
| Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | AEs | 100.0 Percentage of Participants |
| Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | SAEs | 0.0 Percentage of Participants |
| Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | AEs | 100.0 Percentage of Participants |
| Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | SAEs | 33.3 Percentage of Participants |
| Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | AEs | 100.0 Percentage of Participants |
| Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | SAEs | 0.0 Percentage of Participants |
| Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | SAEs | 50.0 Percentage of Participants |
| Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) | Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1 | AEs | 100.0 Percentage of Participants |
Secondary
Apparent Oral Clearance (CL/F) - Part 2
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Apparent Volume of Distribution (Vz/F) - Part 2
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Time frame: 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Population: Data was 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)] - Part 2
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 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Best Overall Response - Part 1
Best overall response based on investigator's disease status assessment. CR: disappearance of all lesions. PR: at least 30% decrease in sum of LDs of target lesions taking as reference baseline sum LDs. Progressive disease (PD): at least 20% increase in sum of LD of target lesions taking as a reference smallest sum of the recorded LDs since treatment start, or the appearance of 1 or more new lesions. Stable disease (SD): neither sufficient shrinkage for PR nor sufficient increase for PD taking as reference smallest sum of LD since treatment started.
Time frame: Part 1 Baseline, every 6 weeks up to 6 months
Population: Per protocol (PP) population included participants who received at least 14 doses of bosutinib and at least 10 doses of capecitabine within a 21-day period, had a baseline and at least 1 post-baseline tumor assessment, and had no major protocol violations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib + Capecitabine 625 mg/m^2 | Best Overall Response - Part 1 | Complete Response | 0 Participants |
| Bosutinib + Capecitabine 625 mg/m^2 | Best Overall Response - Part 1 | Indeterminate | 0 Participants |
| Bosutinib + Capecitabine 625 mg/m^2 | Best Overall Response - Part 1 | Progressive Disease | 1 Participants |
| Bosutinib + Capecitabine 625 mg/m^2 | Best Overall Response - Part 1 | Stable Disease | 0 Participants |
| Bosutinib + Capecitabine 625 mg/m^2 | Best Overall Response - Part 1 | Partial Response | 0 Participants |
| Bosutinib + Capecitabine 750 mg/m^2 | Best Overall Response - Part 1 | Complete Response | 0 Participants |
| Bosutinib + Capecitabine 750 mg/m^2 | Best Overall Response - Part 1 | Progressive Disease | 3 Participants |
| Bosutinib + Capecitabine 750 mg/m^2 | Best Overall Response - Part 1 | Stable Disease | 1 Participants |
| Bosutinib + Capecitabine 750 mg/m^2 | Best Overall Response - Part 1 | Partial Response | 0 Participants |
| Bosutinib + Capecitabine 750 mg/m^2 | Best Overall Response - Part 1 | Indeterminate | 0 Participants |
| Bosutinib + Capecitabine 1000 mg/m^2 | Best Overall Response - Part 1 | Progressive Disease | 2 Participants |
| Bosutinib + Capecitabine 1000 mg/m^2 | Best Overall Response - Part 1 | Stable Disease | 2 Participants |
| Bosutinib + Capecitabine 1000 mg/m^2 | Best Overall Response - Part 1 | Indeterminate | 0 Participants |
| Bosutinib + Capecitabine 1000 mg/m^2 | Best Overall Response - Part 1 | Partial Response | 0 Participants |
| Bosutinib + Capecitabine 1000 mg/m^2 | Best Overall Response - Part 1 | Complete Response | 0 Participants |
| Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Progressive Disease | 5 Participants |
| Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Indeterminate | 0 Participants |
| Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Stable Disease | 0 Participants |
| Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Complete Response | 0 Participants |
| Bosutinib 300 mg + Capecitabine 625 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Partial Response | 0 Participants |
| Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Complete Response | 0 Participants |
| Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Partial Response | 2 Participants |
| Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Stable Disease | 1 Participants |
| Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Indeterminate | 0 Participants |
| Bosutinib 300 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Progressive Disease | 1 Participants |
| Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Complete Response | 0 Participants |
| Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Indeterminate | 1 Participants |
| Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Partial Response | 0 Participants |
| Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Stable Disease | 6 Participants |
| Bosutinib 300 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Progressive Disease | 2 Participants |
| Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Partial Response | 0 Participants |
| Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Indeterminate | 0 Participants |
| Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Progressive Disease | 1 Participants |
| Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Complete Response | 0 Participants |
| Bosutinib 400 mg + Capecitabine 750 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Stable Disease | 1 Participants |
| Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Stable Disease | 1 Participants |
| Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Partial Response | 0 Participants |
| Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Indeterminate | 0 Participants |
| Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Progressive Disease | 0 Participants |
| Bosutinib 400 mg + Capecitabine 1000 mg/m^2 (Part 1) | Best Overall Response - Part 1 | Complete Response | 0 Participants |
Secondary
Clinical Benefit Rate - Part 2
Percent of participants with confirmed CR, PR or SD for at least 24 weeks on study according to RECIST. CR: disappearance of all lesions. PR: at least 30% decrease in sum of LDs of target lesions taking as reference baseline sum LDs. SD: neither sufficient shrinkage for PR nor sufficient increase for PD taking as reference smallest sum of LD since treatment started.
Time frame: Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Duration of Response (DR) - Part 2
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 6 weeks up to 2 to 6 weeks after last dose
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Maximum Observed Plasma Concentration (Cmax) - Part 2
Time frame: 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Plasma Decay Half-Life (t1/2) - Part 2
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Half-life was to be calculated as 0.693/λz.
Time frame: 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Progression Free Survival (PFS) - Part 2
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 PD), or from adverse event (AE) data (where the outcome was Death).
Time frame: Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.
Secondary
Terminal-Phase Disposition Rate Constant (λz) - Part 2
The terminal-phase disposition rate constant measured by a log-linear regression of the terminal mono exponential portion of the observed plasma concentrations.
Time frame: 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Population: Data was 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) - Part 2
Time frame: 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Population: Data was not analyzed because the study was prematurely terminated due to unfavorable risk benefit ratio of the study treatment.