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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00959946




Registration number
NCT00959946
Ethics application status
Date submitted
14/08/2009
Date registered
14/08/2009
Date last updated
18/01/2013

Titles & IDs
Public title
Study Of Bosutinib With Capecitabine In Solid Tumors And Locally Advanced Or Metastatic Breast Cancer
Scientific title
A Phase 1/2, Open-Label Study Of Bosutinib Administered In Combination With Capecitabine In Subjects With Solid Tumor And ErbB2 Negative Locally Advanced Or Metastatic Breast Cancer
Secondary ID [1] 0 0
B1871011
Secondary ID [2] 0 0
3160A6-2208
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Breast Cancer (Parts 1 and 2) 0 0
Advanced Pancreatic Cancer (Part 1) 0 0
Advanced Colorectal Cancer (Part 1) 0 0
Advanced Cholangiocarcinoma (Part 1) 0 0
Advanced Glioblastoma Multiforme (Part 1) 0 0
Advanced Breast Cancer (Parts 1 and 2) 0 0
Advanced Pancreatic Cancer (Part 1) 0 0
Advanced Colorectal Cancer (Part 1) 0 0
Advanced Cholangiocarcinoma (Part 1) 0 0
Advanced Glioblastoma Multiforme (Part 1) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast
Cancer 0 0 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 0 0 0 0
Pancreatic
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Biliary tree (gall bladder and bile duct)
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Bosutinib
Treatment: Drugs - Capecitabine
Treatment: Drugs - Bosutinib
Treatment: Drugs - Capecitabine

Experimental: 1 - In part 1 (phase 1), ascending and descending multiple oral doses of bosutinib + capecitabine. Doses in part 1 include capecitabine 750 mg/m2 BID on days 1-14 + bosutinib 200 mg QD; capecitabine 625 mg/m2 BID on days 1-14 + bosutinib 300 mg QD. Depending on safety, capecitabine can also be administered at 1000 mg/m2 BID and 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).

Experimental: 1 - In part 1 (phase 1), ascending and descending multiple oral doses of bosutinib + capecitabine. Doses in part 1 include capecitabine 750 mg/m2 BID on days 1-14 + bosutinib 200 mg QD; capecitabine 625 mg/m2 BID on days 1-14 + bosutinib 300 mg QD. Depending on safety, capecitabine can also be administered at 1000 mg/m2 BID and 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).


Treatment: Drugs: Bosutinib
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).

Treatment: Drugs: Capecitabine
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).

Treatment: Drugs: Bosutinib
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).

Treatment: Drugs: Capecitabine
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).

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Part 1 Baseline up to Day 21
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
Part 1 Baseline up to 28 days after last dose of study treatment
Primary outcome [3] 0 0
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.
Timepoint [3] 0 0
Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Primary outcome [4] 0 0
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.
Timepoint [4] 0 0
Part 1 Baseline up to Day 21
Primary outcome [5] 0 0
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.
Timepoint [5] 0 0
Part 1 Baseline up to 28 days after last dose of study treatment
Primary outcome [6] 0 0
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.
Timepoint [6] 0 0
Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Part 1 Baseline, every 6 weeks up to 6 months
Secondary outcome [2] 0 0
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").
Timepoint [2] 0 0
Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Secondary outcome [5] 0 0
Maximum Observed Plasma Concentration (Cmax) - Part 2
Timepoint [5] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [6] 0 0
Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 2
Timepoint [6] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [8] 0 0
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).
Timepoint [8] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [10] 0 0
Terminal-Phase Disposition Rate Constant (?z) - 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.
Timepoint [10] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [11] 0 0
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/?z.
Timepoint [11] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [12] 0 0
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.
Timepoint [12] 0 0
Part 1 Baseline, every 6 weeks up to 6 months
Secondary outcome [13] 0 0
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").
Timepoint [13] 0 0
Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Secondary outcome [14] 0 0
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.
Timepoint [14] 0 0
Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Secondary outcome [15] 0 0
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.
Timepoint [15] 0 0
Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose
Secondary outcome [16] 0 0
Maximum Observed Plasma Concentration (Cmax) - Part 2
Timepoint [16] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [17] 0 0
Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 2
Timepoint [17] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [18] 0 0
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.
Timepoint [18] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [19] 0 0
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).
Timepoint [19] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [20] 0 0
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.
Timepoint [20] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [21] 0 0
Terminal-Phase Disposition Rate Constant (?z) - 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.
Timepoint [21] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1
Secondary outcome [22] 0 0
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/?z.
Timepoint [22] 0 0
0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 0 0
Pfizer Investigational Site - Adelaide
Recruitment postcode(s) [1] 0 0
5037 - Adelaide
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
United States of America
State/province [2] 0 0
Michigan
Country [3] 0 0
Belgium
State/province [3] 0 0
Edegem
Country [4] 0 0
France
State/province [4] 0 0
Saint Herblain
Country [5] 0 0
Hong Kong
State/province [5] 0 0
Hong Kong
Country [6] 0 0
Spain
State/province [6] 0 0
Madrid

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Pfizer
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT00959946
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Pfizer CT.gov Call Center
Address 0 0
Pfizer
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT00959946