Study Of Bosutinib With Capecitabine In Solid Tumors And Locally Advanced Or Metastatic Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Advanced Breast Cancer (Parts 1 and 2), Advanced Pancreatic Cancer (Part 1), Advanced Colorectal Cancer (Part 1), Advanced Cholangiocarcinoma (Part 1), Advanced Glioblastoma Multiforme (Part 1)

Intervention / Treatment
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* Drug: Bosutinib
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>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). | Drug: Bosutinib<br>* 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).<br>Drug: Capecitabine<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Part 1 Baseline up to Day 21 | 
| 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. | Part 1 Baseline up to 28 days after last dose of study treatment | 
| 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. | Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Part 1 Baseline, every 6 weeks up to 6 months | 
| 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). | Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose | 
| 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. | Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose | 
| 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. | Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose | 
| 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 | 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. | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | 
| 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). | 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 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. | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | 
| 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. | 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 (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. | 0 hour (Pre-dose) on Day 1 and 2, 3, 4, 6, 8 and 24 hours post-dose on Day 14 of Cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1/2, 2-part study, bosutinib and capecitabine