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

Primary Purpose

Advanced Breast Cancer (Parts 1 and 2), Advanced Pancreatic Cancer (Part 1), Advanced Colorectal Cancer (Part 1)

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Bosutinib

Capecitabine

About this trial

This is an interventional treatment trial for Advanced Breast Cancer (Parts 1 and 2) focused on measuring Phase 1/2, 2-part study, bosutinib and capecitabine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Pfizer Investigational Site
Pfizer Investigational Site
Pfizer Investigational Site
Pfizer Investigational Site
Pfizer Investigational Site
Pfizer Investigational Site
Pfizer Investigational Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm Description

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).

Outcomes

Primary Outcome Measures

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.

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.

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.

Secondary Outcome Measures

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.

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").

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.

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.

Maximum Observed Plasma Concentration (Cmax) - Part 2

Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 2

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.

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).

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.

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.

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.

Full Information

NCT ID

NCT00959946

First Posted

August 14, 2009

Last Updated

January 18, 2013

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT00959946

Brief Title

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

Official 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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2013

Overall Recruitment Status

Terminated

Study Start Date

September 2009 (undefined)

Primary Completion Date

March 2011 (Actual)

Study Completion Date

March 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pfizer

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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)

Keywords

Phase 1/2, 2-part study, bosutinib and capecitabine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

32 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bosutinib

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Intervention Description

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).

Primary Outcome Measure Information:

Title

Maximum Tolerated Dose (MTD) - Part 1

Description

Time Frame

Part 1 Baseline up to Day 21

Title

Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) - Part 1

Description

Time Frame

Part 1 Baseline up to 28 days after last dose of study treatment

Title

Percentage of Participants With Objective Response - Part 2

Description

Time Frame

Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose

Secondary Outcome Measure Information:

Title

Best Overall Response - Part 1

Description

Time Frame

Part 1 Baseline, every 6 weeks up to 6 months

Title

Progression Free Survival (PFS) - Part 2

Description

Time Frame

Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose

Title

Clinical Benefit Rate - Part 2

Description

Time Frame

Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose

Title

Duration of Response (DR) - Part 2

Description

Time Frame

Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose

Title

Maximum Observed Plasma Concentration (Cmax) - Part 2

Time Frame