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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00959946
First received: August 14, 2009
Last updated: January 18, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
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)
Drug: Bosutinib
Drug: Capecitabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) - Part 1 [ Time Frame: Part 1 Baseline up to Day 21 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Part 1 Baseline up to 28 days after last dose of study treatment ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: Part 1 Baseline, every 6 weeks up to 6 months ] [ Designated as safety issue: No ]
    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 Frame: Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose ] [ Designated as safety issue: No ]
    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 [ Time Frame: Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose ] [ Designated as safety issue: No ]
    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 Frame: Part 2 Baseline, every 6 weeks up to 2 to 6 weeks after last dose ] [ Designated as safety issue: No ]
    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 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Apparent Volume of Distribution (Vz/F) - 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 32
Study Start Date: September 2009
Study Completion Date: March 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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).
Drug: 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).
Drug: 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).

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00959946

Locations
United States, Massachusetts
Pfizer Investigational Site
Boston, Massachusetts, United States, 02114
United States, Michigan
Pfizer Investigational Site
Detroit, Michigan, United States, 84202
Australia, South Australia
Pfizer Investigational Site
Adelaide, South Australia, Australia, 5037
Belgium
Pfizer Investigational Site
Edegem, Belgium, 2650
France
Pfizer Investigational Site
Saint Herblain, France, 44805
Hong Kong
Pfizer Investigational Site
Hong Kong, Hong Kong
Spain
Pfizer Investigational Site
Madrid, Spain, 28050
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00959946     History of Changes
Other Study ID Numbers: 3160A6-2208, B1871011
Study First Received: August 14, 2009
Results First Received: October 4, 2012
Last Updated: January 18, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Phase 1/2
2-part study
bosutinib and capecitabine

Additional relevant MeSH terms:
Breast Neoplasms
Pancreatic Neoplasms
Cholangiocarcinoma
Glioblastoma
Colorectal Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Intestinal Neoplasms
Gastrointestinal Neoplasms
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases

ClinicalTrials.gov processed this record on September 16, 2014