A Phase II Combination of Trastuzumab and Ixabepilone Versus Trastuzumab and Docetaxel in Patients With Advanced and/or Metastatic Breast Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00490646
First received: June 21, 2007
Last updated: June 14, 2012
Last verified: June 2012
  Purpose

The purpose of this randomized, Phase 2 open-label study was to assess the response rate of participants with Human Epidermal Growth Factor Receptor 2 (Her2+) locally advanced and/or metastatic breast cancer (not previously treated with chemotherapy or trastuzumab) to treatment with ixabepilone plus trastuzumab and/or docetaxel plus trastuzumab.


Condition Intervention Phase
Metastatic Breast Cancer
Drug: ixabepilone
Drug: docetaxel
Drug: trastuzumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Study of Ixabepilone Plus Trastuzumab vs. Docetaxel Plus Trastuzumab in Female Subjects With Her2+ Locally Advanced and/or Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Percentage of Participants With Objective Response (OR; Assessed by Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1) [ Time Frame: Assessed every 6 weeks from initiation of study therapy up to 12 months; then every 3 months until disease progression (maximum time that any participant was on therapy was 108 weeks) ] [ Designated as safety issue: No ]
    Percentage of participants with best overall response (BOR) of either complete response (CR) or partial response (PR) according to RECIST version 1.1 as determined by the investigator. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (LD) of all lesions. CR and PR criteria should be met again after 4 weeks and before 6 weeks after initial assessment. A two-sided confidence interval (CI) was computed using the Clopper-Pearson method.

  • Number of Participants With Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Assessed every 6 weeks from initiation of study therapy up to 12 months; then every 3 months until disease progression (maximum time that any participant was on therapy was 108 weeks). ] [ Designated as safety issue: No ]
    BOR was the best response recorded from the start of treatment until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the LD of all lesions. CR and PR criteria should be met again after 4 weeks and before 6 weeks after initial assessment. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. Refer to Outcome Measure 3 for definition of PD.


Secondary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: From randomization until the first date of documented progressive disease (PD) or death from any cause without prior documentation of progression (maximum participant PFS of 39.7 months). ] [ Designated as safety issue: No ]

    Time in months from randomization until first date of documented progressive disease (PD) or death from any cause without prior documentation of progression. PD=≥20% increase in sum of LD of target lesions in reference to smallest sum LD recorded at or following baseline or unequivocal progression of existing non-target lesion(s) overall.

    Estimated by the Kaplan-Meier product limit method. A two-sided 95% CI for median duration was computed by the Brookmeyer and Crowley method.


  • Time to Response [ Time Frame: From randomization every 6 weeks for first 12 months and thereafter every 3 months until CR or PR whichever was recorded first (maximum participant time to response of 18.4 weeks.) ] [ Designated as safety issue: No ]

    Time to response was defined as the time in weeks from randomization until the measurement criteria are first met for a CR or PR, whichever is recorded first.

    CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the LD of all lesions. CR and PR criteria should be met again after 4 weeks and before 6 weeks after initial assessment. Estimated by the Kaplan-Meier product limit method. A two-sided 95% CI for median duration was computed by the Brookmeyer and Crowley method.


  • Duration of Response [ Time Frame: From the date of first PR or CR assessment to the date of documented progressive disease or death without prior documentation of progression (maximum participant duration of response of 38 months.) ] [ Designated as safety issue: No ]

    Period measured in months from time that measurement criteria were first met for CR or PR until first date of documented PD or death from any cause without prior documentation of progression.

    PD=≥20% increase in sum of LD of target lesions in reference to smallest sum LD recorded at or following baseline or unequivocal progression of existing non-target lesion(s) overall. Refer to Outcome Measure 1 for definitions of CR and PR. Estimated by the Kaplan-Meier product limit method. A two-sided 95% CI for median duration was computed by Brookmeyer and Crowley method.


  • Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs), and AEs Leading to Discontinuation of Study Therapy Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 [ Time Frame: Assessed from the date of first dose until at least 30 days after the last dose of study drug (maximum time that any participant was on therapy was 108 weeks.) ] [ Designated as safety issue: Yes ]
    AE: New untoward medical occurrence or worsening of a preexisting medical condition that does not have causal relationship with this treatment. SAE: Untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency/abuse; life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization/prolongs existing hospitalization. Grade 3=Severe; and Grade 4=Life-threatening or disabling. GR=Grade.

  • Number of Participants With Hematology Abnormalities by Worst Grade Per National Cancer Institute Common Terminology Criteria Adverse Events (NCI CTCAE), Version 3.0 [ Time Frame: Prior to every cycle of therapy (i.e. before starting of every 21 day or 3 week cycle; maximum time that any participant was on therapy was 108 weeks.) ] [ Designated as safety issue: Yes ]
    Grade (GR)1=mild, GR2=moderate, GR3=severe, GR4=life threatening or disabling. Normal ranges provided by local laboratory and may also vary by age and sex. White blood cell (WBC):GR1=<LLN-3.0*10^9/L; GR2=<3.0-2.0*10^9/L; GR3=<2.0-1.0*10^9/L; GR4=<1.0*10^9/L. Absolute Neutrophil Count (ANC):GR1=<LLN-1.5*10^9 /L; GR2=<1.5-1.0*10^9/L; GR3=<1.0-0.5*10^9/L; GR4=<0.5*10^9/L. Platelets:GR1=<LLN-75.0*10^9/L; GR2=<75.0-50.0*10^9/L; GR3=<50.0-25.0*10^9/L, GR4=<25.0*10^9/L. Hemoglobin:GR1=<LLN-10.0g/dL; GR2=<10.0-8.0g/dL; GR3=<8.0-6.5g/dL, GR4=<6.5g/dL. LLN=lower limit of normal.

  • Number of Participants With Serum Chemistry Abnormalities by Worst Grade Per National Cancer Institure Common Terminology Criteria Adverse Events (NCI CTCAE), Version 3.0 [ Time Frame: Prior to every cycle of therapy (i.e. before starting of every 21 day or 3 week cycle; maximum time that any participant was on therapy was 108 weeks.) ] [ Designated as safety issue: Yes ]
    Grading: NCI CTCAE, Version 3.0. GR1=mild, GR2=moderate, GR3=severe, GR4=life threatening or disabling. Normal ranges provided by local laboratory and may also vary by age and sex. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST): GR1=>ULN-2.5*ULN; GR2=>2.5-5.0*ULN; GR3=>5.0-20.0*ULN; GR4=>20.0*ULN. Total bilirubin: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3-10*ULN, GR4=>10*ULN. Creatinine: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3.0-6.0*ULN, GR4=>6.0*ULN. ULN=upper limit of normal.


Enrollment: 50
Study Start Date: February 2008
Study Completion Date: November 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
trastuzumab 4 mg/kg loading dose, then 2 mg/kg weekly + ixabepilone 40 mg/m^2 intravenous (IV) over 3 hours once every 21 days (using a 21-day cycle); until disease progression or unacceptable toxicity.
Drug: ixabepilone

Ixabepilone 40 mg/m^2 was administered as a 3-hour I.V. continuous infusion on Day 1 in a 21-day cycle until disease progression or unacceptable toxicity.

For the first cycle, ixabepilone was administered the day following the first dose of trastuzumab (in the first cycle trastuzumab was given on Day 0); in all the following cycles, ixabepilone was administered immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated.

Other Names:
  • BMS-247550
  • Epothilone
  • IXEMPRA®
Drug: trastuzumab
Trastuzumab was administered as an IV infusion on Days 1, 8, and 15 of each 21-day cycle at a dose of 2 mg/kg until disease progression or unacceptable toxicity. In cycle 1, a loading dose of 4 mg/kg was administered as a 90-minute IV infusion on a day before initial administration of chemotherapy (i.e. on Day 0). Trastuzumab was given immediately prior to ixabepilone (Arm A) or docetaxel (Arm B) in all subsequent cycles as a 30-minute IV infusion if the initial dose was well tolerated.
Active Comparator: Arm B
trastuzumab 4 mg/kg loading dose, then 2 mg/kg weekly + docetaxel 100 mg/m^2 IV over 1 hour once every 21 days (using a 21-day cycle); until disease progression or unacceptable toxicity.
Drug: docetaxel
Docetaxel 100 mg/m^2 was administered as a 1-hour IV continuous infusion on Day 1 in a 21-day cycle until disease progression or unacceptable toxicity. For the first cycle, docetaxel was administered the day following the first dose of trastuzumab (i.e. in the first cycle trastuzumab was given on Day 0); in all following cycles, docetaxel was administered immediately after trastuzumab if the preceding dose of trastuzumab was well tolerated.
Drug: trastuzumab
Trastuzumab was administered as an IV infusion on Days 1, 8, and 15 of each 21-day cycle at a dose of 2 mg/kg until disease progression or unacceptable toxicity. In cycle 1, a loading dose of 4 mg/kg was administered as a 90-minute IV infusion on a day before initial administration of chemotherapy (i.e. on Day 0). Trastuzumab was given immediately prior to ixabepilone (Arm A) or docetaxel (Arm B) in all subsequent cycles as a 30-minute IV infusion if the initial dose was well tolerated.

  Eligibility

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

Inclusion Criteria:

  • Locally advanced or metastatic HER2+ breast cancer not previously treated with chemotherapy or trastuzumab.
  • Subjects who had received prior (neo)adjuvant chemotherapy or trastuzumab were eligible except if they relapsed within 12 months after the last dose of a taxane or trastuzumab given as (neo)adjuvant therapy.
  • Measurable disease
  • Left Ventricular Ejection Fraction (LVEF) ≥50%

Exclusion Criteria:

  • Prior chemotherapy or trastuzumab for metastatic breast cancer (MBC)
  • Relapse within 1 year after (neo)adjuvant taxane or trastuzumab
  • Neuropathy > Grade 1
  • Significant cardiovascular disease
  • Any brain metastases
  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: NCT00490646

Locations
France
Local Institution
Caen, France, F-14076
Local Institution
Grenoble, France, 38028
Local Institution
St Priest En Jarez, France, 42271
Local Institution
Toulouse, France, 31300
Greece
Local Institution
Athens, Greece, 12462
Local Institution
Athens, Greece, 11522
Local Institution
Pireaus, Greece, 18537
Italy
Local Institution
Bologna, Italy, 40138
Local Institution
Brescia, Italy, 25123
Local Institution
Modena, Italy, 41100
Local Institution
Napoli, Italy, 80131
Local Institution
Roma, Italy, 00144
Local Institution
Sora, Italy, 03039
Spain
Local Institution
Madrid, Spain, 28034
Local Institution
Madrid, Spain, 28007
Turkey
Local Institution
Ankara, Turkey, 06100
Local Institution
Ankara, Turkey, 06500
Local Institution
Izmir, Turkey, 35100
Local Institution
Izmir, Turkey, 35340
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00490646     History of Changes
Other Study ID Numbers: CA163-140, Eudract No: 2007-000721-21
Study First Received: June 21, 2007
Results First Received: June 14, 2012
Last Updated: June 14, 2012
Health Authority: Italy: Ministry of Health

Keywords provided by Bristol-Myers Squibb:
Locally advanced and/or metastatic breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Docetaxel
Trastuzumab
Epothilones
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 23, 2014