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Trastuzumab, Ixabepilone, and Carboplatin in Treating Patients With HER2/Neu-Positive Metastatic Breast Cancer

Primary Purpose

HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
trastuzumab
ixabepilone
carboplatin
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HER2-positive Breast Cancer

Eligibility Criteria

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

Inclusion Criteria: Patients with histologically confirmed adenocarcinoma of the breast which is metastatic and is known to overexpress HER2/neu who have received no prior chemotherapy for metastatic breast cancer; prior hormonal therapy for metastatic disease is allowed; NOTE: for this protocol, HER2 overexpression will be defined as 3+ HER2 positivity as measured by immunohistochemistry using the HercepTest (DAKO) or HER2 gene amplification as measured by fluorescent in-situ hybridization (FISH, e.g. Vysis); representative diagnostic tissue must be submitted for central diagnostic review Patients must not be pregnant or breast feeding because of the teratogenic potential of these drugs; it is recommended that all females of childbearing potential have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective non-hormonal method of contraception Patients must have at least one objective measurable disease parameter; baseline measurements and evaluations using RECIST criteria guidelines must be obtained within 4 weeks prior to registration to the study; NOTE: all areas of disease should be recorded and followed Patients must have an ECOG performance status of 0 or 1 Patients must be disease free of prior malignancy for >= 5 years with the exception of curatively treated basal cell carcinoma or squamous cell carcinomas of the skin or carcinoma in situ of the cervix Patients must not have a history of untreated brain metastasis or brain metastasis currently undergoing radiation; patients with brain metastasis representing the sole site of disease are not eligible for this study; patients with previously treated brain metastasis who have responded to brain radiotherapy and/or surgery and continue in response are eligible provided the brain is not the only site of measurable disease Patients must not have peripheral neuropathy of any grade Patients must not have a history of prior severe (grade 3 or 4) hypersensitivity reaction to a drug formulated in polyoxyethylated castor oil (Cremophor EL) Patients must have left ventricular ejection fraction by MUGA scan or echocardiogram that is at or above the lower institutional limits of normal obtained within 6 weeks prior to registration Patients must not have a history of New York Heart Association class 3 or 4 heart failure Serum creatinine =< 1.5 mg/dl Granulocytes >= 1500/mm^3 Platelets >= 100,000/mm^3 SGOT(AST) and SGPT(ALT) =< 1.5 x upper limit of normal (unless liver is involved by tumor, in which case SGOT(AST) and SGPT(ALT) can be =< 2.0 x upper limit of normal) Patients must have no history of prior therapy with trastuzumab (Herceptin), Ixabepilone (BMS-247550) or carboplatin for metastatic disease; patients who develop metastatic disease =< 6 months after completing adjuvant trastuzumab (Herceptin), paclitaxel, docetaxel, carboplatin, or Ixabepilone (BMS-247550) are considered to have had prior therapy for metastatic disease and are excluded from study participation Patients must not have received a cumulative dose of doxorubicin of greater than 360 mg/m^2 or epirubicin of greater than 640 mg/m^2 Concurrent use of hormonal therapy is not permitted; concurrent radiation therapy is not permitted; hormonal therapy must have been discontinued >= 1 week prior to registration; radiation therapy must have been completed >= 2 weeks prior to registration Patients may have had prior radiation therapy, but the previously irradiated tumors cannot be used to assess a clinical response; patients will not be eligible if they do not have other areas of measurable disease; an exception will be given for patients who have had tumor recurrence in an area that received adjuvant radiation treatments, such as the axilla or chest wall

Sites / Locations

  • Eastern Cooperative Oncology Group

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (trastuzumab, ixabepilone, carboplatin)

Arm Description

Induction therapy: Patients receive trastuzumab (Herceptin®) IV over 30 minutes* on days 1, 8, 15, and 22 and ixabepilone IV over 1 hour and carboplatin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of unacceptable toxicity. NOTE: *Trastuzumab is given over 90 minutes on day 1 of course 1 (induction therapy) only. Maintenance therapy: Patients receive trastuzumab IV over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Objective Response for HER2+ Patients (Best Objective Response a Patient Has Ever Experienced on Study)
To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up. The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.

Secondary Outcome Measures

Objective Response for All Treated Patients (the Best Response a Patient Has Ever Experienced on Study)
To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up. The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.
Time to Disease Progression for HER2+ Patients
This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.
Time to Disease Progression for All Treated Patients
This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.
Time to Treatment Failure for HER2+ Patients
Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.
Time to Treatment Failure for All Treated Patients
Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.
Kaplan-Meier Estimate of Overall Survival at 3 Years for HER2+ Patients
Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.
Kaplan-Meier Estimate of Overall Survival at 3 Years for All Treated Patients
Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.

Full Information

First Posted
February 10, 2004
Last Updated
May 2, 2014
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00077376
Brief Title
Trastuzumab, Ixabepilone, and Carboplatin in Treating Patients With HER2/Neu-Positive Metastatic Breast Cancer
Official Title
A Phase II Trial of Trastuzumab Plus Weekly Ixabepilone(BMS-247550) and Carboplatin in Patients With HER2/Neu-Positive Metastatic Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
December 2012
Overall Recruitment Status
Completed
Study Start Date
March 2005 (undefined)
Primary Completion Date
March 2009 (Actual)
Study Completion Date
March 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
This phase II trial is studying how well giving trastuzumab together with ixabepilone and carboplatin works in treating patients with HER2/neu-positive metastatic breast cancer. Monoclonal antibodies, such as trastuzumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as ixabepilone and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining trastuzumab with ixabepilone and carboplatin may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the response rate (as determined by RECIST criteria) to combination therapy with Ixabepilone (BMS-247550), trastuzumab, and carboplatin in patients with metastatic breast cancer known to overexpress HER2. SECONDARY OBJECTIVES: I. To determine time to disease progression (TTP) and time to treatment failure (TTF) after treatment with Ixabepilone (BMS-247550), trastuzumab and carboplatin in patients with metastatic breast cancer known to overexpress HER2. II. To determine the toxicity of combination therapy with Ixabepilone (BMS-247550), trastuzumab and carboplatin in patients with metastatic breast cancer known to overexpress HER2. III. To evaluate overall survival (OS) of combination therapy with Ixabepilone (BMS-247550), trastuzumab, and carboplatin in patients with metastatic breast cancer known to overexpress HER2. IV. To correlate levels of phospho-STAT3 with levels of HER2, Survivin and EGFR expression as measured in tissue by immunohistochemistry. OUTLINE: This is a multicenter study. Induction therapy: Patients receive trastuzumab (Herceptin®) IV over 30 minutes* on days 1, 8, 15, and 22 and ixabepilone IV over 1 hour and carboplatin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of unacceptable toxicity. NOTE: *Trastuzumab is given over 90 minutes on day 1 of course 1 (induction therapy) only. Maintenance therapy: Patients receive trastuzumab IV over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years and then every 6 months for 3 years from study entry. PROJECTED ACCRUAL: A total of 10-60 patients will be accrued for this study within 1-6 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
61 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (trastuzumab, ixabepilone, carboplatin)
Arm Type
Experimental
Arm Description
Induction therapy: Patients receive trastuzumab (Herceptin®) IV over 30 minutes* on days 1, 8, 15, and 22 and ixabepilone IV over 1 hour and carboplatin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of unacceptable toxicity. NOTE: *Trastuzumab is given over 90 minutes on day 1 of course 1 (induction therapy) only. Maintenance therapy: Patients receive trastuzumab IV over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Biological
Intervention Name(s)
trastuzumab
Other Intervention Name(s)
anti-c-erB-2, Herceptin, MOAB HER2
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
ixabepilone
Other Intervention Name(s)
BMS-247550, epothilone B lactam, Ixempra
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
carboplatin
Other Intervention Name(s)
Carboplat, CBDCA, JM-8, Paraplat, Paraplatin
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Objective Response for HER2+ Patients (Best Objective Response a Patient Has Ever Experienced on Study)
Description
To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up. The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.
Time Frame
Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years
Secondary Outcome Measure Information:
Title
Objective Response for All Treated Patients (the Best Response a Patient Has Ever Experienced on Study)
Description
To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up. The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.
Time Frame
Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years
Title
Time to Disease Progression for HER2+ Patients
Description
This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.
Time Frame
Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years
Title
Time to Disease Progression for All Treated Patients
Description
This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.
Time Frame
Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years
Title
Time to Treatment Failure for HER2+ Patients
Description
Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.
Time Frame
Assessed every cycle until treatment discontinuation
Title
Time to Treatment Failure for All Treated Patients
Description
Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.
Time Frame
Assessed every cycle until treatment discontinuation
Title
Kaplan-Meier Estimate of Overall Survival at 3 Years for HER2+ Patients
Description
Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.
Time Frame
Assessed every 3 months for 2 years, then every 6 months for 3 years
Title
Kaplan-Meier Estimate of Overall Survival at 3 Years for All Treated Patients
Description
Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.
Time Frame
Assessed every 3 months for 2 years, then every 6 months for 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with histologically confirmed adenocarcinoma of the breast which is metastatic and is known to overexpress HER2/neu who have received no prior chemotherapy for metastatic breast cancer; prior hormonal therapy for metastatic disease is allowed; NOTE: for this protocol, HER2 overexpression will be defined as 3+ HER2 positivity as measured by immunohistochemistry using the HercepTest (DAKO) or HER2 gene amplification as measured by fluorescent in-situ hybridization (FISH, e.g. Vysis); representative diagnostic tissue must be submitted for central diagnostic review Patients must not be pregnant or breast feeding because of the teratogenic potential of these drugs; it is recommended that all females of childbearing potential have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective non-hormonal method of contraception Patients must have at least one objective measurable disease parameter; baseline measurements and evaluations using RECIST criteria guidelines must be obtained within 4 weeks prior to registration to the study; NOTE: all areas of disease should be recorded and followed Patients must have an ECOG performance status of 0 or 1 Patients must be disease free of prior malignancy for >= 5 years with the exception of curatively treated basal cell carcinoma or squamous cell carcinomas of the skin or carcinoma in situ of the cervix Patients must not have a history of untreated brain metastasis or brain metastasis currently undergoing radiation; patients with brain metastasis representing the sole site of disease are not eligible for this study; patients with previously treated brain metastasis who have responded to brain radiotherapy and/or surgery and continue in response are eligible provided the brain is not the only site of measurable disease Patients must not have peripheral neuropathy of any grade Patients must not have a history of prior severe (grade 3 or 4) hypersensitivity reaction to a drug formulated in polyoxyethylated castor oil (Cremophor EL) Patients must have left ventricular ejection fraction by MUGA scan or echocardiogram that is at or above the lower institutional limits of normal obtained within 6 weeks prior to registration Patients must not have a history of New York Heart Association class 3 or 4 heart failure Serum creatinine =< 1.5 mg/dl Granulocytes >= 1500/mm^3 Platelets >= 100,000/mm^3 SGOT(AST) and SGPT(ALT) =< 1.5 x upper limit of normal (unless liver is involved by tumor, in which case SGOT(AST) and SGPT(ALT) can be =< 2.0 x upper limit of normal) Patients must have no history of prior therapy with trastuzumab (Herceptin), Ixabepilone (BMS-247550) or carboplatin for metastatic disease; patients who develop metastatic disease =< 6 months after completing adjuvant trastuzumab (Herceptin), paclitaxel, docetaxel, carboplatin, or Ixabepilone (BMS-247550) are considered to have had prior therapy for metastatic disease and are excluded from study participation Patients must not have received a cumulative dose of doxorubicin of greater than 360 mg/m^2 or epirubicin of greater than 640 mg/m^2 Concurrent use of hormonal therapy is not permitted; concurrent radiation therapy is not permitted; hormonal therapy must have been discontinued >= 1 week prior to registration; radiation therapy must have been completed >= 2 weeks prior to registration Patients may have had prior radiation therapy, but the previously irradiated tumors cannot be used to assess a clinical response; patients will not be eligible if they do not have other areas of measurable disease; an exception will be given for patients who have had tumor recurrence in an area that received adjuvant radiation treatments, such as the axilla or chest wall
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stacy Moulder
Organizational Affiliation
Eastern Cooperative Oncology Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
Eastern Cooperative Oncology Group
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Trastuzumab, Ixabepilone, and Carboplatin in Treating Patients With HER2/Neu-Positive Metastatic Breast Cancer

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