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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Trial of Trastuzumab Plus Weekly Ixabepilone(BMS-247550) and Carboplatin in Patients With HER2/Neu-Positive Metastatic Breast Cancer

Conditions
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HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Drug: ixabepilone
* Drug: carboplatin
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (trastuzumab, ixabepilone, carboplatin)<br>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. | Biological: trastuzumab<br>* Given IV<br>* Other names: MOAB HER2;Drug: ixabepilone<br>* Given IV<br>* Other names: Ixempra;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years | 
| 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. | Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years | 
| 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. | Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years | 
| 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. | Assessed every cycle until treatment discontinuation | 
| 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. | Assessed every cycle until treatment discontinuation | 
| 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. | Assessed every 3 months for 2 years, then every 6 months for 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. | Assessed every 3 months for 2 years, then every 6 months for 3 years |