Combination Chemotherapy With or Without Trastuzumab in Treating Women With Metastatic Breast Cancer

Study Overview
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Brief Summary
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Phase II trial to study the effectiveness of combination chemotherapy with or without trastuzumab in treating women who have metastatic breast cancer. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety and feasibility of the combination of liposomal doxorubicin (Doxil) and Taxotere (Taxotere) ± trastuzumab (Herceptin), particularly with respect to cardiotoxicity. II. To evaluate the overall objective response rate, response duration, time to treatment failure, and median survival of patients with metastatic breast cancer treated with Doxil and Taxotere ± Herceptin. III. To determine the overall toxicity of Doxil and Taxotere ± Herceptin in patients with advanced breast cancer. IV. To determine whether there is an association between trough plasma levels of cTnT (cardiac troponin T) and NT-proBNP (brain natriuretic peptide) and any cardiac event (CHF or LVEF decrease). V. To determine tissue and plasma levels of HER2 using several assays and explore potential correlation with protocol treatment toxicity and/or response. OUTLINE: Patients are assigned to one of two treatment arms according to HER2 overexpression status. Arm I (HER2 nonoverexpressed): Patients receive doxorubicin hydrochloride liposome IV over 30 minutes followed by docetaxel IV over 1 hour. Treatment is repeated every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may receive maintenance therapy of docetaxel IV over 1 hour either weekly or every 3 weeks. Maintenance continues in the absence of disease progression or unacceptable toxicity. Arm II (HER2 overexpressed): Patients receive trastuzumab IV over 90 minutes on day 1, with subsequent doses over 30 minutes. Patients receive doxorubicin HCl liposome IV over 30 minutes followed by docetaxel IV over 1 hour on day 2 of course 1, followed by subsequent doses on day 1 of each course. Antibody therapy continues weekly and chemotherapy every 3 weeks for 8 courses. Patients may receive maintenance therapy of trastuzumab IV over 30 minutes weekly followed by docetaxel IV over 1 hour weekly or every 3 weeks. Maintenance continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 89 patients were accrued for this study.

Official Title
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A Safety and Efficacy Study of Doxil and Taxotere ± Herceptin in Advanced Breast Cancer

Conditions
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Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: pegylated liposomal doxorubicin hydrochloride
* Drug: docetaxel
* Biological: trastuzumab
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the breast with manifestations of metastatic progression HER2 expression status in primary breast tissue and/or site(s) of metastasis must be determined by the ECOG Pathology Coordinating Office; (these are the results that will be used at time of registration); NOTE: for this protocol, HER2/neu non-overexpressed status will be defined as 0 and 1+ scores using the DAKO HercepTest; HER2 overexpressed status will be defined as 2+ score (if confirmed amplified by FISH) or 3+ score using the DAKO HercepTest Cytologically positive pleural or peritoneal effusions are considered evaluable disease provided local intra-cavitary treatment is not introduced at the onset of therapy; to be considered as evaluable disease, pleural effusions may not have been previously drained or sclerosed Blastic or mixed blastic/lytic osseous metastases only are evaluable disease provided they are accompanied by an analgesic requirement or a decrease in performance status, and will not require radiation treatment within two cycles from the start of protocol; pure osteolytic disease is evaluable; bone disease must be x-ray proven for the site to be evaluable; patients whose only evidence of metastatic disease is an abnormal bone scan without confirmatory x-rays are not eligible for this study No prior chemotherapy for advanced disease; prior adjuvant chemotherapy (including taxanes) allowed, if completed > 6 months before the diagnosis of metastatic disease; no prior adjuvant anthracycline, nor any prior exposure to other anthracycline- (e.g., epirubicin, any liposomal doxorubicin formulation), nor any anthracenedione- (e.g., mitoxantrone) containing regimen allowed; no prior therapy with Herceptin allowed; NOTE: chemotherapy after ipsilateral breast recurrence following breast conservation surgery would not be considered chemotherapy for advanced disease; however, in post-mastectomy patients chemotherapy for local/regional recurrence is considered treatment for advanced disease No prior radiotherapy other than to the conserved breast, to the post-mastectomy chest wall, or to a limited field involving < 25% of marrow-containing bone; NOTE: previous post-mastectomy radiation therapy involving chest wall ± internal mammary lymph node chain (IMN) is allowed; however, patients who received photon IMN treatment are ineligible; NOTE: radiotherapy must be completed >= 2 weeks prior to registration; it may not be given concurrently with Doxil, Taxotere, or Herceptin Prior hormonal therapy in either a metastatic or adjuvant setting is allowed, but patients must have been off such therapy for >= 2 weeks prior to registration Disease-free of prior non-breast invasive malignancies for >= 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix ECOG performance status of 0, 1, or 2 At least two weeks after any major surgery (including mastectomy) and recovered from all toxicity Creatinine =< 1.5 mg/dl Granulocytes >= 1,500/mm³ Platelets >= 100,000/mm³ SGOT(AST) =< 2.5 x the upper limit of normal Bilirubin within normal limits for institution No history of deep venous thrombosis, pulmonary thromboembolism, or other thromboembolic condition Women must not be pregnant or breastfeeding; the effect of Herceptin to the fetus is unknown; Doxil is known to be harmful to the fetus Women of childbearing potential must be advised to use an accepted and effective method of contraception No patients with untreated brain metastasis or brain metastasis undergoing radiation or for whom brain metastasis represent the sole site of disease; 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 disease The left ventricular ejection fraction must be at or above the lower institutional limits of normal (as assessed by MUGA scan or echocardiogram obtained within six weeks prior to registration); patient will not be eligible if baseline LVEF assessment not performed No prior history of myocardial infarction, congestive heart failure, or arrhythmia requiring medication; no history of hypertension or systolic or diastolic dysfunction; no EKG evidence of ventricular hypertrophy, conduction abnormality, or serious arrhythmia; patient will not be eligible if baseline EKG assessment not performed within 4 weeks

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (combination chemotherapy)<br>Patients receive doxorubicin hydrochloride liposome IV over 30 minutes followed by docetaxel IV over 1 hour. Treatment is repeated every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may receive maintenance therapy of docetaxel IV over 1 hour either weekly or every 3 weeks. Maintenance continues in the absence of disease progression or unacceptable toxicity. | Drug: pegylated liposomal doxorubicin hydrochloride<br>* Given IV<br>* Other names: LipoDox;Drug: docetaxel<br>* Given IV<br>* Other names: TXT;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II (combination chemotherapy, trastuzumab)<br>Patients receive trastuzumab IV over 90 minutes on day 1, with subsequent doses over 30 minutes. Patients receive doxorubicin HCl liposome IV over 30 minutes followed by docetaxel IV over 1 hour on day 2 of course 1, followed by subsequent doses on day 1 of each course. Antibody therapy continues weekly and chemotherapy every 3 weeks for 8 courses. Patients may receive maintenance therapy of trastuzumab IV over 30 minutes weekly followed by docetaxel IV over 1 hour weekly or every 3 weeks. Maintenance continues in the absence of disease progression or unacceptable toxicity. | Drug: pegylated liposomal doxorubicin hydrochloride<br>* Given IV<br>* Other names: LipoDox;Drug: docetaxel<br>* Given IV<br>* Other names: TXT;Biological: trastuzumab<br>* Given IV<br>* Other names: MOAB HER2;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 |
| --- | --- | --- |
| Grades of Cardiotoxicity Events in the Subset of Patients Reporting a Cardiotoxicity Event | This table summarizes the cardiotoxicity events of different grades. Grade 1 is a decline of left ventricular ejection fraction(LVEF) >=10% but <20% of baseline value. Grade 2 is LVEF below LLN (50%) or decline of LVEF >=20% of baseline value. Grade 3 is congestive heart failure responsive to treatment. Please note that only a subset of patients reported cardiotoxic events so the totals will not add up to the total number of participants. | Baseline, after cycle 4 ( 84 days), after cycle 8 ( 168 days), and 30 or more days after last cycle of induction therapy | 
| Summary of Left Ventricular Ejection Fraction Values | This table summarizes the LVEF information at baseline, post Cycle 4, post Cycle 8, and 30 or more days after Cycle 8 on all treated patients and on the eligible subset. LVEF drops reported are absolute (not relative) drops. | Baseline, after cycle 4, after cycle 8, and 30 or more days after last cycle of induction therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Using Eastern Cooperative Group Solid Tumor Response Criteria. | Please note that overall response includes CR and PR. CR is defined as complete disappearance of all clinically detectable malignant disease for at least 4 weeks. PR is greater than or equal to 50% decrease in tumor size for at least 4 weeks without increase in size of any area of known malignant disease of greater than 25%, or appearance of new areas of malignant disease. No change is defined as no significant change in measurable or evaluable disease for at least 4 weeks. Progression is defined as a significant increase in size of lesions present at the start of therapy or after a response. | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually until death or until reaching full study stop date. Data as of Nov 21, 2007 is used for this report. Please note that best overall response is reported in the table. | 
| Overall Survival |  | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually until death or until reaching full study stop date. Data as of November 21, 2007 is used for this report. | 
| Progression-Free Survival | Progression-Free Survival was defined as time from study entry to progression or to death without documentation of progression. A progression is defined as a significant increase in size of lesions present at the start of therapy or after a response. | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually until death or until reaching full study stop date. Data as of November 21, 2007 is used for this report. | 
| Duration of Response | Defined as time from onset of PR or CR, whichever occurred first, until objective evidence of progression. | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually until death or until reaching full study stop date. Data as of November 21, 2007 is used for this report. |