Docetaxel and Trastuzumab With or Without Carboplatin in Treating Women With HER2-Positive Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: 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. It is not yet known if docetaxel and trastuzumab are more effective with or without carboplatin in treating women who have HER2-positive breast cancer. PURPOSE: Randomized phase III trial to study the effectiveness of combining docetaxel and trastuzumab with or without carboplatin in treating women who have HER2-positive stage IIIB or stage IV breast cancer.

Detailed Description
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OBJECTIVES: Compare the time to disease progression in women with HER2-positive stage IIIB, IIIC, or IV breast cancer treated with docetaxel and trastuzumab (Herceptin) with or without carboplatin. Compare the response rate and duration of overall response in patients treated with these regimens. Compare the overall survival of patients treated with these regimens. Compare rate of clinical benefit, defined as complete response, partial response, or stable disease for more than 24 weeks, in patients treated with these regimens. Compare the toxicity of these regimens in these patients. Determine pathologic and molecular markers for predicting efficacy of these regimens in these patients. Determine genetic and biochemical markers for predicting risk of cardiac dysfunction and later cardiac events in patients receiving these regimens. Determine whether peripheral levels of shed HER2 extracellular domain constitute a prognostic and/or predictive factor of time to progression and survival of patients receiving these regimens. OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to prior adjuvant and/or neoadjuvant chemotherapy (none vs with taxanes vs without taxanes) and participating center. Patients are randomized to 1 of 2 treatment arms. Arm I: Course 1: Patients receive trastuzumab (Herceptin) IV over 30-90 minutes on days 1, 8, and 15. Patients receive docetaxel IV over 1 hour and carboplatin IV over 30-60 minutes on day 2. Courses 2 and all subsequent courses: Patients receive docetaxel IV over 1 hour and carboplatin IV over 30-60 minutes on day 1 and trastuzumab IV over 30 minutes on days 1, 8, and 15. Arm II: Patients receive docetaxel and trastuzumab as in arm I. In both arms, treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. After completion of 8 courses, patients continue to receive trastuzumab IV over 30 minutes every 21 days in the absence of disease progression. Patients are followed every 2 months for 3 years. PROJECTED ACCRUAL: A total of 250 patients (125 per treatment arm) will be accrued for this study within 18 months.

Official Title
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A Multicenter Phase III Randomized Trial Comparing Docetaxel (Taxotere) and Trastuzumab (Herceptin) With Docetaxel (Taxotere), Carboplatin and Trastuzumab (Herceptin) as First Line Chemotherapy for Patients With Advanced Breast Cancer Containing the HER2 Gene Amplification

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Drug: carboplatin
* Drug: docetaxel
* Biological: trastuxumab
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed adenocarcinoma of the breast Stage IIIB, IIIC, or IV HER2-positive Measurable or evaluable disease Patients with osteolytic bone lesions as only site of disease must have at least 2 lytic sites confirmed by bone x-ray, MRI, or CT scan None of the following are eligible as only manifestation of metastatic disease: Blastic bone metastases Mixed bone metastases Lymphangitic carcinomatosis Ascites Pleural/pericardial effusion Lymphangitis cutis/pulmonis Inflammatory breast disease Abdominal masses not confirmed and followed by imaging techniques Cystic lesions No prior or known concurrent clinical manifestation of brain or leptomeningeal involvement Hormone receptor status: Not specified PATIENT CHARACTERISTICS: Age 18 to 75 Sex Female Menopausal status Pre- or post-menopausal Performance status Karnofsky 60-100% Life expectancy Not specified Hematopoietic Neutrophil count at least 2,000/mm3 Platelet count at least 100,000/mm3 Hemoglobin at least 10 g/dL Hepatic Bilirubin no greater than upper limit of normal (ULN) AST and ALT no greater than 5 times ULN Alkaline phosphatase no greater than 5 times ULN (unless due to bone metastases or any nonmalignant bone disease and in absence of liver disorders) AST and/or ALT greater than 1.5 times ULN AND alkaline phosphatase greater than 2.5 times ULN ineligible Renal Creatinine no greater than 2 mg/dL Creatinine clearance at least 60 mL/min Cardiovascular LVEF normal by MUGA or echocardiogram No myocardial infarction within the past year No unstable angina pectoris No documentation of congestive heart failure No concurrent grade 3 or 4 cardiovascular arrhythmia No poorly controlled hypertension (i.e., diastolic pressure greater than 100 mmHg) Pulmonary No severe dyspnea due to complications of advanced malignancy No respiratory insufficiency requiring supplemental oxygen Other No significant neurologic or psychiatric disorders (e.g., psychotic disorders, dementia, or seizures) that would preclude study No pre-existing sensory or motor neuropathy grade 2 or greater No other serious illness or medical condition No active uncontrolled infection No active peptic ulcer disease No unstable diabetes mellitus No other prior or concurrent malignancy except for: Curatively treated nonmelanoma skin cancer Carcinoma in situ of the cervix Other curatively treated cancer and disease free for at least 10 years No known allergic reactions to study drugs No contraindications for the use of corticosteroids Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy See Chemotherapy No prior trastuzumab (Herceptin) for locally advanced or metastatic disease Prior trastuzumab-containing regimen (except with taxane) as adjuvant or neoadjuvant therapy allowed provided relapse occurred at least 6 months after therapy Chemotherapy No prior chemotherapy for locally advanced or metastatic disease or local recurrence No prior chemotherapy with anthracycline or anthracenedione regimens with cumulative doses of more than 360 mg/m2 of doxorubicin, 720 mg/m2 of epirubicin, or 72 mg/m2 of mitoxantrone No prior platinum-containing regimen as adjuvant or neoadjuvant chemotherapy At least 4 weeks since prior anthracyclines or anthracenediones Prior taxanes as adjuvant or neoadjuvant chemotherapy allowed provided relapse occurred at least 6 months after therapy Prior taxane with trastuzumab as adjuvant or neoadjuvant chemotherapy allowed provided relapse occurred at least 12 months after therapy No concurrent amifostine Endocrine therapy Prior hormonal therapy in the adjuvant or metastatic setting allowed provided patient has progressive disease and therapy has stopped before study entry Concurrent chronic corticosteroids allowed if initiated more than 6 months before study entry and at a low dose (no greater than 20 mg methylprednisolone or equivalent) No concurrent raloxifene, tamoxifen, or other selective estrogen receptor modulators No concurrent hormonal therapy Radiotherapy No prior radiotherapy to study lesion unless clear progression At least 4 weeks since prior radiotherapy (unless radiotherapy involved only a single field to treat a single metastatic bone lesion) Concurrent radiotherapy for palliative treatment allowed Surgery Not specified Other Recovered from prior antitumor therapy At least 30 days since prior experimental drugs No other concurrent experimental drugs No other concurrent anticancer therapy No concurrent bisphosphonates if osteolytic bone metastases are only site of disease If receiving concurrent bisphosphonates other than for bone metastases only, must have been started at least 3 months before study entry No concurrent primary prophylactic antibiotics No concurrent cardioprotectors (e.g., dexrazoxane)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Herceptin plus docetaxel<br>Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose administered by IV infusion over 90 minutes, Day 2: Docetaxel (T) 100 mg/m2 by IV infusion over 30 minutes, Day 8: (H) 2mg/kg administered by IV infusion over 30 minutes, Day 15: 2mg/kg administered by IV infusion over 30 minutes. Subsequent cycles: Day 1: (T) 100mg/m2 as 1 hour IV infusion given every 3 weeks, followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes. Last cycle: Day 1: (T) 100mg/m2 as 1 hour IV infusion followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 22: (H) 6 mg/kg administered by IV infusion over 30 minutes. | Drug: docetaxel<br>* Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose administered by IV infusion over 90 minutes, Day 2: Docetaxel (T) 100 mg/m2 by IV infusion over 30 minutes, Day 8: (H) 2mg/kg administered by IV infusion over 30 minutes, Day 15: 2mg/kg administered by IV infusion over 30 minutes. Subsequent cycles: Day 1: (T) 100mg/m2 as 1 hour IV infusion given every 3 weeks, followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes. Last cycle: Day 1: (T) 100mg/m2 as 1 hour IV infusion followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 22: (H) 6 mg/kg administered by IV infusion over 30 minutes.<br>* Other names: taxotere;Biological: trastuxumab<br>* Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose administered by IV infusion over 90 minutes, Day 2: Docetaxel (T) 100 mg/m2 by IV infusion over 30 minutes, Day 8: (H) 2mg/kg administered by IV infusion over 30 minutes, Day 15: 2mg/kg administered by IV infusion over 30 minutes. Subsequent cycles: Day 1: (T) 100mg/m2 as 1 hour IV infusion given every 3 weeks, followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes. Last cycle: Day 1: (T) 100mg/m2 as 1 hour IV infusion followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 22: (H) 6 mg/kg administered by IV infusion over 30 minutes.<br>* Other names: herceptin;|
| Experimental: Docetaxel, Carboplatin, and Herceptin<br>Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins. | Biological: trastuzumab<br>* Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins.<br>* Other names: herceptin;Drug: carboplatin<br>* Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins.<br>Drug: Docetaxel<br>* Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins.<br>* Other names: taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate time to disease progression after treatment with either Herceptin in with single-agent docetaxel (TH) or Herceptin with Carboplatin and TH in metastatic breast cancer pts previously untreated with chemo whose cancer contains the HER2 gene amp. |  | till disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare response rate, duration of overall response, overall survival. |  | undefined | 
| To evaluate and compare the rate of clinical benefit, defined as CR, PR, or stable disease > 24 weeks. |  | undefined | 
| To compare toxicity between the 2 arms. |  | 2 years | 
| To evaluate pathologic and molecular markers for predicting efficacy. |  | 2 years | 
| Correlate peripheral levels of shed HER2 extracellular domain (ECD) with FISH results and to determine whether peripheral levels of shed HER2 ECD consitute a prognostic and/or predicitive factor vis-a-vis time to progression and survival. |  | undefined | 
| To evaluate genetic and biochemical markers for predicting risk of developing cardiac dysfunction and later cardiac events in this patient population. |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, recurrent breast cancer