Combination Chemotherapy With or Without Trastuzumab Followed By an Autologous Stem Cell Transplant and Radiation Therapy in Treating Patients With Stage III or Stage IV Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. An autologous stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy with or without trastuzumab followed by an autologous stem cell transplant and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving combination chemotherapy with or without trastuzumab followed by an autologous stem cell transplant and radiation therapy works in treating patients with stage III or stage IV breast cancer.

Detailed Description
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OBJECTIVES: Determine the feasibility of tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation and helical tomotherapy or loco-regional radiotherapy in patients with high-risk stage IIIB, IIIC, or IV breast cancer. Determine the toxic effects of this regimen in these patients. OUTLINE: Patients undergo stem cell collection. Course 1: Patients receive high-dose melphalan IV with or without trastuzumab (Herceptin®). One day later, patients undergo autologous peripheral blood stem cell (PBSC) transplantation. No more than 7 weeks later, patients proceed to course 2. Course 2: Patients receive high-dose carboplatin, thiotepa, and cyclophosphamide IV continuously over 4 days followed by autologous PBSC transplantation. After recover from high-dose chemotherapy and autologous PBSC transplantation, patients with stage IIIB or IIIC disease undergo radiotherapy to the chest wall and lymph nodes. Patients with stage IV disease undergo radiotherapy using helical tomotherapy or standard radiotherapy to oligometastatic sites. PROJECTED ACCRUAL: A total of 100 patients will be accrued for this study.

Official Title
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Phase II Study of Tandem Cycle Dose-Intense Chemotherapy of Melphalan and Carboplatin, Thiotepa and Cyclophosphamide (STMP V) ± Trastuzumab Followed by Helical Tomotherapy or Local Regional Radiation Therapy for Stage IV Metastatic and Stage IIIB/C Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Drug: carboplatin
* Drug: cyclophosphamide
* Drug: melphalan
* Drug: thiotepa
* Procedure: adjuvant therapy
* Procedure: autologous-autologous tandem hematopoietic stem cell transplantation
* Procedure: bone marrow ablation with stem cell support
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer, meeting 1 of the following stage criteria: Stage IIIB or IIIC disease, meeting both of the following criteria: Must have received prior neoadjuvant or adjuvant therapy Must have undergone lumpectomy or mastectomy Stage IV disease, meeting all of the following criteria: Only 1-3 organ sites with disease involvement after induction chemotherapy Achieved at least a partial response after induction chemotherapy No more than 3 lesions in the organ sites combined Inflammatory breast cancer allowed Completed chemotherapy, surgery, or radiotherapy for breast cancer within the past 6 months Hormone receptor status: Not specified PATIENT CHARACTERISTICS: Age 65 and under Sex Male or female Menopausal status Not specified Performance status Karnofsky 80-100% Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic SGOT or SGPT ≤ 2 times upper limit of normal Bilirubin ≤ 1.5 mg/dL Renal Creatinine ≤ 1.2 mg/dL Creatinine clearance ≥ 70 mL/min Cardiovascular LVEF ≥ 55% by MUGA or echocardiogram Pulmonary FEV_1 ≥ 60% of predicted DLCO ≥ 60% of the lower limit of predicted value Oxygen saturation > 92% on room air Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No autoimmune disorders No immunosuppressive condition No other malignancy within the past 5 years PRIOR CONCURRENT THERAPY: Biologic therapy No prior biologic therapy except trastuzumab (Herceptin®) Chemotherapy See Disease Characteristics Endocrine therapy Not specified Radiotherapy See Disease Characteristics No prior radiotherapy to adjacent or involved sites of disease that would preclude study radiotherapy Surgery See Disease Characteristics Other No other concurrent anticancer therapy

Ages Eligible for Study
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Maximum Age: 65 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients undergo stem cell collection. Patients receive high-dose melphalan IV with or without trastuzumab (Herceptin®). One day later, patients undergo autologous peripheral blood stem cell (PBSC) transplantation. No more than 7 weeks later, patients proceed to course 2. After recover from high-dose chemotherapy and autologous PBSC transplantation, patients with stage IIIB or IIIC disease undergo radiotherapy to the chest wall and lymph nodes. Patients with stage IV disease undergo radiotherapy using helical tomotherapy or standard radiotherapy to oligometastatic sites. | Biological: trastuzumab<br>* Cycle 1: 6 mg/kg on day -2 from PBSC reinfusion Cycle 2: 6 mg/kg on day -7 from PBSC reinfusion<br>Drug: melphalan<br>* Cycle 1: 150 mg/m2 on day -1 from PBSC reinfusion<br>Procedure: adjuvant therapy<br>* Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation and helical tomotherapy or loco-regional radiotherapy.<br>Procedure: autologous-autologous tandem hematopoietic stem cell transplantation<br>* Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation.<br>Procedure: bone marrow ablation with stem cell support<br>* Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation<br>Radiation: radiation therapy<br>* After recovery from high-dose chemotherapy and autologous PBSC transplantation; patients with stage IIIB or IIIC disease undergo radiotherapy to the chest wall and lymph nodes. Treatment should be delivered daily M-F @ 180-200 cGY/day to a total of 4,500 to 5,040 cGy. Patients with stage IV disease undergo radiotherapy using helical tomotherapy or standard radiotherapy to oligometastatic sites. Treatment should be delivered daily @180-220 cGY/day to a total of 4,000-5,000 cGy.<br>|
| Experimental: Arm II<br>Patients undergo stem cell collection. Patients receive high-dose carboplatin, thiotepa, and cyclophosphamide IV continuously over 4 days followed by autologous PBSC transplantation. After recover from high-dose chemotherapy and autologous PBSC transplantation, patients with stage IIIB or IIIC disease undergo radiotherapy to the chest wall and lymph nodes. Patients with stage IV disease undergo radiotherapy using helical tomotherapy or standard radiotherapy to oligometastatic sites. | Drug: carboplatin<br>* Cycle 2: 800 mg/m2/96 hours on days -7 to -3 from PBSC reinfusion<br>Drug: cyclophosphamide<br>* Cycle 2: 6000 mg/m2/96 hours on days -7 to -3 from PBSC reinfusion<br>Drug: thiotepa<br>* Cycle 2: 500 mg/m2/96 hours on days -7 to -3 from PBSC reinfusion<br>Procedure: adjuvant therapy<br>* Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation and helical tomotherapy or loco-regional radiotherapy.<br>Procedure: autologous-autologous tandem hematopoietic stem cell transplantation<br>* Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation.<br>Procedure: bone marrow ablation with stem cell support<br>* Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation<br>Radiation: radiation therapy<br>* After recovery from high-dose chemotherapy and autologous PBSC transplantation; patients with stage IIIB or IIIC disease undergo radiotherapy to the chest wall and lymph nodes. Treatment should be delivered daily M-F @ 180-200 cGY/day to a total of 4,500 to 5,040 cGy. Patients with stage IV disease undergo radiotherapy using helical tomotherapy or standard radiotherapy to oligometastatic sites. Treatment should be delivered daily @180-220 cGY/day to a total of 4,000-5,000 cGy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-Year Relapse-free Survival Rate | Estimated using the product-limit method of Kaplan and Meier. Relapse defined as appearance of any new lesions during or after protocol treatment. Whenever possible, relapses should be documented histologically. | From time of initial PBPC rescue until death or disease recurrence (disease progression for patients with stage IV disease), whichever came first, up to 5 years post treatment | 
| 5-Year Overall Survival Rate | Estimated using the product-limit method of Kaplan and Meier. Patients who were still alive were censored at the date of last follow-up | From time of initial PBPC rescue until the date of death from any cause, assessed up to 5 years post treatment. | 

 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, inflammatory breast cancer, male breast cancer, recurrent breast cancer, invasive ductal breast carcinoma with predominant intraductal component, invasive ductal breast carcinoma, medullary ductal breast carcinoma with lymphocytic infiltrate, mucinous ductal breast carcinoma, Paget disease of the breast with invasive ductal carcinoma, papillary ductal breast carcinoma, tubular ductal breast carcinoma, invasive lobular breast carcinoma with predominant in situ component, invasive lobular breast carcinoma, comedo ductal breast carcinoma