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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Biological: trastuzumab; Drug: melphalan; Procedure: adjuvant therapy; Procedure: autologous-autologous tandem hematopoietic stem cell transplantation; Procedure: bone marrow ablation with stem cell support; Radiation: radiation therapy; Drug: carboplatin; Drug: cyclophosphamide; Drug: thiotepa

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; 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; Cycle 1: 6 mg/kg on day -2 from PBSC reinfusion Cycle 2: 6 mg/kg on day -7 from PBSC reinfusion; Drug: melphalan; Cycle 1: 150 mg/m2 on day -1 from PBSC reinfusion; Procedure: adjuvant therapy; 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.; Procedure: autologous-autologous tandem hematopoietic stem cell transplantation; Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation.; Procedure: bone marrow ablation with stem cell support; Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation; Radiation: radiation therapy; 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.
Experimental: Arm II; 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.	Procedure: adjuvant therapy; 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.; Procedure: autologous-autologous tandem hematopoietic stem cell transplantation; Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation.; Procedure: bone marrow ablation with stem cell support; Tandem high-dose chemotherapy comprising melphalan, carboplatin, thiotepa, and cyclophosphamide with or without trastuzumab (Herceptin®) followed by autologous peripheral blood stem cell transplantation; Radiation: radiation therapy; 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.; Drug: carboplatin; Cycle 2: 800 mg/m2/96 hours on days -7 to -3 from PBSC reinfusion; Drug: cyclophosphamide; Cycle 2: 6000 mg/m2/96 hours on days -7 to -3 from PBSC reinfusion; Drug: thiotepa; Cycle 2: 500 mg/m2/96 hours on days -7 to -3 from PBSC reinfusion

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: George Somlo, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: September 15, 2005
• First Submitted That Met QC Criteria: September 15, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Actual): February 23, 2017
• Last Update Submitted That Met QC Criteria: January 31, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer; stage IIIB breast cancer; male breast cancer; stage IIIC breast cancer; invasive ductal breast carcinoma; invasive lobular breast carcinoma; invasive lobular breast carcinoma with predominant in situ component; inflammatory breast cancer; medullary ductal breast carcinoma with lymphocytic infiltrate; mucinous ductal breast carcinoma; papillary ductal breast carcinoma; tubular ductal breast carcinoma; Paget disease of the breast with invasive ductal carcinoma; invasive ductal breast carcinoma with predominant intraductal component; comedo ductal breast carcinoma
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Carboplatin; Trastuzumab; Melphalan; Thiotepa
• Other Study ID Numbers: 05042; P30CA033572 (U.S. NIH Grant/Contract); CDR0000442105 (Registry Identifier: PDQ)