Multimodality Treatment for Women With Stage II, Stage III, or Stage IV Breast Cancer (NRR)

• ClinicalTrials.gov Identifier: NCT00006110
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Results First Posted: July 31, 2017
• Last Update Posted: July 31, 2017
• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Information provided by (Responsible Party): UNC Lineberger Comprehensive Cancer Center

Study Description

Brief Summary:

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. Combining chemotherapy, monoclonal antibody therapy, and surgery may be a more effective treatment for breast cancer.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy, monoclonal antibody therapy, and surgery in treating women who have stage II, stage III, or stage IV breast cancer.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Biological: trastuzumab; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: paclitaxel; Procedure: conventional surgery	Phase 2

Detailed Description:

OBJECTIVES:

• Determine the cardiac and other toxicity of paclitaxel when administered with trastuzumab (Herceptin) after doxorubicin and cyclophosphamide in women with stage IIB, IIIA, IIIB, IIIC, or previously untreated stage IV breast cancer.
• Determine whether the addition of paclitaxel with or without trastuzumab to conventional breast cancer adjuvant therapy (doxorubicin and cyclophosphamide) further decreases tumor size and the number of positive axillary nodes in these patients.
• Determine the 5-year disease-free survival and overall survival of patients treated with these regimens.
• Determine whether the initial pathologic response in patients receiving neoadjuvant therapy correlates with the eventual 5-year disease-free survival or overall survival.
• Compare the number of patients eligible for breast-conserving cancer surgery after treatment with doxorubicin and cyclophosphamide vs paclitaxel and trastuzumab.
• Correlate clinical and radiographic response rate with pathologic response rate in the primary tumor and axillary lymph nodes and determine which parameter best determines the pathologic response rate in patients treated with these regimens.

OUTLINE: Patients either received neoadjuvant therapy (HER-2 overexpressing and non-overexpressing patients) or adjuvant therapy (HER-2 overexpressing patients only).

• Neoadjuvant therapy: Patients receive one of two treatment regimens.

  • Regimen I (HER-2 non-overexpressing patients or HER-2 overexpressing patients who refuse trastuzumab (Herceptin) therapy): Patients receive doxorubicin IV and cyclophosphamide IV over 30 minutes and paclitaxel IV over 3 hours on day 1 every 3 weeks for a total of 4 courses. Patients then undergo surgery with or without adjuvant radiotherapy and/or oral tamoxifen.
  • Regimen II (HER-2 overexpressing patients only): Patients receive doxorubicin and cyclophosphamide as in regimen I. After completion of course 4, patients receive paclitaxel IV and trastuzumab IV over 90-150 minutes weekly on weeks 13-24. Patients then undergo surgery with or without adjuvant radiotherapy. Patients then receive trastuzumab IV over 30 minutes weekly on weeks 29-69 if they did not receive radiotherapy or on weeks 36-76 if they did receive radiotherapy.
• Adjuvant therapy: Patients who receive adjuvant therapy (HER-2 overexpressing patients only) receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1 every 3 weeks for a total of 4 courses. After completion of course 4, patients receive paclitaxel IV and trastuzumab IV over 90 minutes weekly on weeks 13-24. Patients then may undergo radiotherapy followed by trastuzumab IV over 30 minutes weekly on weeks 29-69 if they did not receive radiotherapy or on weeks 36-76 if they did receive radiotherapy.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 125 patients (100 in the neoadjuvant group and 25 in the adjuvant group) will be accrued for this study within 5 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 82 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Nonrandomized Ph II Study of Multimodality Therapy for Stg IIB, IIIA/B, or Stg IV Breast Cancer w/4 Cycles of Adriamycin and Cytoxan (AC),Followed by 12 Weeks of Paclitaxel w/ or w/o Herceptin Followed by Local Therapy Followed by Wkly Herceptin or no Additional Therapy
• Study Start Date: December 1998
• Actual Primary Completion Date: March 2012
• Actual Study Completion Date: April 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: Neo-adjuvant Herceptin with or without radiation; Chemotherapy followed by Taxol plus Herceptin followed by surgery followed by radiation (or no radiation) followed by additional Herceptin	Biological: trastuzumab; infusion 4 mg/kg load week 1; 2 mg/kg weekly thereafter for 12 weeks; Other Name: Herceptin; Drug: cyclophosphamide; 600 mg/m2, intravenous infusion every 3 weeks for four cycles; Other Names: Lyophilized Cytoxan; Endoxan; Cytoxan; Neosar; Procytox; Revimmune; Cycloblastin; Drug: doxorubicin hydrochloride; 60 mg/m2 intravenously, 5-10 minutes, every 3 weeks, up to 12 weeks; Other Name: Adriamycin; Drug: paclitaxel; 90 mg/m2 weekly, intravenously 1 hour after herceptin, given weekly up to 12 weeks or 175 mg/m2, intravenously every 3 weeks, up to 12 weeks (only if not receiving Herceptin®); Other Name: Taxol; Procedure: conventional surgery; Surgical excision will take place 12-13 weeks for the neo-adjuvant herceptin setting and 12-13 weeks in the non-herceptin setting. Surgery will take place prior to chemotherapy in the adjuvant herceptin setting
Experimental: Non-Herceptin with or without radiation; Chemotherapy followed by Taxol followed by surgery followed by radiation (or no radiation)	Drug: cyclophosphamide; 600 mg/m2, intravenous infusion every 3 weeks for four cycles; Other Names: Lyophilized Cytoxan; Endoxan; Cytoxan; Neosar; Procytox; Revimmune; Cycloblastin; Drug: doxorubicin hydrochloride; 60 mg/m2 intravenously, 5-10 minutes, every 3 weeks, up to 12 weeks; Other Name: Adriamycin; Drug: paclitaxel; 90 mg/m2 weekly, intravenously 1 hour after herceptin, given weekly up to 12 weeks or 175 mg/m2, intravenously every 3 weeks, up to 12 weeks (only if not receiving Herceptin®); Other Name: Taxol; Procedure: conventional surgery; Surgical excision will take place 12-13 weeks for the neo-adjuvant herceptin setting and 12-13 weeks in the non-herceptin setting. Surgery will take place prior to chemotherapy in the adjuvant herceptin setting

Outcome Measures

Primary Outcome Measures :

1. Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. [ Time Frame: 78 weeks (1.5 years) ]
   Doxorubicin + cyclophosphamide in combination with paclitaxel and trastuzumab (AC-TP) Associated Systolic Dysfunction. Systolic function was measured by the ventricular ejection fraction (LVEF). LVEF is a measurement in determining how well your heart is pumping out blood and in diagnosing and tracking heart failure.

Secondary Outcome Measures :

1. Overall Response [ Time Frame: 78 weeks (1.5 years) ]
   Measured by the Overall Response. Response: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
2. Disease-free Survival (DFS) in Patients Receiving and Not Receiving Herceptin®. [ Time Frame: 5 years ]
   Percent of patients receiving and not receiving Herceptin who are alive and disease-free at 5 years.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 120 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

• Histologically confirmed stage IIB, IIIA, IIIB, IIIC, or previously untreated stage IV primary carcinoma of the breast

  • Fine needle aspiration, core needle biopsy, or incisional biopsy allowed
  • No excisional biopsy

  • Any of the following:

    • Tumor size 2, Nodes 1 (T2N1) or tumor size 3 nodes 0 (T3N0)
    • Any T with N2 (including axillary lymph nodes matted to one another) or N3
    • Any T4, including inflammatory breast cancer
    • Adjuvant patients with at least 4 positive lymph nodes and HER-2 overexpressing tumor
    • Supraclavicular or infraclavicular positive lymph nodes without distant metastases
    • Distant metastases with measurable disease in breast or lymph nodes
• Synchronous bilateral primary breast cancer allowed if the more serious cancer meets entry criteria
• Measurable or evaluable disease

PATIENT CHARACTERISTICS:

Age: Not specified

Sex: Female

Menopausal status: Not specified

Performance status: Not specified

Life expectancy: Not specified

Hematopoietic:

White cell count > 3000 / mm3 Platelet count > 100,000 / mm3

Hemoglobin > 9 mg / dl Bilirubin < 1.5 x normal Creatinine < 1.5 x normal left ventricular ejection fraction (LVEF) normal by resting nuclear ventriculogram Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception

Exclusions

Prior malignancies except:

Effectively treated squamous cell or basal cell skin cancer Carcinoma in situ of the cervix that has been curatively treated by surgery alone Nonbreast malignancy from which patient has been disease-free for 5 years and is at low risk of recurrence

Contacts and Locations

Locations

United States, North Carolina

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States, 27599-7305

Comprehensive Cancer Center at Wake Forest University

Winston-Salem, North Carolina, United States, 27157-1082

Sponsors and Collaborators

UNC Lineberger Comprehensive Cancer Center

Investigators

• Study Chair: Lisa A. Carey, MD; UNC Lineberger Comprehensive Cancer Center

More Information

Additional Information:

Clinical trial summary from the NIH 

results published in Clinical Breast Cancer 

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00006110
• Other Study ID Numbers: LCCC 9818; LCCC9818 ( Other Identifier: UNC Lineberger Comprehensive Cancer Center ); NCI-G00-1836 ( Other Grant/Funding Number: NCI )
• First Posted: January 27, 2003
• Results First Posted: July 31, 2017
• Last Update Posted: July 31, 2017
• Last Verified: June 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by UNC Lineberger Comprehensive Cancer Center:

stage II breast cancer; stage IV breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer; inflammatory breast cancer

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Paclitaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Trastuzumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Antineoplastic Agents, Immunological