Combination Chemotherapy With or Without Trastuzumab in Treating Women With Metastatic Breast Cancer - Full Text View

Sponsor:	Eastern Cooperative Oncology Group
Collaborator:	National Cancer Institute (NCI)
Information provided by (Responsible Party):	Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:	NCT00004888

Purpose

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.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy with or without trastuzumab in treating women who have metastatic breast cancer.

Condition	Intervention	Phase
Metastatic Breast Cancer	Drug: Trastuzumab Drug: Docetaxel Drug: PLD	Phase II

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Safety and Efficacy Study of Doxil and Taxotere +/- Herceptin in Advanced Breast Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Doxorubicin Doxorubicin hydrochloride Docetaxel Trastuzumab

U.S. FDA Resources

Further study details as provided by Eastern Cooperative Oncology Group:

Primary Outcome Measures:

Grades of Cardiotoxicity Events in the Subset of Patients Reporting a Cardiotoxicity Event [ Time Frame: Baseline, after cycle 4 (~84 days), after cycle 8 (~168 days), and 30 or more days after last cycle of induction therapy ] [ Designated as safety issue: Yes ]
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.
Summary of Left Ventricular Ejection Fraction Values [ Time Frame: Baseline, after cycle 4, after cycle 8, and 30 or more days after last cycle of induction therapy. ] [ Designated as safety issue: Yes ]
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.

Secondary Outcome Measures:

Best Overall Response Using Eastern Cooperative Group Solid Tumor Response Criteria. [ Time Frame: 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. ] [ Designated as safety issue: No ]
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.
Overall Survival [ Time Frame: 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. ] [ Designated as safety issue: No ]
Progression-Free Survival [ Time Frame: 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. ] [ Designated as safety issue: No ]
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.

Enrollment:	89
Study Start Date:	October 2000
Study Completion Date:	May 2009
Primary Completion Date:	April 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Arm I: Doxil and Taxotere	Drug: Docetaxel Docetaxel was administered 60 mg/m^2 IV, one hour after pegylated liposomal doxorubicin hydrochloride (PLD) completion, every three weeks for a total of eight cycles. Other Name: Taxotere Drug: PLD Patients received PLD 30 mg/m^2 and the maximum allowed cumulative dose of PLD was 240 mg/m^2. Other Name: Doxil
Experimental: Arm II: Doxil, Taxotere, and Herceptin	Drug: Trastuzumab Trastuzumab was administered 4 mg/kg IV on Day 1, then 2 mg/kg IV weekly. Other Name: Herceptin Drug: Docetaxel Docetaxel was administered 60 mg/m^2 IV, one hour after pegylated liposomal doxorubicin hydrochloride (PLD) completion, every three weeks for a total of eight cycles. Other Name: Taxotere Drug: PLD Patients received PLD 30 mg/m^2 and the maximum allowed cumulative dose of PLD was 240 mg/m^2. Other Name: Doxil

Arms

Assigned Interventions

Active Comparator: Arm I: Doxil and Taxotere

Drug: Docetaxel

Docetaxel was administered 60 mg/m^2 IV, one hour after pegylated liposomal doxorubicin hydrochloride (PLD) completion, every three weeks for a total of eight cycles.

Other Name: Taxotere

Drug: PLD

Patients received PLD 30 mg/m^2 and the maximum allowed cumulative dose of PLD was 240 mg/m^2.

Other Name: Doxil

Experimental: Arm II: Doxil, Taxotere, and Herceptin

Drug: Trastuzumab

Trastuzumab was administered 4 mg/kg IV on Day 1, then 2 mg/kg IV weekly.

Other Name: Herceptin

Drug: Docetaxel

Docetaxel was administered 60 mg/m^2 IV, one hour after pegylated liposomal doxorubicin hydrochloride (PLD) completion, every three weeks for a total of eight cycles.

Other Name: Taxotere

Drug: PLD

Patients received PLD 30 mg/m^2 and the maximum allowed cumulative dose of PLD was 240 mg/m^2.

Other Name: Doxil

Detailed Description:

OBJECTIVES:

Assess the safety, toxicity, and feasibility of doxorubicin hydrochloride (HCL) liposome and docetaxel with or without trastuzumab (Herceptin™) in patients with metastatic breast cancer, particularly with respect to cardiotoxicity.
Assess the overall objective response rate, response duration, time to treatment failure, and median survival of these patients with these treatment regimens.
Assess any association between trough plasma levels of cardiac troponin T and brain natriuretic peptide and any cardiac event (congestive heart failure or left ventricular ejection fraction decrease).

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histologically confirmed metastatic adenocarcinoma of the breast
HER2 nonoverexpressed (0-1+) OR overexpressed (2-3+)
Measurable or evaluable disease
Prior brain metastases responsive to treatment of radiotherapy and/or surgery allowed (cannot be only site of metastases)
Age 18 and over
Female
Fertile women must use effective contraception
Eastern Cooperative Oncology Group performance status of 0,1,or 2
The following lab values obtained at least 4 weeks prior to registration: granulocyte count at least 1,500/mm^3, platelet count at least 100,000/mm^3, SGOT no greater than 2.5 times upper limit of normal, bilirubin normal, and creatinine no greater than 1.5 mg/dL
Left ventricular ejection fraction at least lower limit of normal (LLN)
Prior adjuvant chemotherapy allowed if completed 6 months before metastasis
Prior endocrine therapy in either a metastatic or adjuvant setting, but patients must have been off such therapy for at least 2 weeks prior to registration
Prior radiotherapy allowed only to conserved breast, postmastectomy chest wall with or without internal mammary lymph node chain (IMN), or field containing less than 25% bone marrow
At least 2 weeks since prior radiotherapy
At least 2 weeks since surgery (including mastectomy) and recovered

Exclusion Criteria:

Prior deep venous thrombosis or thromboembolic condition
Prior myocardial infarction or congestive heart failure
Arrhythmia requiring medication
Hypertension or systolic or diastolic dysfunction
Ventricular hypertrophy or conduction abnormality
Prior pulmonary thromboembolism
Other malignancy within the past 5 years except curatively treated carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin
Pregnant or nursing
Prior trastuzumab (Herceptin™)
Prior chemotherapy for advanced or local/regional recurrent disease
Prior anthracyclines or anthracenediones
Prior photon IMN treatment
Concurrent radiotherapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00004888

Show 24 Study Locations

Sponsors and Collaborators

Eastern Cooperative Oncology Group

National Cancer Institute (NCI)

Investigators

Study Chair:

Antonio C. Wolff, MD

The Johns Hopkins Oncology Center Cancer Research Building

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Wolff AC, Wang M, Sparano JA, et al.: Cardiac safety and clinical activity of pegylated liposomal doxorubicin (D) and docetaxel (T) with and without trastuzumab (H) as 1st line chemotherapy in HER2-positive and HER2-negative metastatic breast cancer (MBC): Eastern Cooperative Oncology Group (ECOG) trial E3198. [Abstract] Breast Cancer Res Treat 88 (Suppl 1): A-3040, 2004.

Wolff AC, Bonetti M, Sparano JA, et al.: Cardiac safety of trastuzumab (H) in combination with pegylated liposomal doxorubicin (D) and docetaxel (T) in HER2-positive metastatic breast cancer (MBC): preliminary results of the Eastern Cooperative Oncology Group trial E3198. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-70, 2003.

Responsible Party:	Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:	NCT00004888 History of Changes
Other Study ID Numbers:	CDR0000067564, E3198, U10CA021115
Study First Received:	March 7, 2000
Results First Received:	June 21, 2011
Last Updated:	October 18, 2011
Health Authority:	United States: Federal Government

Keywords provided by Eastern Cooperative Oncology Group:

Stage IV breast cancer
Recurrent breast cancer
HER2 Overexpression
Trastuzumab

Nonpegylated liposomal doxorubicine
Metastatic breast cancer
Cardiac toxicity

Additional relevant MeSH terms:

Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Doxorubicin

Docetaxel
Trastuzumab
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 12, 2012