Clinical trial NCT00004888: Combination Chemotherapy With or Without Trastuzumab in Treating Women With Metastatic Breast Cancer
Official title: A Safety and Efficacy Study of Doxil and Taxotere ± Herceptin in Advanced Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Recurrent Breast Cancer
Stage IV Breast Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Enrollment: 84
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: PRIMARY OBJECTIVES:

I. To evaluate the safety and feasibility of the combination of liposomal doxorubicin (Doxil) and Taxotere (Taxotere) ± trastuzumab (Herceptin), particularly with respect to cardiotoxicity.

II. To evaluate the overall objective response rate, response duration, time to treatment failure, and median survival of patients with metastatic breast cancer treated with Doxil and Taxotere ± Herceptin.

III. To determine the overall toxicity of Doxil and Taxotere ± Herceptin in patients with advanced breast cancer.

IV. To determine whether there is an association between trough plasma levels of cTnT (cardiac troponin T) and NT-proBNP (brain natriuretic peptide) and any cardiac event (CHF or LVEF decrease).

V. To determine tissue and plasma levels of HER2 using several assays and explore potential correlation with protocol treatment toxicity and/or response.

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 criteria: Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the breast with manifestations of metastatic progression
* HER2 expression status in primary breast tissue and/or site(s) of metastasis must be determined by the ECOG Pathology Coordinating Office; (these are the results that will be used at time of registration); NOTE: for this protocol, HER2/neu non-overexpressed status will be defined as 0 and 1+ scores using the DAKO HercepTest; HER2 overexpressed status will be defined as 2+ score (if confirmed amplified by FISH) or 3+ score using the DAKO HercepTest
* Cytologically positive pleural or peritoneal effusions are considered evaluable disease provided local intra-cavitary treatment is not introduced at the onset of therapy; to be considered as evaluable disease, pleural effusions may not have been previously drained or sclerosed
* Blastic or mixed blastic/lytic osseous metastases only are evaluable disease provided they are accompanied by an analgesic requirement or a decrease in performance status, and will not require radiation treatment within two cycles from the start of protocol; pure osteolytic disease is evaluable; bone disease must be x-ray proven for the site to be evaluable; patients whose only evidence of metastatic disease is an abnormal bone scan without confirmatory x-rays are not eligible for this study
* No prior chemotherapy for advanced disease; prior adjuvant chemotherapy (including taxanes) allowed, if completed \> 6 months before the diagnosis of metastatic disease; no prior adjuvant anthracycline, nor any prior exposure to other anthracycline- (e.g., epirubicin, any liposomal doxorubicin formulation), nor any anthracenedione- (e.g., mitoxantrone) containing regimen allowed; no prior therapy with Herceptin allowed; NOTE: chemotherapy after ipsilateral breast recurrence following breast conservation surgery would not be considered chemotherapy for advanced disease; however, in post-mastectomy patients chemotherapy for local/regional recurrence is considered treatment for advanced disease
* No prior radiotherapy other than to the conserved breast, to the post-mastectomy chest wall, or to a limited field involving \< 25% of marrow-containing bone; NOTE: previous post-mastectomy radiation therapy involving chest wall ± internal mammary lymph node chain (IMN) is allowed; however, patients who received photon IMN treatment are ineligible; NOTE: radiotherapy must be completed \>= 2 weeks prior to registration; it may not be given concurrently with Doxil, Taxotere, or Herceptin
* Prior hormonal therapy in either a metastatic or adjuvant setting is allowed, but patients must have been off such therapy for \>= 2 weeks prior to registration
* Disease-free of prior non-breast invasive malignancies for \>= 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
* ECOG performance status of 0, 1, or 2
* At least two weeks after any major surgery (including mastectomy) and recovered from all toxicity
* Creatinine =\< 1.5 mg/dl
* Granulocytes \>= 1,500/mm³
* Platelets \>= 100,000/mm³
* SGOT(AST) =\< 2.5 x the upper limit of normal
* Bilirubin within normal limits for institution
* No history of deep venous thrombosis, pulmonary thromboembolism, or other thromboembolic condition
* Women must not be pregnant or breastfeeding; the effect of Herceptin to the fetus is unknown; Doxil is known to be harmful to the fetus
* Women of childbearing potential must be advised to use an accepted and effective method of contraception
* No patients with untreated brain metastasis or brain metastasis undergoing radiation or for whom brain metastasis represent the sole site of disease; patients with previously treated brain metastasis who have responded to brain radiotherapy and/or surgery and continue in response are eligible, provided the brain is not the only site of disease
* The left ventricular ejection fraction must be at or above the lower institutional limits of normal (as assessed by MUGA scan or echocardiogram obtained within six weeks prior to registration); patient will not be eligible if baseline LVEF assessment not performed
* No prior history of myocardial infarction, congestive heart failure, or arrhythmia requiring medication; no history of hypertension or systolic or diastolic dysfunction; no EKG evidence of ventricular hypertrophy, conduction abnormality, or serious arrhythmia; patient will not be eligible if baseline EKG assessment not performed within 4 weeks

Primary outcomes:
measure: Grades of Cardiotoxicity Events in the Subset of Patients Reporting a Cardiotoxicity Event
timeFrame: Baseline, after cycle 4 (~84 days), after cycle 8 (~168 days), and 30 or more days after last cycle of induction therapy
measure: Summary of Left Ventricular Ejection Fraction Values
timeFrame: Baseline, after cycle 4, after cycle 8, and 30 or more days after last cycle of induction therapy.
Secondary outcomes:
measure: Best Overall Response Using Eastern Cooperative Group Solid Tumor Response Criteria.
timeFrame: 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.
measure: Overall Survival
timeFrame: 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.
measure: Progression-Free Survival
timeFrame: 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.
measure: Duration of Response
timeFrame: 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.
Other outcomes:
Locations:
city: Boston
country: United States
facility: Eastern Cooperative Oncology Group
state: Massachusetts
Study officials:
affiliation: Eastern Cooperative Oncology Group
name: Antonio Wolff
role: PRINCIPAL_INVESTIGATOR
References: