A Multicenter Phase III Randomized Trial of Adjuvant Therapy for Patients With HER2-Positive Node-Positive or High Risk Node-Negative Breast Cancer Comparing Chemotherapy Plus Trastuzumab With Chemotherapy Plus Trastuzumab Plus Bevacizumab

NSABP Foundation Inc639 sites in 1 country3,509 target enrollmentApril 2008

ConditionsBreast Cancer

InterventionsCarboplatin Docetaxel Trastuzumab Bevacizumab 5-Fluorouracil Epirubicin Cyclophosphamide

DrugsDocetaxel Trastuzumab Carboplatin Bevacizumab 5-Fluorouracil Epirubicin Cyclophosphamide

Overview

Phase: Phase 3
Intervention: Carboplatin
Conditions: Breast Cancer
Sponsor: NSABP Foundation Inc
Enrollment: 3509
Locations: 639
Primary Endpoint: Invasive Disease-free Survival (IDFS)
Status: Terminated
Last Updated: 5 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The trial will determine the value of adding bevacizumab to chemotherapy plus trastuzumab in patients with resected node-positive or high risk node-negative, HER2-positive breast cancer.

Detailed Description

This Phase III, randomized, open-label trial will determine whether the regimens of chemotherapy plus trastuzumab plus bevacizumab improve invasive disease-free survival (IDFS) relative to the regimens of chemotherapy plus trastuzumab. Secondary aims include determining whether the addition of bevacizumab to chemotherapy plus trastuzumab will improve disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), and distant recurrence-free interval (DRFI). The benefit of adding bevacizumab for IDFS, DFS, OS, RFI, and DRFI will also be evaluated for each of the two chemotherapy regimens. The cardiac and non-cardiac toxicities of each of the regimens will also be evaluated. Following local determination that the tumor is HER2-positive for gene amplification by in situ hybridization or is IHC 2+ or 3+, a tumor sample must be submitted for HER2 testing by a designated central laboratory. If central testing confirms that the tumor is HER2-positive (either positive by FISH or IHC 3+) and all other eligibility criteria have been met, the patient will be randomized to a regimen of chemotherapy and trastuzumab with or without bevacizumab. Patients in the trial will be enrolled in one of two chemotherapy regimen cohorts. One cohort will receive 6 cycles of docetaxel/carboplatin plus trastuzumab (TCH) with or without bevacizumab; the other cohort will receive 3 cycles of docetaxel plus trastuzumab given with or without bevacizumab followed by 3 cycles of 5-Fluorouracil, Epirubicin, Cyclophosphamide (TH-FEC). With both regimens, patients will continue trastuzumab with or without bevacizumab following chemotherapy to complete 1 year of targeted therapy. Following completion of chemotherapy, patients will also receive adjuvant radiotherapy and endocrine therapy as clinically indicated. The trial will be conducted by investigators affiliated with the Cancer International Research Group (CIRG) and the National Surgical Adjuvant Breast and Bowel Project (NSABP). CIRG and NSABP investigators will only enroll patients in the TCH regimen cohort. Additional investigators, referred to in the protocol as Independent Investigators, will enroll patients in both the TCH regimen or the TH-FEC regimen cohort depending on institutional preference for the one regimen that will be used by that institution for the duration of the trial. Patients will be given the option of allowing their tumor samples to be used for the BETH translational research and correlative science studies. Also, patients will be asked to consent to the submission of blood and serum samples at scheduled time points during the study. LVEF assessments will be performed before study entry and then at scheduled time points during therapy and at 18, 36, and 60 months following randomization. The planned sample size for the trial is 3,000 patients randomized in the faster accruing cohort and a minimum of 3,500 patients overall.

Registry

clinicaltrials.gov

Start Date

April 2008

End Date

July 2014

Last Updated

5 years ago

Study Type

Interventional

Study Design

Parallel

Sex

Female

Investigators

Sponsor

NSABP Foundation Inc

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Life expectancy of at least 10 years, excluding their diagnosis of breast cancer.
•Women who have had breast reconstruction utilizing tissue expanders must be in agreement with delaying surgery to replace the tissue expanders with permanent implants until 3 months following the last dose of bevacizumab
•Women of reproductive potential must agree to use an effective non-hormonal method of contraception (for example condoms, some intrauterine devices, diaphragms, vasectomized partner, or abstinence) during therapy and for at least 6 months after the last dose of bevacizumab and/or trastuzumab.
•Submission of tumor samples from the breast surgery for central HER2 testing is required for all patients prior to enrollment in the BETH Trial
•Signed and dated IRB/EC-approved consent
•ECOG performance status of 0 or 1
•The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
•The breast cancer must be HER2-positive based on test results as follows: Local testing (if available) should demonstrate that the tumor is IHC 2+ or 3+ or is considered to be HER2-positive for gene amplification by FISH, CISH, or other in situ hybridization (ISH) method. If local ISH test results are considered equivocal, the tumor can be submitted for central HER2 testing. (If local testing is not possible, the tumor can be submitted for central HER2 testing.) Central testing (a requirement for ALL patients) must demonstrate that the tumor is HER2-positive which is defined as FISH-positive and/or IHC 3+.
•All of the following staging criteria (according to the 6th edition of the AJCC Cancer Staging Manual) must be met: By pathologic evaluation, primary tumor must be pT1-3; By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b. If pN0, at least one of the following criteria must be met: Pathologic tumor size \> 2.0 cm; ER negative and PgR negative; Histologic and/or nuclear grade 2 (intermediate) or 3 (high); or Age \< 35 years
•Patients must have undergone either a total mastectomy or breast conserving surgery (lumpectomy).

Exclusion Criteria

•Inflammatory breast cancer.
•Definitive clinical or radiologic evidence of metastatic disease. (Chest imaging \[mandatory for all patients\] and other imaging \[if required\] must have been performed within 3 months prior to randomization.)
•Synchronous or previous contralateral invasive breast cancer (Patients with synchronous or previous contralateral DCIS or LCIS are eligible).
•History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral DCIS treated with excision and RT. (Patients with history of ipsilateral LCIS are eligible.)
•History of non-breast malignancies within the 5 years prior to study entry, except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin.
•Previous therapy with anthracyclines, taxanes, carboplatin, trastuzumab, or bevacizumab for any malignancy.
•RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to randomization.
•Continued therapy with any hormonal agent such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor. (Patients are eligible if these medications are discontinued prior to randomization.)
•Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy, etc. Patients are eligible if these medications are discontinued prior to randomization.
•Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens. This includes but is not confined to: Active cardiac disease - angina pectoris that requires the use of anti-anginal medication; ventricular arrhythmias except for benign premature ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker; valvular disease with documented compromise in cardiac function; and symptomatic pericarditis. History of cardiac disease - myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function; history of documented CHF; and documented cardiomyopathy.

Intervention: Cyclophosphamide

Outcomes

Primary Outcomes

Invasive Disease-free Survival (IDFS)

Time Frame: up to 10 years

Secondary Outcomes

Invasive disease-free survival (IDFS) within chemotherapy cohorts(up to 10 years)
Disease-free survival (DFS)(up to 10 years)
Identification of biomarkers (from tumor and serum/plasma) predictive for the level of benefit from the addition of bevacizumab to standard adjuvant systemic treatment for HER2-positive breast cancer as well as for cardiac toxicity(baseline, during therapy and follow-up, within 2 weeks of LVEF assessments, any protocol-specified cardiac event, and after diagnosis of recurrence)
Cardiac toxicity. Cumulative incidence of severe cardiac events defined as definite or probable cardiac death, or NYHA Class III or IV CHF(2-3 weeks after cycle 3; 2-3 weeks after last chemotherapy dose; 7, 10, 18, 36, and 60 months from randomization)
Distant recurrence-free interval (DRFI)(Time from randomization until distant disease recurrence only or up to a maximum of 10 years from study entry)
Overall survival (OS)(Time from randomization until death from any cause or up to a maximum of 10 years from study entry)
Non-cardiac toxicity. Frequencies of adverse events categorized using the NCI CTCAE v3.0.(within 3 days of each chemotherapy cycle; 2-3 weeks following last chemotherapy dose; every 6 weeks during targeted therapy; every 6 months through year 5; every 12 months years 6 - 10)
Recurrence-free interval (RFI)(Time from randomization until local, regional or distant recurrence or up to a maximum of 10 years from study entry)