A Randomized Phase III Trial of Adjuvant Therapy Comparing Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel With or Without Carboplatin for Node-Positive or High-Risk Node-Negative Triple-Negative Invasive Breast Cancer
Overview
- Phase
- Phase 3
- Intervention
- Cyclophosphamide
- Conditions
- Breast Adenocarcinoma
- Sponsor
- NRG Oncology
- Enrollment
- 782
- Locations
- 1288
- Primary Endpoint
- IDFS
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
This randomized phase III trial studies how well doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel with or without carboplatin work in treating patients with triple-negative breast cancer. Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether doxorubicin hydrochloride and cyclophosphamide is more effective when followed by paclitaxel alone or paclitaxel and carboplatin in treating triple-negative breast cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin (doxorubicin hydrochloride)/cyclophosphamide followed by paclitaxel will improve the invasive disease-free survival (IDFS) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. SECONDARY OBJECTIVES: I. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel will improve the overall survival (OS) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. II. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel will improve the breast cancer-free survival (BCFS) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. III. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel will improve the recurrence-free interval (RFI) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. IV. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel will improve the distant recurrence-free interval (DRFI) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. V. To determine the toxicity of doxorubicin/cyclophosphamide followed by paclitaxel administered concurrently with carboplatin compared to the toxicity of doxorubicin/cyclophosphamide followed by paclitaxel alone. VI. To determine if germline breast cancer (BRCA) status is associated with benefit in IDFS or OS from the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel in patients with operable node-positive or high-risk node-negative triple-negative breast cancer. VII. To determine if the addition of carboplatin will improve the RFI among the homologous recombination (HR) deficient patients as determined by the homologous recombination deficiency (HRD) score. VIII. To determine whether the efficacy of carboplatin on RFI in HR-deficient patients differs from that in patients who are not HR-deficient. IX. To collect tissue and blood samples at several occasions for future biomarkers development in predicting risk of breast cancer recurrence in patients with operable node-positive or high-risk node-negative triple-negative breast cancer treated with doxorubicin/cyclophosphamide followed by paclitaxel with or without carboplatin and predicting benefit from the addition of carboplatin among these patients. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I (DOXORUBICIN HYDROCHLORIDE \[A\] CYCLOPHOSPHAMIDE \[C\]--\>WEEKLY PACLITAXEL \[WP\]): Patients receive doxorubicin hydrochloride intravenously (IV) over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive paclitaxel IV over 60 minutes on day 1. Treatment repeats weekly for 12 courses in the absence of disease progression or unacceptable toxicity. ARM II (AC--\>WP + CARBOPLATIN): Patients receive doxorubicin hydrochloride and cyclophosphamide as in Arm I. Patients then receive paclitaxel IV over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 5 years and then every 12 months for 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The patient must have signed and dated an institutional review board (IRB)-approved consent form that conforms to federal and institutional guidelines
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination
- •All of the following staging criteria (according to the 7th edition of the American Joint Committee on Cancer \[AJCC\] 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, pN2b, pN3a, or pN3b
- •If pN0, pathological tumor must be greater than or equal to 3.0 cm
- •The tumor must have been determined to be human epidermal growth factor receptor 2 (HER2)-negative as follows:
- •Immunohistochemistry (IHC) 0-1+; or
- •IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to centromere enumerator probe 17 (CEP17) less than 2.0, and if reported, average HER2 gene copy number less than 4 signals/cells; or
Exclusion Criteria
- •T4 tumors including inflammatory breast cancer
- •Definitive clinical or radiologic evidence of metastatic disease; required imaging studies must have been performed within 90 days prior to randomization
- •Synchronous or previous contralateral invasive breast cancer; (patients with synchronous and/or previous contralateral DCIS or LCIS are eligible)
- •Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS; (patients with synchronous or previous ipsilateral LCIS are eligible)
- •History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization
- •Previous therapy with anthracyclines or taxanes for any malignancy
- •Chemotherapy administered for the currently diagnosed breast cancer prior to randomization
- •Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy; 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
Arms & Interventions
Arm I (AC-->WP)
Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive paclitaxel IV over 60 minutes on day 1. Treatment repeats weekly for 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Arm I (AC-->WP)
Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive paclitaxel IV over 60 minutes on day 1. Treatment repeats weekly for 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin Hydrochloride
Arm I (AC-->WP)
Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive paclitaxel IV over 60 minutes on day 1. Treatment repeats weekly for 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm I (AC-->WP)
Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive paclitaxel IV over 60 minutes on day 1. Treatment repeats weekly for 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Paclitaxel
Arm II (AC-->WP + carboplatin)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in Arm I. Patients then receive paclitaxel IV over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Carboplatin
Arm II (AC-->WP + carboplatin)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in Arm I. Patients then receive paclitaxel IV over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Arm II (AC-->WP + carboplatin)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in Arm I. Patients then receive paclitaxel IV over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin Hydrochloride
Arm II (AC-->WP + carboplatin)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in Arm I. Patients then receive paclitaxel IV over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm II (AC-->WP + carboplatin)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in Arm I. Patients then receive paclitaxel IV over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Paclitaxel
Outcomes
Primary Outcomes
IDFS
Time Frame: Up to 10 years
IDFS events are local invasive recurrence after mastectomy, local invasive recurrence in the ipsilateral breast after lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause before recurrence or second primary cancer. IDFS will be compared between the two treatment arms by the stratified log-rank test. The Kaplan-Meier estimates will be calculated separately for patients under the different treatment regimens.
Secondary Outcomes
- OS(From randomization until death from any cause, assessed up to 10 years)
- Frequencies of adverse events categorized using the National Cancer Institute CTCAE v4.0(Up to 10 years)
- BCFS(From randomization until local recurrence (invasive or DCIS), regional recurrence, or distant recurrence, contralateral breast cancer (invasive or DCIS), or death from any causes, assessed up to 10 years)
- DRFI(From randomization until distant metastasis or death from breast cancer, regardless of occurrence of any intervening local or regional recurrences, contralateral breast cancers, or non-breast second primary cancers, assessed up to 10 years)
- RFI(From randomization until invasive local, regional, or distant recurrence, or death from breast cancer (censored for death from other causes), assessed up to 10 years)