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Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2016 by NRG Oncology
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology
ClinicalTrials.gov Identifier:
NCT02488967
First received: June 30, 2015
Last updated: October 4, 2016
Last verified: October 2016
  Purpose
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.

Condition Intervention Phase
Breast Adenocarcinoma
Estrogen Receptor Negative
HER2/Neu Negative
Progesterone Receptor Negative
Stage IB Breast Cancer
Stage IIA Breast Cancer
Stage IIB Breast Cancer
Stage IIIA Breast Cancer
Stage IIIC Breast Cancer
Triple-Negative Breast Carcinoma
Drug: Carboplatin
Drug: Cyclophosphamide
Drug: Doxorubicin Hydrochloride
Other: Laboratory Biomarker Analysis
Drug: Paclitaxel
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by NRG Oncology:

Primary Outcome Measures:
  • IDFS [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • BCFS [ Time Frame: 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 ] [ Designated as safety issue: No ]
    The stratified log-rank tests will be 2-sided with significance level 0.05. Treatment efficacy in these secondary endpoints will be assessed by Cox models adjusting for clinical factors such as age, number of positive nodes, BRCA mutation status, tumor size, and tumor grade.

  • DRFI [ Time Frame: 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 ] [ Designated as safety issue: No ]
    The stratified log-rank tests will be 2-sided with significance level 0.05. Treatment efficacy in these secondary endpoints will be assessed by Cox models adjusting for clinical factors such as age, number of positive nodes, BRCA mutation status, tumor size, and tumor grade.

  • Frequencies of adverse events categorized using the National Cancer Institute CTCAE v4.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    Frequencies of all adverse events during the treatment period will be tabulated by treatment, toxicity type, and grade. The Pearson Chi-squared test with continuity adjustment will be used to compare toxicity grades in each type between the two treatment regimens. The test will be 2-sided with significance level 0.05.

  • OS [ Time Frame: From randomization until death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
    The stratified log-rank tests will be 2-sided with significance level 0.05. Treatment efficacy in these secondary endpoints will be assessed by Cox models adjusting for clinical factors such as age, number of positive nodes, BRCA mutation status, tumor size, and tumor grade.

  • RFI [ Time Frame: 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 ] [ Designated as safety issue: No ]
    The stratified log-rank tests will be 2-sided with significance level 0.05. Treatment efficacy in these secondary endpoints will be assessed by Cox models adjusting for clinical factors such as age, number of positive nodes, BRCA mutation status, tumor size, and tumor grade.


Estimated Enrollment: 990
Study Start Date: July 2015
Estimated Primary Completion Date: April 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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.
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat
Experimental: 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.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplat
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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, tumor must be > 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) < 2.0, and if reported, average HER2 gene copy number < 4 signals/cells; or
    • ISH non-amplified with a ratio of HER2 to CEP17 < 2.0, and if reported, average HER2 gene copy number < 4 signals/cells
  • The tumor must have been determined to be estrogen receptor (ER)-and progesterone receptor (PgR)-negative assessed by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines; patients with < 1% ER and PgR staining by IHC are considered negative
  • The patient must have undergone either a mastectomy (total, skin-sparing, or nipple-sparing) or lumpectomy
  • For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist; if pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins; if tumor is still present at the resected margin after re-excision(s), the patient must undergo mastectomy to be eligible; (patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection)
  • For patients who undergo mastectomy, the margins must be free of residual gross tumor; (patients with microscopic positive margins are eligible as long as post-mastectomy radiation therapy [RT] of the chest wall will be administered)
  • The patient must have completed one of the procedures for evaluation of pathologic nodal status listed below.

    • Sentinel lymphadenectomy alone:

      • If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b;
      • If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1a and the patient has undergone breast conserving surgery (with planned breast radiotherapy), the primary tumor must be T1 or T2 by pathologic evaluation and the nodal involvement must be limited to 1 or 2 positive nodes
    • Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or
    • Axillary lymphadenectomy with or without SN isolation procedure
  • The interval between the last surgery for breast cancer (including re-excision of margins) and randomization must be no more than 60 days
  • Absolute neutrophil count (ANC) must be >= 1200/mm^3
  • Platelet count must be >= 100,000/mm^3
  • Hemoglobin must be >= 10 g/dL
  • Total bilirubin must be =< upper limit of normal (ULN) for the laboratory (lab) unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin
  • Alkaline phosphatase must be =< 2.5 x ULN for the lab
  • Aspartate aminotransferase (AST) must be =< 1.5 x ULN for the lab

    • Note: If alanine aminotransferase (ALT) is performed instead of AST (per institution's standard practice), the ALT value must be =< 1.5 x ULN; if both were performed, the AST must be =< 1.5 x ULN
  • Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]-CT, or PET scan) performed within 90 days prior to randomization does not demonstrate metastatic disease and the requirements above are met
  • Patients with alkaline phosphatase that is > ULN but =< 2.5 x ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease
  • Adequate renal function determined within 6 weeks prior to randomization defined as the most recent serum creatinine =< ULN or measured or calculated creatinine clearance > 60 mL/min
  • Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days prior to randomization; (LVEF assessment performed by 2-dimensional [D] echocardiogram is preferred; however, multi gated acquisition [MUGA] scan may be substituted based on institutional preferences;) the LVEF must be >= 50% regardless of the cardiac imaging facility's lower limit of normal

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

      • Angina pectoris that requires the current 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; or
      • Symptomatic pericarditis
    • History of cardiac disease

      • Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricle (LV) function;
      • History of documented congestive heart failure (CHF); or
      • Documented cardiomyopathy
  • Uncontrolled hypertension defined as sustained systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg; (patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria)
  • Active hepatitis B or hepatitis C with abnormal liver function tests
  • Patients known to be human immunodeficiency virus (HIV) positive with a baseline cluster of differentiation (CD)4 count of < 250 cells/mm^3 or have a history of acquired immune deficiency syndrome (AIDS) indicator conditions
  • Intrinsic lung disease resulting in dyspnea
  • History of hospitalization in past 12 months for diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic nonketotic syndrome (HHNS)
  • Active infection or chronic infection requiring chronic suppressive antibiotics
  • Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0
  • Conditions that would prohibit administration of corticosteroids
  • Chronic daily treatment with corticosteroids with a dose of >= 10 mg/day methylprednisolone equivalent (excluding inhaled steroids)
  • Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor® EL
  • Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up
  • Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
  • Pregnancy or lactation at the time of study entry; (note: pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to randomization)
  • Use of any investigational product within 4 weeks prior to randomization
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02488967

  Show 1079 Study Locations
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
Principal Investigator: Vicente Valero NRG Oncology
  More Information

Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT02488967     History of Changes
Other Study ID Numbers: NRG-BR003  NCI-2015-00128  NRG-BR1428  NRG-BR003  NRG-BR003  U10CA180868 
Study First Received: June 30, 2015
Last Updated: October 4, 2016
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Breast Neoplasms
Adenocarcinoma
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Paclitaxel
Liposomal doxorubicin
Albumin-Bound Paclitaxel
Doxorubicin
Cyclophosphamide
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on December 02, 2016