Clinical Trials /

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

NCT02488967

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Doxorubicin Hydrochloride</span> and <span class="go-doc-concept go-doc-intervention">Cyclophosphamide</span> Followed by <span class="go-doc-concept go-doc-intervention">Paclitaxel</span> With or Without <span class="go-doc-concept go-doc-intervention">Carboplatin</span> in Treating Patients With <span class="go-doc-concept go-doc-keyword">Triple-Negative</span> <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer
  • 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
  • Clinical Trial IDs

    NCT ID: NCT02488967

    ORG ID: NRG-BR003

    NCI ID: NCI-2015-00128

    Trial Conditions

    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

    Trial Interventions

    Drug Synonyms Arms
    Carboplatin Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplat, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo Arm II (AC-->WP + carboplatin)
    Cyclophosphamide (-)-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 Arm I (AC-->WP), Arm II (AC-->WP + carboplatin)
    Doxorubicin Hydrochloride 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 Arm I (AC-->WP), Arm II (AC-->WP + carboplatin)
    Paclitaxel Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat Arm I (AC-->WP), Arm II (AC-->WP + carboplatin)

    Trial 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.

    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.

    Trial Arms

    Name Type Description Interventions
    Arm I (AC-->WP) Active Comparator 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. Cyclophosphamide, Doxorubicin Hydrochloride, Paclitaxel
    Arm II (AC-->WP + carboplatin) Experimental 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. Carboplatin, Cyclophosphamide, Doxorubicin Hydrochloride, Paclitaxel

    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, 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    IDFS

    Secondary Outcome Measures

    BCFS

    DRFI

    Frequencies of adverse events categorized using the National Cancer Institute CTCAE v4.0

    OS

    RFI

    Trial Keywords