Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER-2 Negative Breast Cancer

Sponsor
SCRI Development Innovations, LLC (Other)
Overall Status
Completed
CT.gov ID
NCT00866905
Collaborator
Bristol-Myers Squibb (Industry)
168
20
1
66
8.4
0.1

Study Details

Study Description

Brief Summary

We propose to evaluate ixabepilone in combination with cyclophosphamide for the neoadjuvant treatment of locally advanced breast cancer. In this regimen, ixabepilone is substituted for docetaxel, since preclinical and clinical

studies suggest that ixabepilone is more active than either docetaxel or paclitaxel. The combination of ixabepilone and cyclophosphamide could further improve the efficacy of non-anthracycline neoadjuvant therapy.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

In this study, patients with early stage, HER2-negative breast cancer will receive neoadjuvant treatment with ixabepilone and cyclophosphamide given every three weeks for a total of six cycles. Following surgery patients with hormone receptor-positive tumors will receive anti-estrogen treatment. Patients may receive local regional radiation therapy after surgery per institutional guidelines at the investigator's discretion. Baseline tumor tissue and tumor tissue removed at the time of surgery will be tested by Oncotype Detailed Description (DX) assay to determine whether it is predictive of response to this neoadjuvant treatment regimen. This study will be one of the first investigations of the combination of ixabepilone and cyclophosphamide as neoadjuvant treatment for HER2-negative breast cancer. It will examine this treatment regimen for potential advantages gained from substitution of ixabepilone for a taxane and use of non-anthracycline agents.

Study Design

Study Type:
Interventional
Actual Enrollment :
168 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase II Study of Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER2-Negative Breast Cancer
Study Start Date :
Apr 1, 2009
Actual Primary Completion Date :
Jul 1, 2014
Actual Study Completion Date :
Oct 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ixabepilone/Cyclophosphamide

Systemic Therapy followed by surgery and possible radiation therapy

Drug: Ixabepilone
40 mg/m2 IV infusion over 3 hours on day 1 of a 21 day cycle for 6 cycles
Other Names:
  • Systemic therapy
  • Ixempra
  • Drug: Cyclophosphamide
    600 mg/m2 IV infusion per institutional guidelines on day 1 of a 21 day cycle for 6 cycles
    Other Names:
  • Systemic therapy
  • Cytoxan
  • Outcome Measures

    Primary Outcome Measures

    1. Pathologic Complete Response Rate (pCR) [6 months]

      Pathologic complete response (pCR) rate will be determined by the pathologic evaluation of breast and lymph node samples collected at the time of surgery. pCR is defined as no residual disease in breast or lymph nodes in resected tissue samples.

    Secondary Outcome Measures

    1. Absence of Grade-4 Non-hematologic Toxicity Excluding, Alopecia, Nausea, Vomiting and Bone Pain [3 months]

      Non hematologic treatment-related grade 4 toxicities measured according to CTCAE 3.0

    2. Overall Survival [36 months]

      Overall survival (OS) determined as the time between day 1 cycle 1 to the date of death from any cause. The percentage of patients who were alive at 3 years, estimated by Kaplan Meier method as the probability of being event free at 3 years is reported here.

    3. Disease Free Survival [36 Months]

      Defined as the time between Day 1 Cycle 1, and date of first documented recurrence, initiation of additional chemotherapy, or death.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Female patients, age ≥18 years.

    2. Histologically confirmed invasive adenocarcinoma of the breast.

    3. Primary palpable disease confined to a breast and axilla on

    physical examination. For patients without clinically suspicious

    axillary adenopathy, the primary tumor must be larger than 2 cm

    in diameter by physical exam or imaging studies (clinical T2-T3,

    N0-N1, M0). For patients with clinically suspicious axillary

    adenopathy, the primary breast tumor can be any size (clinical

    T1-3, N1-2, M0). (T1N0M0 lesions are excluded.)

    1. Patients without clearly defined palpable breast mass or axillary

    lymph nodes but radiographically measurable tumor masses are

    acceptable. Accepted procedures for measuring breast disease

    are mammography, MRI, and breast ultrasound. This will need to

    be re-evaluated after 3 cycles and prior to surgery.

    1. Eastern Cooperative Oncology Group performance status (ECOG

    PS) 0-2.

    1. No metastatic disease, as documented by complete staging workup
    • 6 weeks prior to initiation of study treatment.
    1. No previous treatment for breast cancer.

    2. HER2-negative tumor status. HER2-negative is defined as:

    • Immunohistochemical (IHC) 0, IHC 1+ OR

    • IHC 2+ or IHC 3+ must be confirmed as FISH (fluorescence in situ

    hybridization) negative (defined by ratio <2.2).

    1. Adequate hematologic function with:
    • Absolute neutrophil count (ANC) >1500/μL.

    • Platelets ≥100,000/μL.

    • Hemoglobin ≥10 g/dL.

    1. Adequate hepatic function with:
    • Serum bilirubin ≤ the institutional upper limit of normal (ULN).

    • Aspartate aminotransferase (AST) ≤2.5 x institutional ULN.

    • Alanine aminotransferase (ALT) ≤2.5 x institutional ULN.

    1. Adequate renal function with serum creatinine ≤1.5 x ULN.

    2. Estrogen and progesterone receptor status in the primary tumor

    known or pending at the time of study registration.

    1. Knowledge of the investigational nature of the study and ability to

    provide consent for study participation.

    1. For patients who had, or will have sentinel lymph node and/or

    axillary dissection prior to initiation of study treatment, completion

    at least 4 weeks prior to starting study treatment and well-healed

    wound

    1. Bilateral, synchronous breast cancer is allowed if one primary

    tumor meets the inclusion criteria.

    1. Sufficient archived breast tumor specimen available at baseline

    for the Oncotype DX assay.

    -

    Exclusion Criteria:
    1. Inflammatory breast cancer.

    2. Peripheral neuropathy (motor or sensory) ≥ grade 1 by the

    Common Terminology Criteria for Adverse Events version 3.0

    (CTCAE v 3.0).

    1. Prior radiation that included ≥30% of major bone marrow containing

    areas (pelvis, lumbar, spine).

    1. Chronic use of cytochrome P450 (CYP) 3A4 inhibitors and use of

    the following strong CYP3A4 inhibitors: ketoconazole,

    itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir,

    telithromycin, ritonavir, amprenavir, indinavir, nelfinavir,

    delavirdine, and voriconazole. Use of these agents should be

    discontinued at least 72 hours prior to initiation of study treatment.

    1. Chemotherapy within 5 years of starting study treatment except

    for low doses of agents used for anti-inflammatory indications

    such as rheumatoid arthritis, psoriasis, and connective tissue

    disorders. Although such doses and schedules cannot result in

    myelosuppression, patients must discontinue this therapy while

    they are receiving study treatment.

    1. Known or suspected hypersensitivity to Cremophor®EL

    (polyoxyethylated castor oil) or a drug formulated in

    Cremophor®EL such as paclitaxel, or any other agent given in the

    course of this study.

    1. Pregnancy or breast-feeding. A negative serum pregnancy test

    within 7 days prior to first study treatment (Day 1, Cycle 1) for all

    women of childbearing potential is required. Patients of

    childbearing potential must agree to use a birth control method

    that is approved by their study physician while receiving study

    treatment and for 3 weeks after their last dose of study treatment.

    Patients must agree to not breast-feed while receiving study

    treatment.

    1. Concurrent treatment with an ovarian hormonal replacement

    therapy or with hormonal agents such as raloxifene, tamoxifen or

    other selective estrogen receptor modulator (SERM). Patients

    must have discontinued use of such agents prior to beginning

    study treatment.

    1. History of malignancy treated with curative intent within the

    previous 5 years with the exception of skin cancer, cervical

    carcinoma in situ, or follicular thyroid cancer. Patients with

    previous invasive cancers (including breast cancer) are eligible if

    the treatment was completed more than 5 years prior to initiating

    current study treatment, and there is no evidence of recurrent

    disease.

    1. Uncontrolled intercurrent illness including (but not limited to)

    ongoing or active infection.

    1. Chronic treatment with corticosteroid unless treatment was begun

    6 months prior to study treatment and is at a low dose (≤20 mg

    methylprednisolone or equivalent).

    1. Use of any investigational agent within 30 days of administration

    of the first dose of study drug.

    1. Requirement for radiation therapy concurrent with neoadjuvant

    study chemotherapy.

    1. Concurrent treatment with any anti-cancer therapy other than

    those agents used in this study.

    1. Inability or unwillingness to comply with study procedures

    including follow-up visits.

    1. Mental condition or psychiatric disorder that would prevent patient

    comprehension of the nature, scope, and possible consequences

    of the study or that would limit compliance with study

    requirements.

    1. Any other disease(s), metabolic dysfunction, or findings from a

    physical examination or clinical laboratory test result that would

    cause reasonable suspicion of a disease or condition that

    contraindicates the use of study drugs, that may affect the

    interpretation of the results, or that renders the patient at high risk

    from treatment complications

    -

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Aventura Medical Center Aventura Florida United States 33180
    2 Florida Cancer Specialists Fort Myers Florida United States 33901
    3 Watson Clinic Center for Cancer Care and Research Lakeland Florida United States 33805
    4 Medical Oncology Associates of Augusta Augusta Georgia United States 30901
    5 Northeast Georgia Medical Center Gainesville Georgia United States 30501
    6 Providence Medical Group Terre Haute Indiana United States 47802
    7 Mercy Hospital Portland Maine United States 04101
    8 Center for Cancer and Blood Disorders Bethesda Maryland United States 20817
    9 National Capital Clinical Research Consortium Bethesda Maryland United States 20817
    10 St. Louis Cancer Care Chesterfield Missouri United States 63017
    11 Methodist Cancer Center Omaha Nebraska United States 68114
    12 Hematology Oncology Associates of Northern NJ Morristown New Jersey United States 07960
    13 Oncology Hematology Care Cincinnati Ohio United States 45242
    14 Cancer Centers of Southwest Oklahoma Lawton Oklahoma United States 73505
    15 South Carolina Oncology Associates, PA Columbia South Carolina United States 29210
    16 Chattanooga Oncology Hematology Associates Chattanooga Tennessee United States 37404
    17 Family Cancer Center Collierville Tennessee United States 38017
    18 Tennessee Oncology Nashville Tennessee United States 37203
    19 South Texas Oncology and Hematology San Antonio Texas United States 78258
    20 Virginia Cancer Institute Richmond Virginia United States 23235

    Sponsors and Collaborators

    • SCRI Development Innovations, LLC
    • Bristol-Myers Squibb

    Investigators

    • Study Chair: Denise A Yardley, M.D., SCRI Development Innovations, LLC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    SCRI Development Innovations, LLC
    ClinicalTrials.gov Identifier:
    NCT00866905
    Other Study ID Numbers:
    • SCRI BRE 133
    First Posted:
    Mar 23, 2009
    Last Update Posted:
    Nov 22, 2021
    Last Verified:
    Nov 1, 2021
    Keywords provided by SCRI Development Innovations, LLC
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Ixabepilone/Cyclophosphamide
    Arm/Group Description Ixabepilone: 40 mg/m2 via intraveous (IV) infusion over 3 hours Cyclophosphamide: 600 mg/m2 via IV infusion per institutional guidelines
    Period Title: Overall Study
    STARTED 168
    COMPLETED 135
    NOT COMPLETED 33

    Baseline Characteristics

    Arm/Group Title Arm/Group 1
    Arm/Group Description All patients who received at least one dose of treatment.
    Overall Participants 168
    Age (Years) [Median (Full Range) ]
    Median (Full Range) [Years]
    53
    Sex: Female, Male (Count of Participants)
    Female
    168
    100%
    Male
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    168
    100%

    Outcome Measures

    1. Primary Outcome
    Title Pathologic Complete Response Rate (pCR)
    Description Pathologic complete response (pCR) rate will be determined by the pathologic evaluation of breast and lymph node samples collected at the time of surgery. pCR is defined as no residual disease in breast or lymph nodes in resected tissue samples.
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    To be evaluable, patients had to undergo surgery after neoadjuvant therapy. Out of 168 patients, only 161 patients underwent surgery after neoadjuvant therapy and were included in this analysis.
    Arm/Group Title Ixabepilone/Cyclophosphamide
    Arm/Group Description Systemic Therapy followed by surgery and possible radiation therapy
    Measure Participants 161
    Number [participants]
    27
    16.1%
    2. Secondary Outcome
    Title Absence of Grade-4 Non-hematologic Toxicity Excluding, Alopecia, Nausea, Vomiting and Bone Pain
    Description Non hematologic treatment-related grade 4 toxicities measured according to CTCAE 3.0
    Time Frame 3 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Ixabepilone/Cyclophosphamide
    Arm/Group Description Systemic Therapy followed by surgery and possible radiation therapy
    Measure Participants 168
    Fatigue
    1
    0.6%
    Peripheral neuropathy
    1
    0.6%
    Arthralgia/myalgia
    1
    0.6%
    3. Secondary Outcome
    Title Overall Survival
    Description Overall survival (OS) determined as the time between day 1 cycle 1 to the date of death from any cause. The percentage of patients who were alive at 3 years, estimated by Kaplan Meier method as the probability of being event free at 3 years is reported here.
    Time Frame 36 months

    Outcome Measure Data

    Analysis Population Description
    All patients who received a dose of study treatment.
    Arm/Group Title Ixabepilone/Cyclophosphamide
    Arm/Group Description Systemic Therapy followed by surgery and possible radiation therapy Ixabepilone: 40 mg/m2 IV infusion over 3 hours on day 1 of a 21 day cycle for 6 cycles Cyclophosphamide: 600 mg/m2 IV infusion per institutional guidelines on day 1 of a 21 day cycle for 6 cycles
    Measure Participants 168
    Number [percentage of participants]
    90
    53.6%
    4. Secondary Outcome
    Title Disease Free Survival
    Description Defined as the time between Day 1 Cycle 1, and date of first documented recurrence, initiation of additional chemotherapy, or death.
    Time Frame 36 Months

    Outcome Measure Data

    Analysis Population Description
    All patients who received a dose of study treatment.
    Arm/Group Title Ixabepilone/Cyclophosphamide
    Arm/Group Description Ixabepilone: 40 mg/m2 via intraveous (IV) infusion over 3 hours Cyclophosphamide: 600 mg/m2 via IV infusion per institutional guidelines
    Measure Participants 168
    Median (95% Confidence Interval) [months]
    NA

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Ixabepilone/Cyclophosphamide
    Arm/Group Description All patients who received a dose of study treatment
    All Cause Mortality
    Ixabepilone/Cyclophosphamide
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Ixabepilone/Cyclophosphamide
    Affected / at Risk (%) # Events
    Total 6/168 (3.6%)
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA 3/168 (1.8%) 3
    Gastrointestinal disorders
    ENTERITIS 1/168 (0.6%) 1
    Nervous system disorders
    PERIPHERAL NEUROPATHY 2/168 (1.2%) 2
    Psychiatric disorders
    DEPRESSION 1/168 (0.6%) 1
    Other (Not Including Serious) Adverse Events
    Ixabepilone/Cyclophosphamide
    Affected / at Risk (%) # Events
    Total 167/168 (99.4%)
    Blood and lymphatic system disorders
    ANEMIA 118/168 (70.2%) 430
    FEBRILE NEUTROPENIA 12/168 (7.1%) 15
    LEUKOPENIA 128/168 (76.2%) 457
    NEUTROPENIA 127/168 (75.6%) 457
    THROMBOCYTOPENIA 56/168 (33.3%) 136
    Gastrointestinal disorders
    ABDOMINAL PAIN 14/168 (8.3%) 29
    CONSTIPATION 60/168 (35.7%) 175
    DIARRHEA 60/168 (35.7%) 127
    DYSPEPSIA 32/168 (19%) 88
    MUCOSITIS 17/168 (10.1%) 31
    NAUSEA 102/168 (60.7%) 297
    VOMITING 32/168 (19%) 54
    General disorders
    CHEST PAIN 9/168 (5.4%) 16
    EDEMA 14/168 (8.3%) 32
    FATIGUE 136/168 (81%) 547
    FEVER 16/168 (9.5%) 18
    PAIN 13/168 (7.7%) 23
    Pain 21/168 (12.5%) 37
    Immune system disorders
    ALLERGIC REACTION 10/168 (6%) 10
    Infections and infestations
    INFECTION 13/168 (7.7%) 18
    Investigations
    WEIGHT LOSS 11/168 (6.5%) 22
    Metabolism and nutrition disorders
    ANOREXIA 41/168 (24.4%) 92
    DEHYDRATION 10/168 (6%) 12
    HYPERGLYCEMIA 14/168 (8.3%) 31
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA 87/168 (51.8%) 290
    ASTHENIA 17/168 (10.1%) 30
    BACK PAIN 18/168 (10.7%) 34
    BONE PAIN 16/168 (9.5%) 26
    MYALGIA 55/168 (32.7%) 168
    PAIN IN EXTREMITY 40/168 (23.8%) 96
    Nervous system disorders
    DIZZINESS 23/168 (13.7%) 41
    HEADACHE 38/168 (22.6%) 95
    PARESTHESIA 13/168 (7.7%) 34
    PERIPHERAL NEUROPATHY 117/168 (69.6%) 399
    TASTE ALTERATION 35/168 (20.8%) 122
    Psychiatric disorders
    ANXIETY 25/168 (14.9%) 79
    DEPRESSION 17/168 (10.1%) 40
    INSOMNIA 48/168 (28.6%) 145
    Reproductive system and breast disorders
    BREAST PAIN 15/168 (8.9%) 34
    Respiratory, thoracic and mediastinal disorders
    ALLERGIC RHINITIS 15/168 (8.9%) 38
    COUGH 35/168 (20.8%) 58
    DYSPNEA 26/168 (15.5%) 39
    SORE THROAT 10/168 (6%) 11
    UPPER RESPIRATORY INFECTION 11/168 (6.5%) 16
    Skin and subcutaneous tissue disorders
    ALOPECIA 100/168 (59.5%) 390
    NAIL CHANGES 12/168 (7.1%) 27
    PRURITUS 11/168 (6.5%) 22
    RASH 29/168 (17.3%) 53
    Vascular disorders
    HOT FLASHES 30/168 (17.9%) 79
    HYPERTENSION 13/168 (7.7%) 28

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from the date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish results until 18 mos. after the trial has been completed at all sites.

    Results Point of Contact

    Name/Title John D. Hainsworth, MD
    Organization Sarah Cannon Research Institute
    Phone 1-877-691-7274
    Email asksarah@scresearch.net
    Responsible Party:
    SCRI Development Innovations, LLC
    ClinicalTrials.gov Identifier:
    NCT00866905
    Other Study ID Numbers:
    • SCRI BRE 133
    First Posted:
    Mar 23, 2009
    Last Update Posted:
    Nov 22, 2021
    Last Verified:
    Nov 1, 2021