Preoperative Dose-dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab in Operable Breast Cancer

Sponsor
Ian E. Krop, MD, PhD (Other)
Overall Status
Completed
CT.gov ID
NCT00546156
Collaborator
Genentech, Inc. (Industry), Massachusetts General Hospital (Other), Brigham and Women's Hospital (Other), New Hampshire Oncology-Hematology PA (Other)
104
Enrollment
4
Locations
2
Arms
62
Duration (Months)
26
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Dose dense chemotherapy, which is the term for Adriamycin and Cyclophosphamide (AC) followed by Taxol chemotherapy given every two weeks, is the standard chemotherapy for the treatment of ER+ or PR+ breast cancer. In this trial, the standard chemotherapy is being combined with bevacizumab. Bevacizumab is an antibody which works differently from the way other chemotherapy drugs work. Bevacizumab slows or stops cell growth in cancerous tumors by decreasing the blood supply to the tumors by binding to a substance found on cancer cells called VEGF (vascular endothelial growth factor). Bevacizumab is approved by the FDA for the treatment of colorectal cancer and lung cancer. However, it is not approved for the treatment of breast cancer. Another goal of this research is to determine whether we can develop a way to identify tumors that will respond well to this study treatment.

Detailed Description

  • To prepare for the surgery that will occur at the end of the study treatment, a small "clip" will be placed into the tumor area so that the surgeon can locate the site of the tumor at the time of surgery. This is a standard procedure for breast cancer.

  • During the clip placement, a needle will be inserted into the tumor to measure interstitial fluid pressure (IFP measurement). IFP is done for research purposes to help understand how the tumor responds to the study treatment.

  • Study treatment will begin with one dose of bevacizumab alone, followed two weeks later by chemotherapy and bevacizumab in eight two-week cycles. The study treatment will be given intravenously in the clinic.

  • After the first dose of bevacizumab and prior to starting chemotherapy, a needle biopsy of the breast tumor will be performed for research purposes. A second measurement of IFP will also be done at this time.

  • During the treatment period, tests and procedures will be performed at specified intervals and include the following: research MRI, physical exams, blood tests, urine tests, EKG, and MUGA or ECHO.

  • Surgery to remove the tumor will occur no less than four weeks after the last dose of Paclitaxel.

Study Design

Study Type:
Interventional
Actual Enrollment :
104 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Study of Preoperative Dose-dense (dd) Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel (T) With Bevacizumab in ER+ and/or PR+, HER2-negative Operable Breast Cancer
Study Start Date :
Oct 1, 2007
Actual Primary Completion Date :
Oct 1, 2011
Actual Study Completion Date :
Dec 1, 2012

Arms and Interventions

ArmIntervention/Treatment
Active Comparator: HR+, HER2-

Patients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.

Drug: Doxorubicin
Standard chemotherapy regimen
Other Names:
  • Adriamycin
  • Drug: Cyclophosphamide
    Standard chemotherapy regimen
    Other Names:
  • Cytoxan
  • Drug: Paclitaxel
    Standard chemotherapy regimen
    Other Names:
  • Taxol
  • Drug: Bevacizumab
    One intravenous dose given followed 2 weeks later with standard chemotherapy drugs and bevacizumab given intravenously in 8 two-week cycles.
    Other Names:
  • Avastin
  • Active Comparator: Triple Negative Breast Cancer Cohort

    Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.

    Drug: Doxorubicin
    Standard chemotherapy regimen
    Other Names:
  • Adriamycin
  • Drug: Cyclophosphamide
    Standard chemotherapy regimen
    Other Names:
  • Cytoxan
  • Drug: Paclitaxel
    Standard chemotherapy regimen
    Other Names:
  • Taxol
  • Drug: Bevacizumab
    One intravenous dose given followed 2 weeks later with standard chemotherapy drugs and bevacizumab given intravenously in 8 two-week cycles.
    Other Names:
  • Avastin
  • Outcome Measures

    Primary Outcome Measures

    1. Pathologic Complete Response Rate After Preoperative Therapy in This Patient Population. [3 Years]

      Pathological Complete response is defined as complete disappearance of invasive tumor in the breast at the time of surgery

    Secondary Outcome Measures

    1. Decrease in Interstitial Fluid Pressure. [3 years]

      To determine if bevacizumab monotherapy results in a decrease in interstitial fluid pressure

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Documented primary invasive breast cancer by histologic assessment

    • Tumors must express estrogen (ER) and/or progesterone receptors (PR) by standard immunohistochemical methods. Tumors must be negative for HER2. There must be sufficient sample for further protocol-specified immunohistochemical analysis

    • Patients must have high risk ER+ or PR+ breast cancer as defined by criteria listed in protocol

    • 18 year of age or older

    • Performance status of 0 or 1 by ECOG criteria

    • Use of an effective means of contraception in subjects of childbearing potential

    • Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to starting therapy.

    • Patients taking exogenous sex-steroid hormone treatments for any reason at the time of diagnosis must discontinue all hormonal treatments at least 2 weeks prior to enrollment

    • Patients must have preoperative treatment within 60 days of initial diagnosis of breast cancer

    • No other malignancy that requires on-going treatment

    • Normal organ function as outlined in the protocol

    Exclusion Criteria:
    • Prior cytotoxic chemotherapy or radiation for the current breast cancer

    • Patients with inflammatory breast cancer

    • HER2 positive disease defined as HER2-amplified by FISH or IHC 3+. HER2 2+ must be negative by FISH

    • Known metastatic (Stage IV) disease

    • Other investigational agents within 4 weeks prior to the start of study treatment

    • Life expectancy of less than 6 months

    • Peripheral neuropathy greater than or equal to grade 2

    • Inadequately controlled hypertension

    • Any prior history of hypertensive crisis or hypertensive encephalopathy

    • NYHA grade II or greater congestive heart failure

    • History of prior myocardial infarction

    • History of unstable angina within 12 months prior to study enrollment

    • Any history of stroke or transient ischemic attack at any time

    • Known CNS disease

    • Significant vascular disease

    • Symptomatic peripheral vascular disease

    • Evidence of significant bleeding within 6 months of study; any serious non-healing wound, skin ulcers, or bone fracture; any abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within the past 6 months; any major surgical procedure within 28 days prior to randomization or anticipation of need for major surgery during course of study.

    • Known HIV positive

    • Unwilling to undergo pretreatment biopsy and consent to acquisition of archival tissue

    • Pregnant of lactating

    • Known hypersensitivity to any component of bevacizumab

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Massachusetts General HospitalBostonMassachusettsUnited States02114
    2Dana-Farber Cancer InstituteBostonMassachusettsUnited States02115
    3Dana-Farber at Faulkner HospitalBostonMassachusettsUnited States02130
    4New Hampshire Oncology-Hematology PAHooksettNew HampshireUnited States03106

    Sponsors and Collaborators

    • Ian E. Krop, MD, PhD
    • Genentech, Inc.
    • Massachusetts General Hospital
    • Brigham and Women's Hospital
    • New Hampshire Oncology-Hematology PA

    Investigators

    • Principal Investigator: Ian Krop, MD, PhD, Dana-Farber Cancer Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Ian E. Krop, MD, PhD, Medical Oncologist, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT00546156
    Other Study ID Numbers:
    • 07-130
    First Posted:
    Oct 18, 2007
    Last Update Posted:
    May 18, 2021
    Last Verified:
    Apr 1, 2021
    Keywords provided by Ian E. Krop, MD, PhD, Medical Oncologist, Dana-Farber Cancer Institute
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment DetailsStudy was activated on 10/17/2007 and Closed to accrual on 7/1/2011.
    Pre-assignment Detail
    Arm/Group TitleHR+, HER2-Triple Negative Breast Cancer Cohort
    Arm/Group DescriptionPatients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.
    Period Title: Overall Study
    STARTED8420
    COMPLETED7019
    NOT COMPLETED141

    Baseline Characteristics

    Arm/Group TitleHR+, HER2-Triple Negative Breast Cancer CohortTotal
    Arm/Group DescriptionPatients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.Total of all reporting groups
    Overall Participants8420104
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    47.5
    47.5
    47.5
    Sex: Female, Male (Count of Participants)
    Female
    84
    100%
    20
    100%
    104
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    84
    100%
    20
    100%
    104
    100%

    Outcome Measures

    1. Primary Outcome
    TitlePathologic Complete Response Rate After Preoperative Therapy in This Patient Population.
    DescriptionPathological Complete response is defined as complete disappearance of invasive tumor in the breast at the time of surgery
    Time Frame3 Years

    Outcome Measure Data

    Analysis Population Description
    Participants who met all study eligibility criteria and signed informed consent.
    Arm/Group TitleHR+, HER2-Triple Negative Breast Cancer Cohort
    Arm/Group DescriptionPatients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.
    Measure Participants8420
    Number [percentage of participants]
    8
    9.5%
    44
    220%
    2. Secondary Outcome
    TitleDecrease in Interstitial Fluid Pressure.
    DescriptionTo determine if bevacizumab monotherapy results in a decrease in interstitial fluid pressure
    Time Frame3 years

    Outcome Measure Data

    Analysis Population Description
    This represents the number of patients with paired IFP measurements from day 0 and day 14
    Arm/Group TitleHR+, HER2-Triple Negative Breast Cancer Cohort
    Arm/Group DescriptionPatients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.
    Measure Participants5213
    Median (Inter-Quartile Range) [mm Hg]
    0.70
    1.04

    Adverse Events

    Time Frame4 years
    Adverse Event Reporting Description
    Arm/Group TitleAll Study Participants
    Arm/Group DescriptionPatients with HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.
    All Cause Mortality
    All Study Participants
    Affected / at Risk (%)# Events
    Total/ (NaN)
    Serious Adverse Events
    All Study Participants
    Affected / at Risk (%)# Events
    Total4/104 (3.8%)
    Blood and lymphatic system disorders
    Neutropenia1/104 (1%) 1
    Leukopenia2/104 (1.9%) 2
    General disorders
    paranasal sinus reaction1/104 (1%) 1
    Skin and subcutaneous tissue disorders
    cellulitis1/104 (1%) 1
    Other (Not Including Serious) Adverse Events
    All Study Participants
    Affected / at Risk (%)# Events
    Total104/104 (100%)
    Blood and lymphatic system disorders
    febrile neutropenia6/104 (5.8%) 10
    Hematologic-other38/104 (36.5%) 194
    Hemoglobin86/104 (82.7%) 387
    Leukocytes24/104 (23.1%) 39
    Lymphopenia56/104 (53.8%) 182
    Nose-hemorrhage33/104 (31.7%) 68
    Platelets30/104 (28.8%) 54
    Endocrine disorders
    Hot flashes15/104 (14.4%) 29
    Hyperglycemia79/104 (76%) 304
    Eye disorders
    Neutrophils20/104 (19.2%) 32
    Gastrointestinal disorders
    Abdomen-pain10/104 (9.6%) 16
    Anorexia20/104 (19.2%) 40
    constipation47/104 (45.2%) 89
    Diarrhea34/104 (32.7%) 65
    Dyspepsia21/104 (20.2%) 45
    GI-other20/104 (19.2%) 34
    Hemorrhoids12/104 (11.5%) 29
    Nausea76/104 (73.1%) 197
    Vomiting25/104 (24%) 29
    General disorders
    Constitutional-other6/104 (5.8%) 7
    Fatigue91/104 (87.5%) 367
    fever w/o neutropenia22/104 (21.2%) 35
    Insomnia19/104 (18.3%) 35
    Oral cavity-pain6/104 (5.8%) 8
    Pain-other27/104 (26%) 41
    Taste disturbance6/104 (5.8%) 7
    Voice changes/dysarthria15/104 (14.4%) 32
    Weight loss7/104 (6.7%) 17
    Hepatobiliary disorders
    ALT-SGPT48/104 (46.2%) 84
    AST-SGOT48/104 (46.2%) 120
    Immune system disorders
    Allergic Reaction10/104 (9.6%) 10
    Infections and infestations
    Infection-other7/104 (6.7%) 8
    Muco/stomatitis (symptom) oral cavity23/104 (22.1%) 49
    Muco/stomatitis by exam-oral cavity18/104 (17.3%) 28
    Investigations
    Alkaline Phosphatase36/104 (34.6%) 87
    Metabolism and nutrition disorders
    Bicarbonate19/104 (18.3%) 41
    Hypoalbuminemia7/104 (6.7%) 18
    Hypocalcemia13/104 (12.5%) 24
    Hypoglycemia7/104 (6.7%) 8
    Hyponatremia11/104 (10.6%) 18
    Metabolic/laboratory-other37/104 (35.6%) 123
    Musculoskeletal and connective tissue disorders
    Back-pain22/104 (21.2%) 27
    Bone-pain16/104 (15.4%) 27
    Extremity-limb-pain13/104 (12.5%) 18
    Joint-pain31/104 (29.8%) 60
    Muscle-pain53/104 (51%) 96
    Rigors/chills6/104 (5.8%) 7
    Throat/pharynx/larynx-pain30/104 (28.8%) 44
    Nervous system disorders
    Dizziness9/104 (8.7%) 11
    Headache57/104 (54.8%) 129
    Neuropathy-motor9/104 (8.7%) 11
    Psychiatric disorders
    Anxiety18/104 (17.3%) 32
    Depression6/104 (5.8%) 9
    Renal and urinary disorders
    Creatinine34/104 (32.7%) 115
    Proteinuria30/104 (28.8%) 53
    Respiratory, thoracic and mediastinal disorders
    Cough26/104 (25%) 59
    Dyspnea21/104 (20.2%) 47
    Infection Gr0-2 neut-upper airway10/104 (9.6%) 15
    Pulmonary-Upper Respiratory-other19/104 (18.3%) 36
    Skin and subcutaneous tissue disorders
    Alopecia39/104 (37.5%) 179
    Dry Skin9/104 (8.7%) 13
    erythema multiforme7/104 (6.7%) 8
    Flushing8/104 (7.7%) 13
    Hand-foot reaction6/104 (5.8%) 12
    Nail changes9/104 (8.7%) 19
    Neuropathy-sensory64/104 (61.5%) 150
    Rash/desquamation25/104 (24%) 36
    Sweating6/104 (5.8%) 9
    Vascular disorders
    Hypertension27/104 (26%) 59
    Skin-other8/104 (7.7%) 13

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleDr Ian Krop
    OrganizationDana-Farber Cancer Institute
    Phone617-632-2335
    Emailian.krop@dfci.harvard.edu
    Responsible Party:
    Ian E. Krop, MD, PhD, Medical Oncologist, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT00546156
    Other Study ID Numbers:
    • 07-130
    First Posted:
    Oct 18, 2007
    Last Update Posted:
    May 18, 2021
    Last Verified:
    Apr 1, 2021