Pilot Study of the Safety & Efficacy of Two Docetaxel-Based Regimens Plus Bevacizumab for the Adjuvant Treatment of Subjects With Node Positive or High Risk Node Negative Breast Cancer
Condition: Breast Neoplasms
MeSH terms: Breast Neoplasms
Intervention: Docetaxel; Doxorubicin; Carboplatin; Cyclophosphamide; Trastuzumab; Bevacizumab
Intervention description: 75 mg/m^2 administered IV on Day 1 for Cycles 1-6
All participants received a prophylactic steroid regimen prior to each dose of docetaxel - Dexamethasone 8 mg orally 12 hours prior to docetaxel, dexamethasone 10 mg IV just prior the docetaxel infusion and 8 mg orally 12 hours after docetaxel administration. If a participant had not taken their oral dexamethasone the evening prior to receiving docetaxel, the dose of the pre-docetaxel infusion of dexamethasone was increased from 10 mg IV to 15 mg IV. A Dexamethasone 8 mg equivalent may have been used (dexamethasone 8 mg = methylprednisolone 40 mg = prednisone 50 mg = prednisolone 50 mg).; 50 mg/m^2 administered IV on Day 1 for Cycles 1-6; 6 mg/mL/min (target area under the curve [AUC] dose) administered IV on Day 1 for Cycles 1-6; 500 mg/m^2 administered IV on Day 1 for Cycles 1-6; A single loading dose of 8 mg/kg administered IV on Day 2 for Cycle 1, and 6 mg/kg administered IV on Day 1 for Cycles 2-6 and for maintenance therapy; 15 mg/kg administered IV on Day 1 for Cycles 1-6, and for maintenance therapy
Intervention MeSH terms: Cyclophosphamide; Bevacizumab; Carboplatin; Docetaxel; Doxorubicin; Trastuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 127.0
Sex: Female
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This is a phase II, open-label, multicenter, pilot study of the safety and efficacy of two
      Docetaxel-based regimens plus bevacizumab for the adjuvant treatment of participants with
      node positive or high risk node negative breast cancer.

      The primary objective of this study was to evaluate the cardiac safety, and the secondary
      objectives were to evaluate safety and toxicity of participants treated with bevacizumab ±
      trastuzumab administered with 2 different docetaxel-based combination regimens.

      This study was originally designed to also evaluate disease-free survival (DFS) and overall
      survival (OS); however, based on a protocol amendment, follow-up was shortened from 10 years
      to 2 years, and the efficacy endpoints of disease free survival and overall survival were
      deleted from the protocol.
    

Eligibility criteria:

        Inclusion Criteria:

        Participants who met the following criteria were eligible for this study:

          1. Woman aged 18 to 70 years, inclusive

          2. Had histologically proven breast cancer with the most recent surgery done for breast
             cancer up to 60 days prior to study registration

          3. Had definitive surgical treatment - either mastectomy, or breast conserving surgery
             with axillary lymph node dissection (or sentinel lymph node biopsy) for operable
             breast cancer (T1-3, clinical N0-1, and M0)

          4. Must have been either "lymph node positive" or "high risk lymph node negative"

               1. Were lymph node positive participants who had at least 1 axillary lymph node
                  involved by breast cancer. (with lymph node metastasis >0.2 mm)

               2. Were high risk lymph node negative participants had no lymph node involvement and
                  at least 1 of the following factors:

                    -  tumor size >2 cm

                    -  estrogen receptor (ER) and progesterone receptor (PR) status negative

                    -  histologic and/or nuclear Grade 2/3

                    -  age <35 years

          5. Were participants with the Human Epidermal growth factor Receptor 2 (HER2/neu) status
             (positive or negative) known at the time of signing the informed consent

          6. Had the estrogen and progesterone receptor status known prior to study registration

          7. Had Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

          8. Had normal cardiac function, confirmed by left ventricular ejection fraction (LVEF) or
             shortening fraction (echocardiography [ECHO] or multiple-gated acquisition [MUGA] scan
             respectively)

          9. Had the following hematology criteria confirmed within 2 weeks prior to study
             registration:

               -  Absolute neutrophil count (ANC) >1,500/microL

               -  Platelets >100,000/microL

               -  Hemoglobin ≥ 9 g/dL

         10. Met hepatic function evaluation criteria for bilirubin and AST levels within 2 weeks
             prior to study registration

         11. Had completed staging work-up within 35 days (within 1 year for mammography or breast
             magnetic resonance imaging (MRI) prior to study registration

         12. May have had MammoSite® brachytherapy radiation when performed immediately following
             surgery and prior to receiving chemotherapy. The balloon catheter must have been
             removed at least 28 days prior to the start of study treatment

         13. May have had bilateral, synchronous breast cancer provided one primary tumor met the
             staging criteria

         14. Women of child bearing potential must have had a negative pregnancy test within 14
             days prior to day 1 cycle 1

         15. Had consented to using an effective, non-hormonal method of contraception while
             receiving study treatment and for at least six (6) months following the last dose of
             bevacizumab, and must have been advised not to breast feed for at least six (6) months
             following the last dose of bevacizumab.

         16. Signed an informed consent prior to beginning any protocol-specific procedures, and
             had documented expected cooperation during the study treatment and follow-up periods

        Exclusion Criteria:

        Participants with the following criteria were excluded from this study:

          1. Had prior systemic anticancer therapy for invasive breast cancer
             (immunotherapy,hormonotherapy, chemotherapy)

          2. Had prior anthracycline therapy, taxoids, or platinum salts for any malignancy

          3. Had prior radiation therapy for breast cancer or any radiotherapy to the chest wall
             for any other malignancy

          4. Was pregnant or lactating

          5. Had pre-existing motor or sensory neurotoxicity of a severity >Grade 2 by National
             Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 3.0

          6. Had cardiac disease or risk for same as follows:

               -  Any documented myocardial infarction

               -  Angina pectoris that required the use of anti-anginal medication

               -  Any history of documented congestive heart failure

               -  Grade 3 or Grade 4 cardiac arrhythmia (NCI CTCAE, version 3.0)

               -  Clinically significant valvular heart disease

               -  Had cardiomegaly

               -  Had poorly controlled hypertension, i.e., diastolic greater than 100 mmHg.
                  (Participants who were well controlled on medication were eligible)

               -  Were currently receiving medications administered for cardiac arrhythmia, angina
                  or congestive heart failure (e.g., digitalis, beta-blockers, calcium
                  channel-blockers), that alter cardiac conduction, unless the medications were
                  administered for other reasons (e.g., hypertension)

          7. Had other serious illness or medical conditions including

               -  History of significant neurologic or psychiatric disorders including psychotic
                  disorders, dementia or seizures that prohibited the understanding and giving of
                  informed consent

               -  Active uncontrolled infection

               -  Active peptic ulcer

               -  Unstable diabetes mellitus

               -  with symptomatic, intrinsic lung disease resulting in dyspnoea at rest

               -  Clinically significant peripheral vascular disease

               -  Evidence of bleeding diathesis or coagulopathy

               -  Urine protein:creatinine ratio >1.0 at screening

               -  History of abdominal fistula, gastrointestinal perforation, intra-abdominal
                  abscess, inflammatory bowel disease or other gastrointestinal condition
                  increasing the risk of perforation within 6 months of beginning chemotherapy

               -  Serious, non-healing wound, ulcer, or bone fracture

               -  Known central nervous system (CNS) disease

               -  History of stroke or transient ischemic attack (TIA)

               -  Known hepatic cirrhosis

          8. Had past or current history of neoplasm other than breast carcinoma, except for:

               -  Curatively treated non-melanoma skin cancer

               -  In situ carcinoma of the cervix

               -  Other cancer curatively treated and with no evidence of disease for at least 10
                  years

               -  Ductal carcinoma in-situ (DCIS) of the breast

               -  Lobular carcinoma in-situ (LCIS) of the breast

          9. Was currently on therapy with any hormonal agent such as raloxifene, tamoxifen, or
             other selective estrogen receptor modulators (SERMs), either for osteoporosis or
             prevention of breast cancer

         10. Had chronic treatment with corticosteroids unless initiated >6 months prior to study
             registration and at low dose (<20 mg methylprednisolone or equivalent)

         11. Had concurrent treatment with ovarian hormonal replacement therapy

         12. Had concurrent treatment with other experimental drugs

         13. Had concurrent treatment with any other anticancer therapy

         14. Was male

         15. Had known hypersensitivity to Chinese hamster ovary products or other recombinant
             human or humanized antibodies and/or hypersensitivity to any of the study drugs or
             their ingredients (e.g., polysorbate 80 in docetaxel)

         16. Had minor surgical procedures within 7 days prior to day 1 of study treatment; or
             major surgical procedures within 28 days prior to day 1 of study treatment or had any
             anticipated a surgical procedure during the chemotherapy portion of this study

         17. Was directly (or was a relative of the study staff) involved in the conduct of the
             protocol

         18. Had a mental condition or psychiatric disorder rendering her unable to understand the
             nature, scope, and possible consequences of the study

         19. Was unlikely to comply with protocol