Clinical trial NCT00446030: 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
Official title: A Phase II, Open-Label, Multicenter, 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Neoplasms
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2007-03-12
Enrollment: 127
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Percent of Participants With Grade 3/4 Clinical Congestive Heart Failure (CHF)
timeFrame: up to 2 years
Secondary outcomes:
measure: Disease-free Survival (DFS) & Overall Survival (OS) of Participants
timeFrame: up to 10 years
Other outcomes:
Locations:
city: Bridgewater
country: United States
facility: Sanofi-Aventis Administrative Office
state: New Jersey
Study officials:
affiliation: Sanofi
name: Vicki Erickson, MSN
role: STUDY_DIRECTOR
References:
citation: Hurvitz SA, Bosserman LD, Chan D, Hagenstad CT, Kass FC, Smith FP, Rodriguez GI, Childs BH, Slamon DJ. Cardiac safety results from a phase II, open-label, multicenter, pilot study of two docetaxel-based regimens plus bevacizumab for the adjuvant treatment of subjects with node-positive or high-risk node-negative breast cancer. Springerplus. 2014 May 12;3:244. doi: 10.1186/2193-1801-3-244. eCollection 2014.