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

• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Neoplasms	Drug: Docetaxel; Drug: Doxorubicin; Drug: Carboplatin; Drug: Cyclophosphamide; Drug: Trastuzumab; Drug: Bevacizumab	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	127 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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 Start Date :	March 2007
Actual Primary Completion Date :	August 2010
Actual Study Completion Date :	August 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Stratum 1: TAC + Bevacizumab; Human epidermal growth factor receptor-2 (HER2) negative participants stratified at registration, were administered chemotherapy with docetaxel, doxorubicin and cyclosphosphamide (TAC) + bevacizumab for Cycles 1-6 (every 3 weeks), and followed with maintenance therapy with bevacizumab every 3 weeks for a total of 52 weeks. All participants were administered prophylactic recombinant Granulocyte Colony Stimulating Factor (G-CSF) during chemotherapy, based on a dose recommended by the manufacturer. For participants with estrogen receptor (ER) or progesterone receptor (PR) positive tumors, anti-estrogen therapy was recommended. Participants could receive radiation therapy at the discretion of the treating medical and radiation oncologist.	Drug: Docetaxel; 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).; Other Name: Taxotere®; Drug: Doxorubicin; 50 mg/m^2 administered IV on Day 1 for Cycles 1-6; Drug: Cyclophosphamide; 500 mg/m^2 administered IV on Day 1 for Cycles 1-6; Drug: Bevacizumab; 15 mg/kg administered IV on Day 1 for Cycles 1-6, and for maintenance therapy
Experimental: Stratum 2: TCH + Bevacizumab; HER2 positive participants stratified at registration, were administered chemotherapy with docetaxel, carboplatin and trastuzumab (TCH) + bevacizumab for Cycles 1-6 (every 3 weeks), and followed with maintenance therapy with bevacizumab and trastuzumab every 3 weeks for a total of 52 weeks. All participants were administered prophylactic recombinant Granulocyte Colony Stimulating Factor (G-CSF) during chemotherapy, based on a dose recommended by the manufacturer. For participants with estrogen receptor (ER) or progesterone receptor (PR) positive tumors, anti-estrogen therapy was recommended. Participants could receive radiation therapy at the discretion of the treating medical and radiation oncologist.	Drug: Docetaxel; 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).; Other Name: Taxotere®; Drug: Carboplatin; 6 mg/mL/min (target area under the curve [AUC] dose) administered IV on Day 1 for Cycles 1-6; Other Name: Gemzar®; Drug: Trastuzumab; 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; Drug: Bevacizumab; 15 mg/kg administered IV on Day 1 for Cycles 1-6, and for maintenance therapy

Outcome Measures

Primary Outcome Measures :

1. Percent of Participants With Grade 3/4 Clinical Congestive Heart Failure (CHF) [ Time Frame: up to 2 years ]
   The percentage of participants with Grade 3/4 clinical CHF was calculated. Grade 3/4 CHF symptoms included cardiac failure congestive, cardiomyopathy, and left ventricular dysfunction (LVEF). Echocardiography (ECG) or multiple-gated acquisition (MUGA) scans were scheduled after Cycles 3 and 6 of chemotherapy, after every 3rd cycle of trastuzumab alone, at end of therapy and every 6 months at follow-up to measure changes in LVEF. Clinical symptoms e.g., shortness of breath, tachycardia, cough, neck vein distention, cardiomegaly, hepatomegaly were further investigated for CHF.

Secondary Outcome Measures :

1. Disease-free Survival (DFS) & Overall Survival (OS) of Participants [ Time Frame: up to 10 years ]

   DFS is the time from study registration until recurrence of tumor or death from any cause in the absence of previous documentation of tumor recurrence. For participants who are removed from the study follow-up prior to documentation of the tumor recurrence, DFS will be censored at the last date the participant was known to be disease-free.

   OS is the time from date of registration to date of death. In the absence of confirmation of death, survival time will be censored at the last date the participant is known to be alive.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 70 Years (Adult, Older Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Locations

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United States, New Jersey
Sanofi-Aventis Administrative Office
Bridgewater, New Jersey, United States, 08807

Sponsors and Collaborators

Sanofi

Investigators

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Study Director:	Vicki Erickson, MSN	Sanofi

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Sanofi
ClinicalTrials.gov Identifier:	NCT00446030 History of Changes
Other Study ID Numbers:	DOCET_L_00713
First Posted:	March 12, 2007
Results First Posted:	November 4, 2011
Last Update Posted:	June 26, 2012
Last Verified:	June 2012

Additional relevant MeSH terms:

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Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Bevacizumab; Trastuzumab; Cyclophosphamide; Carboplatin; Docetaxel; Doxorubicin; Liposomal doxorubicin; Sargramostim; Lenograstim; Antineoplastic Agents, Immunological	Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Myeloablative Agonists; Tubulin Modulators; Antimitotic Agents