Phase II Study With Abraxane, Bevacizumab and Carboplatin in Triple Negative Metastatic Breast Cancer (ABC)

Study Description

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Brief Summary:

Taxanes (such as paclitaxel) are highly active to treat breast cancer. Abraxane® (nanoparticle albumin-bound paclitaxel) compared to standard paclitaxel improves efficacy and tolerability. When combined with a taxane, platinum agents improve response in metastatic breast cancer, with carboplatin conferring less toxicity than cisplatin. Monoclonal antibodies including bevacizumab target vascular endothelial growth factor (VEGF) to reduce angiogenesis. We hypothesize that the previously-untested combination of weekly Abraxane® and carboplatin plus biweekly bevacizumab will lengthen time to progression without producing intolerable toxicity.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Abraxane; Drug: Bevacizumab; Drug: Carboplatin	Phase 2

Detailed Description:

Anthracycline-based chemotherapy is widely used as adjuvant treatment for breast cancer. In addition to the challenge posed by anthracycline-induced cardiotoxicity, there are issues surrounding previous treatment with anthracyclines which limit its utility in the metastatic disease setting. Many patients with advanced disease will have had prior anthracycline-based adjuvant therapy, may have reached a maximum cumulative lifetime dose, or developed refractory disease, creating an obvious need for non-anthracycline treatment strategies.3 Platinum- and taxane-based chemotherapies as first-line therapy for metastatic breast cancer have demonstrated significant activity, producing single-agent response rates > 50%; in combination these rates increased to > 60% in both previously untreated and in patients who previously received anthracyclines.3 However, overall survival has remained relatively unchanged.4 As there is currently no standard of care for patients with metastatic breast cancer, various physical and psychological factors must be considered when evaluating chemotherapy treatment options, including the patient's tumor biology and growth rate, presence and extent of metastases, history of prior treatment and response, sensitivity and tolerance to therapy, and quality of life.2 Strategies to develop combination, higher dose, or sequential regimens using these active agents, while improving response rates and/or time to progression, may produce increased toxicity without increased survival.2 Because metastatic breast cancer remains essentially incurable using cytotoxic therapy alone, the study of targeted biologics offers new opportunities to enhance drug delivery via their ability to regulate specific receptors that are associated with clinically aggressive disease processes.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	41 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase II Study of Abraxane®, Carboplatin and Bevacizumab in "Triple Negative" (Demonstrating No Expression for Estrogen, Progesterone, or Her2 Receptors) Metastatic Breast Cancer
Study Start Date :	May 2007
Actual Primary Completion Date :	March 2014
Actual Study Completion Date :	March 2014

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Abraxane, Carboplatin, Bevacizumab; Abraxane 100 mg/m2 IV over 30 min days 1,8,15.; Carboplatin AUC=2 IV over 15 min days 1,8,15., Bevacizumab 10 mg/kg IV days 1,15

Drug: Abraxane; 100 mg/m2 IV over 30 min days 1,8,15. Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria, intolerable toxicity, or death..; Other Name: nanoparticle albumin-bound paclitaxel Drug: Bevacizumab; 10 mg/kg IV days 1,15 Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria,intolerable toxicity, or death.; Other Name: Avastin Drug: Carboplatin; area under curve (AUC)=2 IV over 15 min days 1,8,15. Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria, intolerable toxicity, or death.

Outcome Measures

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Primary Outcome Measures :

1. Best Clinical Response Expressed as Percentage of Participants Treated With Combination Regimen of Weekly Abraxane® and Carboplatin Plus Biweekly Bevacizumab to Treat Women With Stage IV or Inoperable Stage III "Triple Negative" Metastatic Breast Cancer. [ Time Frame: 5 years ]
   Best clinical response is based on RECIST criteria, the proportion in each response category along with the exact binomial confidence intervals are estimated. Toxicity summaries are also provided.

Secondary Outcome Measures :

1. Median Proportion Progression-free as Estimated by Kaplan-Meier Methods [ Time Frame: 5 years ]
   PFS was defined as time from trial enrollment to disease progression or death, whichever occurred first.
2. To Evaluate Sequential Plasma Samples for Presence of Selected Angiogenic Markers [ Time Frame: 18 months ]
3. to Determine if Apolipoprotein Alleles (Apo-E) Correlate With Treatment-related Neuropathy [ Time Frame: 18 months ]
4. to Determine if SPARC Expression in Breast Tumors Predicts Progression-free Survival (PFS) [ Time Frame: 18 months ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Tissue block containing tumor to confirm metastatic breast cancer is required;
• Measurable disease according to RECIST criteria
• "Triple negative" disease defined as tumor demonstrating no expression for estrogen, progesterone or human epidermal growth factor receptor 2(HER2)receptors. "No expression" is categorized as ≤ 10% of cells staining or Allred ≤ 2;
• Aged 18 years or older;
• Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status of 0 or 1; life expectancy ≥ 3 months;
• Patients may have received 0 - 1 prior therapies (except taxanes in the metastatic setting). An interval of at least 1 week must have elapsed since prior chemotherapy or hormonal therapy for metastatic disease; at least 6 months must have elapsed since prior adjuvant therapy;
• ≥ 2 weeks between surgery and study enrollment (≥ 4 weeks between major surgery (defined as open abdominal/thoracic/cardiac) and study enrollment;

• Laboratory tests performed within 14 days of study entry:

  • Granulocytes ≥ 1,500/µL;
  • Platelets ≥ 100,000/µL;
  • Hemoglobin ≥ 9 gm/dL;
  • Total bilirubin ≤ institutional upper limit of normal (ULN);

  • Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 5 times ULN;

    • Alkaline phosphatase ≤ 2.5 times ULN;
  • Estimated creatinine clearance ≥ 60 mL/min.
• left ventricular ejection fraction (LVEF)≥ 50% by multigated acquisition (MUGA)/Echocardiogram;
• Informed consent to receive protocol treatment, to provide biologic specimens, and to complete neurotoxicity questionnaires;
• Cognitive and communication skills to comply with study and/or follow-up procedures;

• No reproductive potential:

  • If pre-menopausal: Negative serum pregnancy test and patient agreement to use adequate contraceptive method (abstinence, intrauterine device, barrier device with spermicide or surgical sterilization) during and for 3 months after completion of treatment.
  • If post-menopausal: Amenorrhea for ≥ 12 months.

Exclusion Criteria:

• Pregnant or breast feeding;
• Prior treatment with Abraxane®, carboplatin or bevacizumab, or any taxane for metastatic breast cancer;
• Known hypersensitivity to any component of any study drug;
• Active infection;
• Current neuropathy ≥ grade 2;
• central nervous system (CNS) metastases as determined by head CT with contrast;
• History of bleeding within the past 6 months or active bleeding disorder;
• Serious non-healing wound, ulcer or bone fracture;
• Uncontrolled congestive heart failure (CHF), or history of myocardial infarction(MI), unstable angina, stroke, or transient ischemia within previous 6 months;
• Inadequately controlled hypertension (defined as systolic blood pressure < 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications; prior history of hypertensive crisis or hypertensive encephalopathy;
• Proteinuria (defined as urine protein: creatinine (UPC) ratio ≥ 1.0 or urine dipstick ≥ 2+.
• Significant vascular disease (aortic aneurysm, aortic dissection) or symptomatic peripheral vascular disease;
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within previous 6 months;
• Uncontrolled serious contraindicated medical condition or psychiatric illness.

Contacts and Locations

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Locations

United States, North Carolina
Presbyterian Health Care
Charlotte, North Carolina, United States, 28204
Northeast Oncology Associates
Concord, North Carolina, United States, 28205
Duke University Medical Center
Durham, North Carolina, United States, 27710
Forsyth Regional Cancer Center
Winston-Salem, North Carolina, United States, 27103-3019

Sponsors and Collaborators

Duke University

Genentech, Inc.

Celgene Corporation

Investigators

Principal Investigator:	Kimberly Blackwell, MD	Duke University

More Information

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Additional Information:

Nab- Paclitaxel/Bevacizumab/Carboplatin chemotherapy in the first line triple negative metastatic breast cancer 

Responsible Party:	Duke University
ClinicalTrials.gov Identifier:	NCT00479674 History of Changes
Other Study ID Numbers:	Pro00014837; AVF3962s
First Posted:	May 28, 2007
Results First Posted:	February 18, 2015
Last Update Posted:	February 18, 2015
Last Verified:	January 2015

Keywords provided by Duke University:

Metastatic Breast Cancer; Advanced Breast Cancer; Hormone Receptor AND Her2/neu Negative	Triple Negative; Triple Negative Breast Cancer; Stage IV or Inoperable Stage III Breast Cancer

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Bevacizumab; Carboplatin; Albumin-Bound Paclitaxel; Paclitaxel; Angiogenesis Inhibitors	Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action