Trastuzumab (Herceptin), Bevacizumab, and Docetaxel (Taxotere) Trial in Stage IV Metastatic Breast Cancer (MBC) Patients

Study Overview
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Brief Summary
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The primary objectives are to determine the progression-free survival (PFS) and to evaluate safety of the trastuzumab, bevacizumab and docetaxel regimen.

Detailed Description
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Rationale: Antibodies are proteins that are normally part of the immune system that bind to foreign agents in the body. Researchers manufacture antibodies outside of the human body that bind to specific targets such as proteins in cancer cells. Herceptin is a monoclonal antibody that binds to the human epidermal growth factor receptor (HER-2), and can kill HER2-positive cancer cells. Herceptin is used to treat breast cancer that is HER2-positive, and has spread after treatment with other drugs. Bevacizumab is a signal transduction inhibitor that works by preventing the growth of new blood vessels from surrounding tissue into tumors. Bevacizumab specifically inhibits the vascular endothelial growth factor (VEGF), a substance made by cells that stimulates new blood vessel formation. Research indicates that HER-2 signaling helps to induce VEGF expression. Therefore, cancer treatments targeting both HER-2 and VEGF may improve anti-cancer efficacy in patients. Docetaxel is a chemotherapy agent used against breast and other types of cancer. The current study builds on previous research suggesting the safety and potential for efficacy with combination trastuzumab, bevacizumab, and docetaxel. Purpose: The primary objectives are to determine the progression free survival and evaluate the safety of trastuzumab, bevacizumab, and docetaxel. Secondary objectives are to assess early changes in circulating tumor cells and circulating endothelial cells as predictors of progression free survival and clinical benefit, as well as to determine the overall clinical benefit rate. Treatment: Study participants will be given trastuzumab, bevacizumab, and docetaxel. All study drugs will be given through intravenous infusions once every 21 days. A cycle is considered 3 weeks. A minimum of 6 study treatment cycles is required unless study participants experience disease growth or intolerable toxicity. The decision to stop docetaxel after 6 cycles is up to the discretion of the treating physician and the patient. Study participants who are deriving a benefit from the study drugs may continue on trastuzumab and bevacizumab alone. Several tests and exams will be given throughout the study to closely monitor study participants.

Official Title
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Phase II Trial of Trastuzumab (Herceptin), Bevacizumab, and Docetaxel (Taxotere) Trial in Stage IV Metastatic Breast Cancer (MBC) Patients

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Bevacizumab
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed breast cancer with evidence of metastatic disease HER2 3+ or FISH (fluorescent in situ hybridization)+ Age ≥ 18 years No prior trastuzumab, except as given in the adjuvant or neoadjuvant setting. No prior chemotherapy in the metastatic setting. Exclusion Criteria: CNS (central nervous system) metastases Prior radiation therapy within the last 4 weeks Pregnant (positive pregnancy test) or lactating women Major surgical procedure, open biopsy, non-healing wounds, or significant traumatic injury within 28 days prior to starting study or anticipation of need for major surgical procedure during the study Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to start of study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab, Bevacizumab, and Docetaxel<br>Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²] | Drug: Trastuzumab<br>* administered every three weeks on day 1, every 21 days. The dose given will be 6 mg/kg. The initial loading dose is 8mg/kg and is administered as a 90-minute infusion. Thereafter, the maintenance dose is 6mg/kg every three weeks administered as a 30 minute infusion (unless the treating physician indicates a longer infusion duration is warranted). Trastuzumab is given prior to bevacizumab. Trastuzumab is to be continued until disease progression or unacceptable toxicity.<br>* Other names: Herceptin;Drug: Bevacizumab<br>* administered every three weeks on day 1, every 21 days. The dose given will be 15 mg/kg. The initial dose is administered over 90 minutes. If the first infusion is well tolerated, the second dose is given over 60 minutes, and if that is well tolerated, then subsequent doses may be given over 30 minutes. Avastin is given after trastuzumab and prior to docetaxel.<br>* Other names: Avastin;Drug: Docetaxel<br>* administered every three weeks on day 1, every 21 days. The dose given will be 75 mg/M². All doses of docetaxel are administered over 60 minutes. Docetaxel is given after trastuzumab and bevacizumab.<br>* Other names: Taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) and to Evaluate Safety of the Trastuzumab, Bevacizumab and Docetaxel Regimen. | The trial was designed as a single-stage phase II rather then usual two-stage design because of the progression free survival (PFS) primary endpoint, as it is impractical to wait to assess PFS for patients in the first stage. We will consider a PFS of 50% at twelve months (median PFS of 12 months) or less uninteresting and a PFS of 70% at twelve months (median PFS of twenty months) worthy of pursuing the regimen in a future trials. The single-stage design is as follows: p0=0.50, p1=0.70, α=0.10, β= 0.10. This leads to a total sample size of 39 patients, 24 or higher of who are progression-free at 12 months. | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in CTCs as Predictors of PFS and Clinical Benefit | Circulating tumor cells (CTCs) evaluated at baseline (day 1 of treatment) and after 1 treatment cycle (day 22 prior to cycle 2 treatment). | Day 1 and Day 22 | 
| Overall Clinical Benefit Rate (CR+PR+SD) | Defined as best response of CR or PR or stable disease for at least 24 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions | at least 24 weeks | 
| Changes in CECs as Predictors of PFS and Clinical Benefit | Circulating endothelial cells (CECs) are to be collected day 1 prior to treatment and day 22 prior to treatment. These samples are to be collected at the PI's discretion based upon the availability of the cell processing laboratory, the patients will be informed when consented if the samples will collected or not. | Day 1 and Day 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic, Breast Cancer, MBC