Bevacizumab, Metronomic Chemotherapy (CM), Diet and Exercise After Preoperative Chemotherapy for Breast Cancer

Study Overview
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Brief Summary
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If residual breast cancer is found in the breast or lymph node tissue removed after preoperative chemotherapy, one may be at increased risk of breast cancer recurrence in the future. The purpose of this research study is to determine if having additional treatment after preoperative chemotherapy and surgery with bevacizumab and metronomic chemotherapy would make a difference in reducing the participants chance of breast cancer recurrence compared to the standard of care, which is observation alone. This study will also evaluate the potential additional benefits from participating in an exercise and dietary intervention compared to the dietary intervention alone. Because no one knows which which post-neoadjuvant strategy is best, participants will be randomized to one of the study groups: 1. Diet Intervention arm, 2. Diet and Exercise Intervention Arm, 3. Bevacizumab, cyclophosphamide, methotrexate and diet intervention, 4. Bevacizumab, cyclophosphamide, methotrexate, diet and exercise intervention arm.

Detailed Description
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Bevacizumab is an antibody that is made in the laboratory. Bevacizumab works differently from the way chemotherapy drugs work. Bevacizumab works to slow or stop the growth of cells in cancer tumors by decreasing the blood supply to tumors. Bevacizumab has been approved by the U.S Food and Drug Administration to treat advanced colorectal, lung and kidney cancers. Metronomic chemotherapy also attacks tumor blood supply. Standard chemotherapy drugs are used, cyclophosphamide and methotrexate (CM), but in very small daily doses by mouth, well below the threshold where they can cause people to feel sick. Previous research studies have shown that women with breast cancer who take metronomic CM and bevacizumab feel very well, and the combination therapy is active in reducing their cancer. Participants in this study will also be provided with diet or diet and exercise counseling over the telephone. Studies have shown that many women who are treated for breast cancer will gain weight during and after their treatment, and may also experience fatigue and weakness. Many studies have shown that making changes in diet and increasing exercise can help prevent weight gain and also may increase energy and decrease other side effects of chemotherapy and other breast cancer treatments.

Official Title
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ABCDE: A Phase II Randomized Study of Adjuvant Bevacizumab, Metronomic Chemotherapy (CM), Diet and Exercise After Preoperative Chemotherapy for Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Cyclophosphamide
* Drug: Methotrexate
* Behavioral: Lifestyle: Diet
* Behavioral: Lifestyle: Diet+Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed invasive breast cancer. HER2 positive disease is not allowed. Metastatic breast cancer (Stage IV) is not allowed. For patients entering the trial after neoadjuvant chemotherapy, there must be the presence of residual invasive disease on pathologic review following neoadjuvant chemotherapy. Residual disease is defined as a Miller-Payne response in the breast of 0-4 and/or residual carcinoma in one or more regional lymph nodes that would meet AJCC 7th edition criteria for N1 - N3 disease. The presence of DCIS without invasion does not qualify as residual disease. Alternatively, if Miller-Payne grading is not available, the patient will be eligible if the pathology report indicates any residual invasive carcinoma following neoadjuvant therapy. If tumor is triple negative (ER-/PR-/HER2-) and the patient received neoadjuvant chemotherapy, disease may be clinical stage I-III pre-operatively, per AJCC 7th edition, based on baseline evaluation by clinical examination and/or breast imaging. Patients must have the presence of residual invasive disease on pathologic review following their neoadjuvant chemotherapy. If tumor is triple negative and the patient did not receive neoadjuvant chemotherapy, there must be pathologic lymph node positivity and Stage IIB or greater disease after surgery. For the purposes of eligibility, lymph node positivity can refer to either axillary or intramammary lymph nodes. If tumor is hormone receptor positive, disease must be clinical Stage III neoadjuvantly, per AJCC 7th edition, based on baseline evaluation by clinical examination and/or breast imaging, or pathologic Stage IIB or greater at time of definitive surgery. Patients with hormone receptor positive breast cancer who do not receive neoadjuvant chemotherapy are not eligible for this protocol. For patients who completed neoadjuvant chemotherapy, the regimen must contain an anthracycline, a taxane, or both. Patients who have received neoadjuvant therapy as part of a clinical trial are acceptable. Protocol therapy must be initiated < 180 days after last surgery for breast cancer. For triple negative patients who receive adjuvant chemotherapy only, the regimen must contain both an anthracycline and a taxane. For these patients, protocol therapy must be initiated < 28 weeks after initiation of adjuvant chemotherapy. Patients with ER+ and/or PR+ breast cancer should receive adjuvant hormonal therapy No prior exposure to bevacizumab or other inhibitors of angiogenesis is allowed. Patients must have completed definitive resection of primary tumor. Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however positive margins are acceptable if the treatment team believes no further surgery is possible and patient has received radiotherapy. Patients with margins positive for lobular carcinoma in situ are eligible. Post-mastectomy radiotherapy is suggested for all patients with a primary tumor 5cm or greater or involvement of 4 or more lymph nodes. Whole breast radiotherapy is required for patients who underwent breast conserving therapy, including lumpectomy, partial mastectomy, and excisional biopsy. Patients must have the presence of residual invasive disease on pathologic review following their preoperative chemotherapy. The presence of DCIS without invasion does not qualify as residual disease. Alternatively, if Miller-Payne grading is not available, the patient will be eligible if the pathology report indicates any residual invasive carcinoma following preoperative therapy. LVEF equal to or greater than institutional limits of normal after preoperative chemotherapy, as assessed by echocardiogram, within 30 days prior to registration ECOG Performance Status 0-1 within 2 weeks of registration 18 years of age or greater Exclusion Criteria: Laboratory assessments as outlined in the protocol Stage IV breast cancer. Patients with metastatic disease are ineligible. However, specific staging studies are not required in the absence of symptoms Prior history of hypertensive crisis or hypertensive encephalopathy History if myocardial infarction or unstable angina within 12 months prior to registration History of stroke or transient ischemic attack at any time Significant vascular disease within 6 months prior to registration History of hemoptysis within 1 month prior to registration Ongoing or active infection NYHA Grade II or greater congestive heart failure Unstable angina pectoralis Psychiatric illness/social situations that would limit compliance with study requirements Evidence of bleeding diathesis or significant coagulopathy Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to registration or anticipation of need for major surgical procedure during the course of the study Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to registration History of abdominal fistula or gastrointestinal perforation within 6 months prior to registration Serious, non-healing wound, active ulcer, or unhealed bone fracture Known hypersensitivity to any component of bevacizumab or compounds of similar chemical or biologic composition to cyclophosphamide or methotrexate Known HIV infection, as immunosuppression could be worsened by use of cyclophosphamide and methotrexate, and the impact of chemotherapy and/or bevacizumab therapy on the pharmacology of standard anti-HIV therapy is not known Patient may not be pregnant, expect to become pregnant, plan to conceive a child while on study or breastfeeding. Prior history of any malignancy treated without curative intent, or treated with curative intent within the past 5 years. Prior history of DCIS > 5 years before current breast cancer diagnosis is acceptable if ipsilateral (and no radiotherapy given) or contralateral (with or without radiotherapy) or contralateral (with or without radiotherapy). Prior history of contralateral stage 1 breast cancer > 5 years prior to the current breast cancer diagnosis is acceptable, however prior ER/PR+ breast cancer > stage 1 at any time is not allowed. Patients with a pleural effusion or abdominal ascites are excluded because of the theoretical risk for methotrexate accumulation and related toxicity Current use of anticoagulants is allowed as long as patients have been on a stable dose for more than two weeks with stable INR Chronic therapy with full dose aspirin or standard non-steroidal anti-inflammatory agents is allowed While on study, patients may not receive other investigational agents as part of other clinical trials Adjuvant bisphosphonate use, on or off of clinical trial, is allowed. Patients may be started on adjuvant bisphosphonate therapy either before or after ABCDE trial enrollment

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lifestyle: Diet<br>The dietary intervention focuses on the Food Pyramid, emphasizing diet that is low in fat and high in fruits, vegetables and fiber. Patients receive a series of 13 telephone calls over the course of one-year with a dedicated and trained counselor. | Behavioral: Lifestyle: Diet<br> <br> |
| Experimental: Lifestyle: Diet+Exericise<br>The dietary intervention focuses on the Food Pyramid, emphasizing diet that is low in fat and high in fruits, vegetables and fiber. The exercise intervention is comprised of a target physical activity goal of 180 minutes of moderate-intensity activity each week. Patients receive a series of 13 telephone calls over the course of one-year with a dedicated and trained counselor. | Behavioral: Lifestyle: Diet<br> <br> Behavioral: Lifestyle: Diet+Exercise<br> <br> |
| Experimental: Lifestyle: Diet and Bevicizumab+CM<br>The dietary intervention focuses on the Food Pyramid, emphasizing diet that is low in fat and high in fruits, vegetables and fiber. Patients receive a series of 13 telephone calls over the course of one-year with a dedicated and trained counselor. Bevicizumab: 15 mg/kg administered intravenously day 1 of a 3-week cycle for 6 months and day 1 of a 6 week cycle up to 2 years Cyclophosphamide: 50 mg orally each day of a 3-week cycle for 6 months Methotrexate: 2.5 mg orally twice daily of a 3-week cycle for 6 months | Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;Drug: Methotrexate<br> <br> * Other names: MTX;Behavioral: Lifestyle: Diet<br> <br> |
| Experimental: Lifestyle: Diet+Exericise and Bevicizumab+CM<br>The dietary intervention focuses on the Food Pyramid, emphasizing diet that is low in fat and high in fruits, vegetables and fiber. The exercise intervention is comprised of a target physical activity goal of 180 minutes of moderate-intensity activity each week. Patients receive a series of 13 telephone calls over the course of one-year with a dedicated and trained counselor. Bevicizumab: 15 mg/kg administered intravenously day 1 of a 3-week cycle for 6 months and day 1 of a 6 week cycle up to 2 years Cyclophosphamide: 50 mg orally each day of a 3-week cycle for 6 months Methotrexate: 2.5 mg orally twice daily of a 3-week cycle for 6 months | Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan;Drug: Methotrexate<br> <br> * Other names: MTX;Behavioral: Lifestyle: Diet<br> <br> Behavioral: Lifestyle: Diet+Exercise<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median 3-year Recurrence-free Survival (RFS) | RFS events is defined as the duration of time from randomization to time of an RFS event, marked as positive if any of listed event shows: local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive), any other second cancer (excluding non-melanomatous skin cancer or cervical cancer in situ), or death from any cause. The diagnosis of local or distant recurrence should be pathologically confirmed however if biopsy if not possible, radiology confirmation acceptable. | Disease assessments occurred every 12 weeks on treatment and every 6 months in long-term follow-up up to 7.5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility Rate | The feasibility of post-adjuvant maintenance metronomic chemotherapy is open to women with hormone receptor negative tumors and either node negative or node positive disease. | 2 years | 
| Number of Serious Adverse Event of Bevacizumab | Adverse event evaluations will occur at each study visit throughout the treatment period of 2 years and will continue every 6 months during the follow-up period. Only Grade 3/4 AE (CTCAE v4) was reported. | Followed every 6 months for 7.5 years after study entry, or completion of final analysis, whichever comes first. | 
| Number of Serious Adverse Event of Metronomic Chemotherapy | Adverse event evaluations will occur at each study visit throughout the treatment period of 2 years and will continue every 6 months during the follow-up period. Only Grade 3/4 AE (CTCAE v4) was reported. | Followed every 6 months for 7.5 years after study entry, or completion of final analysis, whichever comes first. | 
| Number of Serious Adverse Event (AE) of Lifestyle | Exercise and/or dietary lifestyle interventions defined per protocol. The lifestyle intervention will be administered by telephone, supplemented with a participant workbook (Appendix 9 in protocol). Only Grade 3/4 AE (CTCAE v4) was reported. | Followed every 6 months for 7.5 years after study entry, or completion of final analysis, whichever comes first. | 
| Change in Level of Fasting Insulin | Change in level of fasting insulin from baseline at study entry to 6 months. | Baseline and 6 months | 
| Change in Body Weight | data not collected due to early termination of the study. | Baseline and 6 months | 
| Change in IGF-1 | Change in level of insulin-like growth factor -1 (IGF-1) from baseline at study entry to 6 months. | Baseline and 6 months | 
| Changes in Diet and Physical Activity Upon Biomarkers | To evaluate the impact of changes in diet and physical activity upon biomarkers associated with breast cancer risk and prognosis, including leptin, adiponectin, testosterone, estradiol and inflammatory mediators (including: TNF alpha, IL-1 beta, IL-2, IL-5, IL-6, IL-8, IL-10, and IL-12) | Participants will undergo a series of measures at baseline and 6- and 12-months after study enrollment to assess the impact of the telephone-based lifestyle interventions upon biomarkers | 
| Changes in Physical Activity and Dietary Behaviors |  | Participants will undergo a series of measures at baseline and 6- and 12-months after study enrollment to assess the impact of the telephone-based lifestyle interventions upon physical activity | 
| Impact Upon Anthropometric Measures, Quality of Life and Fatigue |  | Participants will undergo a series of measures at baseline and 6- and 12-months after study enrollment to assess the impact of the telephone-based lifestyle interventions upon physical activity | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CM, bevacizumab, cyclophosphamide, methotrexate, exercise intervention, diet intervention