Bevacizumab, Metronomic Chemotherapy (CM), Diet and Exercise After Preoperative Chemotherapy for Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Bevacizumab; Cyclophosphamide; Methotrexate; Lifestyle: Diet; Lifestyle: Diet+Exercise
Intervention MeSH terms: Cyclophosphamide; Bevacizumab; Methotrexate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CM; bevacizumab; cyclophosphamide; methotrexate; exercise intervention; diet intervention

Summary:

      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.
    

Eligibility criteria:

        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