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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Breast Cancer

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Trial Information

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


- Because no one knows which of the study options are 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.

- Participants assigned to groups 1 or 2 will receive a diet intervention or diet and
exercise intervention. They will be seen by the doctor for physical examination every
12 weeks for the first two years during the intervention, and then on an every 6 month
basis. Routine laboratory testing will be done at the time of the visits as well.
Other blood tests will be done to measure the effect of the diet and exercise
interventions at the beginning of the treatment, at 6 months, and at 1 year from the
start of the treatment. Additionally, one blood test will be done at the beginning of
the treatment to look for hereditary differences in genes related to metabolism.

- Participants assigned to groups 3 or 4 will undergo the following: Medication:
Participants that are placed in the bevacizumab and cyclophosphamide and methotrexate
(CM) arm will receive bevacizumab intravenously once every 3 weeks for approximately 6
months, followed by every 6 week treatments for additional 1.5 years; cyclophosphamide
orally once a day and methotrexate orally twice a day for the first two days of each
week. The treatments with CM therapy and bevacizumab will continue for approximately 6
months. Physical Exams: once 6 weeks of drug therapy (2 cycles)is completed, physical
examination frequency is reduced to every 6 weeks (every other cycle) for the
additional 6 cycles. Once 24 weeks of drug therapy (8 cycles or about 6 months since
the start of therapy) are completed, physical examination will be done every 12 weeks
for the duration of protocol therapy. Blood Tests: chemistry and hematology testing
will be done prior to start of Cycles 1, 2 and 3 and then every 6 weeks (every other
cycle) for the duration of cyclophosphamide and methotrexate chemotherapy. After 24
weeks (8 cycles) of drug treatment, hematology/chemistry testing frequency can be
reduced to every 12 weeks (every other cycle) for the rest of bevacizumab treatment.
Urine Tests will be done every other cycle for the duration of treatment. Heart
function testing by echocardiogram will be done at 6 months, 1, 2, and 3 years after
participants start the study. Ultrasound of the blood vessels will be done on those
randomized to receive bevacizumab with CM chemotherapy. This test will be done at
baseline and after completion of the first and second cycles of therapy.

- Activities for all Groups: Lifestyle Intervention: All women in this study will
complete a number of tests at baseline, 6 and 12 months. Diet Only Group:
Participants assigned to this group will be asked to participate in a series of 13
telephone calls over the course of 1 year with. Those assigned to the Diet and
Exercize Group (in addition to the information listed above) will receive counseling
targeted toward increasing physical activity.


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recurrence-free survival

Outcome Description:

To compare the recurrence-free survival, defined as time on study before local, regional, or distant tumor recurrence, in patients who are randomized to post-neoadjuvant angiogenesis inhibitor therapy compared to those who are randomized to not receive the angiogenesis inhibitor therapy.

Outcome Time Frame:

2 years

Safety Issue:

No

Principal Investigator

Erica Mayer, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

09-134

NCT ID:

NCT00925652

Start Date:

September 2010

Completion Date:

September 2017

Related Keywords:

  • Breast Cancer
  • CM
  • bevacizumab
  • cyclophosphamide
  • methotrexate
  • exercise intervention
  • diet intervention
  • Breast Neoplasms

Name

Location

Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Faulkner HospitalJamaica Plain, Massachusetts  02130
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Duke University Medical CenterDurham, North Carolina  27710
University of North Carolina Lineberger Comprehensive Cancer CenterChapel Hill, North Carolina  27599
Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical CenterMilford, Massachusetts  01757
Indiana Unversity Simon Cancer CenterIndianapolis, Indiana  46202