Bevacizumab in Combination With Chemotherapy in the Neo-adjuvant Setting for HER2 (-) Breast Cancer

Phase II, Open-label Non-randomized Trial to Investigate the Efficacy of Bevacizumab in Combination With Dose Dense Sequential Chemotherapy in the Neo-adjuvant Setting for HER2 Negative Breast Cancer Patients

Investigators propose to study the efficacy of Bevacizumab plus systemic chemotherapy prior to surgery in order to make a locally advanced tumor operable. Treatment is thus expected to induce a maximum tumor shrinkage within a short period (usually 3-6 months). In addition Bevacizumab (Avastin) is to be administered as early as possible during the disease stages. The primary aim of this study is to evaluate the preliminary antitumor activity in terms of pathological complete responses (pCR) of bevacizumab in combination with chemotherapy.

The aim of administering systemic therapy prior to surgery is to make a locally advanced tumor operable or to allow conservative surgery in the case of a T2-T3 tumor. Therefore, treatment is expected to induce a maximum tumor shrinkage within a short period. In addition and based on the anti-angiogenic MoA, bevacizumab (Avastin) is to be administered as early as possible during the disease stages. Bevacizumab has already been tested in the neoadjuvant setting with encouraging results. In a first trial patients with inoperable locally advanced breast cancer received docetaxel with or without bevacizumab with five clinical Complete Responses and 24 Partial Responses. In a second trial there was also reported the results of the combination of bevacizumab with doxorubicin and docetaxel for the treatment of inflammatory breast cancer. Then, a set of studies of primary therapy exploring the activity of different regimens have confirmed the role of baseline pathological features of the tumor in predicting the responsiveness to primary therapy. A 22% pathological complete responses (pCR) rate has been achieved in a study combining bevacizumab together with Xeloda and Taxotere suggesting that bevacizumab addition to chemotherapy in the neoadjuvant treatment is feasible showing promising activity while no unexpected toxicities were reported.

Thus, a very high interest exists from our clinicians mostly within our cooperative groups which cover the largest national oncology centers to be involved and run such a study.

Inclusion Criteria:

• Female patients with histologic proven, corebiopsied, invasive ductal adenocarcinoma of the breast >2 cm in size and of any N stage (clinical and/or radiological T-stage > T1, including T4d), scheduled to receive preoperative chemotherapy.

• Age 18-70 years

• ECOG performance-status ≤1

• No prior or current neoplasm except for curatively treated non melanoma skin cancer, in situ carcinoma of the cervix

• No distant disease/secondary carcinoma

• Normal cardiac function

• Results of the following assessments at the time of inclusion must be available:

  1. bilateral Mammography (before enrolment)
  2. histology
  3. grading
  4. hormone-receptor-status
  5. HER2 status negative (is defined as FISH/CISH negative or IHC0 or IHC1+, or IHC2+ and FISH/CISH negative)

• Laboratory requirements (within 1 week before enrolment):

  1. Hematology: Neutrophils ≥ 1.5 x 109/l, Platelets ≥ 100 x 109/l, Hemoglobin>11 g/dl
  2. Hepatic function: Total bilirubin < 1 x ULN, SGOT and SGPT < 1.5 x ULN, Alkaline phosphatases < 1.5 x ULN. In case of abnormal values, the liver function tests have to be repeated within 3 days before study treatment.
  3. Renal function: Creatinine < 1 x ULN
  4. Urinalysis: Urine dipstick of proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1 g of protein / 24 hours.

• Signed and dated Informed Consent before the start of specific protocol procedures

• If of childbearing potential, negative pregnancy test

Exclusion Criteria:

• Cytological only confirmation of diagnosis
• Lobular or other non-ductal types of breast cancer
• Pregnant, or lactating patients; patients of childbearing potential must implement adequate contraceptive measures during study participation
• Pre-existing motor or sensory neurotoxicity of a severity > grade 2 by NCI-CTC AE
• Preoperative local treatment for breast cancer (i.e. incomplete surgery, radiotherapy)
• Prior or concurrent systemic antitumor therapy
• Evidence of wound healing complications, bone fracture, ulcer or the presence of clinically significant peripheral vascular disease
• Clinically significant cardiac disease e.g. congestive heart failure.
• Other serious illness or medical condition-uncontrolled hypertension or high risk uncontrolled arrythmias -history of significant neurologic or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent-active uncontrolled infection-unstable peptic ulcer, unstable diabetes mellitus or other contraindication for the use of corticosteroids
• Known hypersensitivity reaction to the compounds or incorporated substances.
• Evidence of bleeding diathesis or coagulopathy
• The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR, or appropriate monitoring test is within therapeutic limits and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of randomization. Patients not receiving anti coagulant medication must have an INR ≤ 1.5 an aPTT ≤ 1.5 x ULN within 7 days of randomization.
• Ongoing treatment with aspirin (> 325mg / day) or other medications known to predispose to gastrointestinal ulceration.
• Major surgery (including open biopsy), significant traumatic injury within 28 days prior to enrolment.
• Minor surgery, including insertion of an indwelling catheter, within 24 hours prior to the first bevacizumab infusion
• Treatment with an investigational drug within 30 days prior to study entry.
• Legally incapacitated and/or other circumstances which make it undesirable for the subject to understand the nature, meaning and consequences of the clinical study