Phase II randomized trial of combination therapy of paclitaxel and bevacizumab versus paclitaxel, capecitabine and bevacizumab as first-line treatment for locally recurrent or metastatic breast cancer patients with HER2/neu negative tumor

1. Patients with histologically or cytologically confirmed, HER2/neu-negative, pre- or postmenopausal adenocarcinoma of the breast with measurable or non-measurable locally recurrent or metastatic disease, who are candidates for chemotherapy. Locally recurrent disease must not be amenable to resection and/or radiotherapy with curative intent.

2. Documented ER/PR status

3. HER2/neu-negative disease as determined by immunohistochemistry or FISH/CISH

4. Prior adjuvant chemotherapy is allowed provided that the last dose of chemotherapy was not within 6 months (not within 12 months if taxane-based) prior to randomization.

5. Prior maximum cumulative dose must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin

6. Female only

7. Age > 18 years and ≤ 75 years

8. ECOG PS of 0 or 1

9. Life expectancy of > 12 weeks

10. Able to comply with the protocol

11. Written informed consent (Informed Consent document to be approved by the institution’s Independent Ethics Committee [IEC]) obtained prior to any study specific screening

* Previous treatment

• Previous chemotherapy for locally recurrent or metastatic breast cancer

• Prior hormonal therapy for locally recurrent or metastatic disease should have been discontinued at least 2 weeks before randomization.

• Patients with bone metastases only are allowed provided that they are on bisphosphonate treatment > 3 months.

- Patients who have received adjuvant radiotherapy as part of the treatment of early breast cancer are eligible if the last fraction of radiotherapy was administered at least 6 months prior to randomization. Radiotherapy administered for the relief of metastatic bone pain is allowed prior to study entry, but

• no more than 30% of marrow-bearing bone should have been irradiated

• the last fraction of radiotherapy should not have been administered within 3 weeks prior to randomization.

- Other primary tumors within the last 5 years before inclusion, except for adequately controlled basal cell carcinoma of the skin, or carcinoma in situ of the cervix



* Neurological signs and symptoms

- Previous or current CNS metastases. A CT or MRI of the brain must be performed within 4 weeks prior to randomization if the presence of metastases at this site is suspected.

- History or evidence upon physical/neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy e.g. uncontrolled seizures.

- Pre-existing peripheral neuropathy ≥ NCI-CTC (version 3.0) grade 1 at randomization



* Hematology, coagulation and biochemistry

- Inadequate bone marrow function: ANC: < 1.5 x 109/L, platelet count < 100 x 109/L and hemoglobin < 6 mmol/L.

- Patients with INR > 1.5 x ULN and/or aPTT > 1.5 x ULN within 7 days prior to randomization

- Inadequate liver function:

• Serum (total) bilirubin above the normal limit for the institution, and or

• ASAT & ALAT > 2.5 x ULN ( > 5 x ULN in patients with liver metastases) Patients are not eligible for the study if they have ASAT/ALAT levels > 1.5 x ULN concurrent with:

- serum alkaline phosphatase levels of > 2.5 x ULN at baseline
or

- ASAT/ALAT > ULN concurrent with alkaline phosphatase > 6 x ULN

- Inadequate renal function:

• Serum creatinine > 177 µmol/L or calculated creatinine clearance < 30 mL/min.

Note: In patients with moderate renal impairment (calculated creatinine clearance 30-50 mL/min) at baseline, a dose reduction to 75% of the capecitabine starting dose is recommended.

• Urine dipstick for proteinuria ≥ 2+. Patients with ≥ 2+proteinuria on dipstick analysis at baseline should undergo a 24-hour urine collection and must demonstrate < 1 g of protein/24 h.



* Cardiovascular problems

- Current or recent use (within 10 days of first dose of bevacizumab) of aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day). No therapeutic treatment with LMWH or oral anticoagulants. Prophylactic doses of LMWH are allowed.

- History or evidence or inherited bleeding diathesis or coagulopathy with the risk of bleeding

- History of cerebrovascular accident

- Arterial or venous thrombosis ≤ 12 months prior to registration

- Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm
Hg) or clinically significant (i.e. active) cardiovascular disease: CVA/stroke (≤ 6 months prior to randomization), myocardial infarction (≤ 6 months prior to randomization), unstable angina, New York Heart Association (NYHA) class ≥ II congestive heart failure, or serious cardiac arrhythmia requiring medication that might interfere with protocol treatment or not controlled by medication.

- Inadequate left ventricular ejection fraction at baseline. LVEF by MUGA or ECHO must be ≥ 50% and should be performed within 4 weeks prior to randomization if cardiac failure is suspected.



* Wounds and infection

- Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study treatment

- Minor surgical procedures within 24 hours prior to treatment, including insertion of an indwelling catheter

- Serious non-healing wound, active peptic ulcer, or non-healing bone fracture

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of randomization

- Active infection requiring i.v. antibiotics at randomization




* Other

- Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to randomization, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.

- Women of childbearing potential (< 2 years after last menstruation) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile), during the study and for a period of 6 months following the last administration of treatment.

- Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect patient compliance with study routines, or places the patient at high risk from treatment related complications.

- Psychiatric disability judged by the investigator to be interfering with compliance for oral drug intake should be excluded from the study



* Hypersensitivity, investigational agents, co-medication

- Known hypersensitivity to any of the study drugs or excipients

- Hypersensitivity to Chinese hamster ovary cell products or recombinant human or humanized antibodies

- Clinically significant malabsorption syndrome, or inability to take oral medication

- Current or recent (within 30 days of inclusion) treatment with another investigational drug or participation in another investigational study

- Chronic daily treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids)

- Requirement for concurrent use of the antiviral agent sorivudin (antiviral) or chemically related analogues, such as brivudine

- Patients with a known DPD deficiency