2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab

Study Overview
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Brief Summary
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First-line treatment of patients with locally recurrent or metastatic, HER2-negative breast cancer who have not received prior chemotherapy for locally recurrent or metastatic disease.

Detailed Description
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Arm A: Bevacizumab 10 mg/kg intravenous (i.v.), days 1 and 15, every 4 weeks Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks Arm B: Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks Capecitabine 1000 mg/m² twice-daily, days 1-14, every 3 weeks In both arms treatment will be given until first disease progression (PD), unacceptable toxicity or withdrawal of patient consent. For patients who stop chemotherapy for any reason before PD (e.g. toxicity) the other treatment should be given as monotherapy until PD.

Official Title
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A Randomized Phase III 2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab for the First-line Treatment of Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Locally Recurrent or Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Biological: Bevacizumab and Paclitaxel
* Biological: Bevacizumab and Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Written informed consent obtained prior to any study-specific procedure. Age ≥18 years. Able to comply with the protocol. Histologically or cytologically confirmed, HER2-negative, 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 radiotherapy or resection with curative intent. Eastern Cooperative Oncology Group (ECOG) performance Status (PS) of 0-2. Life expectancy more than 12 weeks. Prior (neo)adjuvant chemotherapy is allowed provided that the last dose of chemotherapy was more than 6 months prior to randomization. However, if (neo)adjuvant chemotherapy was: Taxane-based, patients are eligible only if they received their last taxane more than 12 months prior to randomization. Anthracycline-based, the maximum cumulative dose of prior anthracycline therapy must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin. Prior adjuvant radiotherapy is allowed as part of the treatment of early breast cancer provided that last fraction of radiotherapy occurred at least 6 months prior to randomization. Radiotherapy administered solely for the relief of metastatic bone pain is allowed prior to study entry, providing that: no more than 30% of marrow-bearing bone was irradiated the last fraction of radiotherapy was administered ≥ 3 weeks prior to randomization. Adequate left ventricular ejection function (LVEF) at baseline, defined as LVEF ≥ 50% by either echocardiogram or multigated acquisition scan (MUGA). Adequate hematological function Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Hemoglobin ≥ 9 g/dL (may be transfused to maintain or exceed this level). Adequate liver function Total bilirubin ≤ 1.25 x upper normal limit (ULN) Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) < 2.5 x ULN in patients without liver metastases; < 5.0 x ULN in patients with liver metastases. Adequate renal function Serum creatinine ≤ 1.25 x ULN or calculated creatinine clearance ≥ 50 mL/min. Urine dipstick for proteinuria < +2. Patients discovered to have ≥ +2 proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours The use of full-dose oral or parenteral anticoagulants is permitted as long as the patient has been on a stable level of anticoagulation for at least two weeks at the time of randomization Patients on heparin treatment should have a baseline activated partial thromboplastin time (aPTT) between 1.5 - 2.5 times ULN or patients value before starting heparin treatment Patients on low molecular weight heparins (LMWH) should receive daily dose of 1.5 - 2 mg/kg (of enoxaparin) or appropriate doses of the correspondent anticoagulant, according to package insert Patients on coumarin derivatives should have an international normalized ratio (INR) between 2.0 and 3.0 assessed at baseline in two consecutive measurements 1-4 days apart Patients not receiving anticoagulant medication must have an INR ≤ 1.5 and aPTT ≤ 1.5 times ULN within 7 days prior to randomization Exclusion Criteria Previous chemotherapy for metastatic or locally recurrent breast cancer. Concomitant hormonal therapy for locally recurrent or metastatic disease. Note: previous hormonal therapy is allowed for adjuvant, locally recurrent or metastatic breast cancer, but must have been discontinued at least 3 weeks prior to randomization. Previous radiotherapy for the treatment of metastatic disease (unless given for the relief of metastatic bone pain and with the precautions mentioned above). Other primary tumors within the last 5 years, except for adequately controlled limited basal cell carcinoma of the skin, or carcinoma in situ of the cervix. Pre-existing peripheral neuropathy NCI CTCAE grade > 2 at randomization. Evidence of spinal cord compression or current evidence of central nervous system (CNS) metastases (even if previously treated). If suspected, the patient should be scanned by CT or magnetic resonance imaging (MRI) within 28 days prior to randomization to rule out spinal / CNS metastases. History or evidence upon physical/neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures). 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, including insertion of an indwelling catheter, within 24 hours prior to randomization. Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day). Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids). History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg). Clinically significant (i.e. active) cardiovascular disease, requiring medication during the study and might interfere with regularity of the study treatment, or not controlled by medication. Non-healing wound, active peptic ulcer or bone fracture. History of abdominal fistula, or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of randomization. Active infection requiring i.v. antibiotics at randomization. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, 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 the 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 study drug. Men who do not agree to use effective contraception during the study and for a period of 6 months following the last administration of study drug. Current or recent (within 28 days of randomization) treatment with another investigational drug or participation in another investigational study Clinically significant malabsorption syndrome or inability to take oral medication. Psychiatric disability judged by the Investigator to be interfering with compliance for oral drug intake. Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine. 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. Known Dihydropyrimidine Dehydrogenase (DPD) deficiency or prior unanticipated severe reaction to fluoropyrimidine therapy (with or without documented DPD deficiency) Known hypersensitivity to any of the study drugs (including 5-FU) or excipients. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies. History of hypersensitivity reactions with drugs formulated in Cremophor® EL (polyoxyethylated castor oil), or previous therapy with bevacizumab.

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 |
| --- | --- |
| Active Comparator: A Bev+Pac<br>Bevacizumab plus Paclitaxel | Biological: Bevacizumab and Paclitaxel<br>* A: Bevacizumab 10 mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks<br>|
| Active Comparator: B Bev+Cap<br>Bevacizumab plus Capecitabine | Biological: Bevacizumab and Capecitabine<br>* B:Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks Capecitabine twice-daily 1000 mg/m², day 1 to 14, every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (PP Population) | Overall survival (OS) defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at Interim after 47% of information was 0.0010. Alpha spent at final analysis after 99% of information was 0.0250. | Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years | 
| Overall Survival (ITT Population) | Overall survival (OS) defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at Interim after 50% of information was 0.0014. Alpha spent at final analysis after 99% of information was 0.0250. | Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observation Time (ITT Population) | Median observation time estimated with reverse Kaplan-Meier methods. Observation time (in months) is defined as time from randomization to the day the patient was last confirmed to be alive. In case of patient deaths the time was censored at the day of death. | Up to approximately 6 years | 
| Best Overall Response (ITT Population) | The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | 
| Best Overall Response (PP Population) | The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | 
| Unconfirmed Best Overall Response (ITT Population) | The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment. | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | 
| Unconfirmed Best Overall Response (PP Population) | The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment. | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | 
| Objective Response Rate and Disease Control Rate (ITT Population) | Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | 
| Objective Response Rate and Disease Control Rate (PP Population) | Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | 
| Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population) | Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment. | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | 
| Unconfirmed Objective Response Rate and Disease Control Rate (PP Population) | Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment | Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years. | 
| Progression Free Survival (ITT Population) | Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization. Median PFS, associated stratified Hazard Ratio (HR). | Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years. | 
| Progression Free Survival (PP Population) | Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization. Median PFS, associated stratified Hazard Ratio (HR). | Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years. | 
| Time to Treatment Failure (ITT Population) | Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last. Median TTF, associated stratified Hazard Ratio (HR). | From first drug intake to progression, death or withdrawal from study treatment or study closure (whichever occurred first), assessed up to approximately 4.5 years | 
| Time to Treatment Failure (PP Population) | Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last. Median TTF, associated stratified Hazard Ratio (HR). | From first drug intake to progression, death or withdrawal from study treatment or study closure (whichever occurred first), assessed up to approximately 4.5 years | 
| Time to Response (ITT Population) | Time to response (TR) was defined as time from randomization until occurrence of response (complete response (CR) or partial response (PR)) according to RECIST criteria. Patients without response were censored after the longest time to response observed in any patient. Median TR, associated stratified Hazard Ratio (HR). Since the median TR was not observed, the number of subjects with a response at given timepoints were reported. | Time from randomization until occurrence of response, assessed up 1.7 years | 
| Time to Response (PP Population) | Time to response (TR) was defined as time from randomization until occurrence of response (complete response (CR) or partial response (PR)) according to RECIST criteria. Patients without response were censored after the longest time to response observed in any patient. Median TR, associated stratified Hazard Ratio (HR). Since the median TR was not observed, the number of subjects with a response at given timepoints were reported. | Time from randomization until occurrence of response, assessed up 1.7 years | 
| Duration of Response (ITT Population) | Duration of response (DR) was defined as time from date of first occurrence of any response (complete response (CR) or partial response (PR)) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment. Median DR, associated stratified Hazard Ratio (HR). | Time from first occurrence of CR or PR until disease progression, death or study closure, whichever occurred first, assessed up to 3.4 years after occurrence of response. | 
| Duration of Response (PP Population) | Duration of response (DR) was defined as time from date of first occurrence of any response (complete response (CR) or partial response (PR)) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment. Median DR, associated stratified Hazard Ratio (HR). | Time from first occurrence of CR or PR until disease progression, death or study closure, whichever occurred first, assessed up to 3.4 years after occurrence of response. |