| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006198 |
| E.1.2 | Term | Breast cancer recurrent |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To show non-inferiority of Arm B versus Arm A in terms of overall survival (OS). Overall survival is assessed from randomization until date of death. |
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| E.2.2 | Secondary objectives of the trial |
To compare in Arms A and B:
• Overall response rate (ORR) RECIST criteria
• Progression Free Survival (PFS) will be assessed from randomization until the occurrence of PD or death
• Time to response will be assessed from randomization until the occurrence of any response
• Duration of response (DR) assessed from date of occurrence of any response (CR or PR) until the occurrence of PD or death
• Time to treatment failure (TTF) assessed from first drug intake until the occurrence of PD, death or withdrawal of therapy
• Safety
• Quality of life (QoL) EORTC-QLQ-30
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained prior to any study-specific procedure.
2. Age at least 18 years.
3. Able to comply with the protocol.
4. 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.
5. ECOG performance status of 0–2.
6. Life expectancy more than 12 weeks.
7. 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.
8. 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 at least 3 weeks prior to randomization
9. Adequate left ventricular ejection function at baseline, defined as LVEF at least 50% by either echocardiogram or MUGA.
10. Adequate hematological function
– Absolute neutrophil count (ANC) at least 1.5 x 109/L
– Platelet count at least 100 x 109/L
– Hemoglobin at least 9 g/dL (may be transfused to maintain or exceed this level).
11. Adequate liver function
– Total bilirubin ≤ 1.25 x upper normal limit (ULN)
– AST, ALT ≤ 2.5 x ULN in patients without liver metastases; ≤ 5.0 x ULN in patients with liver metastases.
12. Adequate renal function
– Serum creatinine ≤ 1.25 x ULN or calculated creatinine clearance at least 50 mL/min.
– Urine dipstick for proteinuria < +2. Patients discovered to have more or equal to +2 proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate below 1g of protein in 24 hours
13. 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 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 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
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| E.4 | Principal exclusion criteria |
1. Previous chemotherapy for metastatic or locally recurrent breast cancer.
2. 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.
3. Previous radiotherapy for the treatment of metastatic disease (unless given for the relief of metastatic bone pain and with the precautions mentioned above).
4. 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.
5. Pre-existing peripheral neuropathy NCI CTCAE grade > 2 at randomization.
6. 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.
7. History or evidence upon physical/neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
8. 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.
9. Minor surgical procedures, including insertion of an indwelling catheter, within 24 hours prior to randomization.
10. Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day).
11. Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
12. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
13. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg).
14. 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.
15. Non-healing wound, active peptic ulcer or bone fracture.
16. History of abdominal fistula, or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of randomization.
17. Active infection requiring i.v. antibiotics at randomization.
18. 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.
19. 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.
20. 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.
21. Current or recent (within 28 days of randomization) treatment with another investigational drug or participation in another investigational study
22. Clinically significant malabsorption syndrome or inability to take oral medication.
23. Psychiatric disability judged by the Investigator to be interfering with compliance for oral drug intake.
24. Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine.
25. 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.
26. Known DPD deficiency or prior unanticipated severe reaction to fluoropyrimidine therapy (with or without documented DPD deficiency)
27. 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary study endpoint is overall survival. OS will be assessed from randomization until time of death.
The safety analyses will include listings and frequency tables for adverse events. For laboratory data, listings, frequency tables and shift tables will be provided
The Intent-To-Treat population (ITT) consists of all consenting patients randomized into the study. The safety population comprises all patients who received at least one dose of study medication. The Per-Protocol population excludes all patients who violated inclusion or exclusion criteria of the protocol.
The primary efficacy analysis will be based on the Per Protocol population being primarily a non-inferiority trial. Major efficacy analyses will be repeated using the ITT population to confirm the overall study results. All safety analyses will be based on the safety population.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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