E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally recurrent (LR) or metastatic breast cancer (mBC) progressing after first-line chemotherapy and bevacizumab treatment. |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10055113 |
E.1.2 | Term | Breast cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 determine the clinical benefit of continued or re-induced bevacizumab treatment in combination with secondline chemotherapy for patients with LR or mBC who have progressed after treatment with first-line chemotherapy combined with bevacizumab, as measured by second-line progression-free survival (PFS). |
|
E.2.2 | Secondary objectives of the trial |
To further evaluate the efficacy and characterize the safety of continued treatment with bevacizumab in
combination with second and subsequent lines of chemotherapy as measured by the following:
• Third-line PFS
• Second- and third-line PFS
• Second-line PFS in stratified subgroups
• Overall survival (OS)
• One-year survival
• Second-line Overall response rate (ORR) in patients with measurable disease at baseline
• Quality of life (QoL)
• Safety profile |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent prior to initiation of any study-specific procedures or treatment, as confirmation of the patient’s awareness and willingness to comply with the study requirements
2. Female patients ≥18 years of age
3. Histologically confirmed HER2-negative adenocarcinoma of the breast with documented progression of disease per investigator assessment following or during first-line treatment with bevacizumab in combination with chemotherapy for LR or mBC; patients can have measurable or non-measurable disease.
4. A minimum of 4 cycles of bevacizumab 15 mg/kg or 6 cycles 10 mg/kg received in the first-line setting. Note:
patients who have received bevacizumab treatment as part of (neo-) adjuvant therapy are eligible but these
bevacizumab cycles do not count towards the minimum required number of cycles.
5. Patients must have received bevacizumab in combination with chemotherapy. Patients may have received:
• Bevacizumab monotherapy
• Bevacizumab in combination with endocrine treatment
• Endocrine treatment
• Nothing
as part of their maintenance treatment.
6. ECOG performance status (PS) of 0 or 2
7. At least 28 days since prior radiation therapy or surgery and recovery from treatment
8. Estimated life expectancy of ≥12 weeks |
|
E.4 | Principal exclusion criteria |
Disease-specific exclusions
1. Patients who have received anti-angiogenic therapy or anti-vascular endothelial growth factors other than bevacizumab for the first-line treatment of LR/mBC
2. Patients who have exclusively received endocrine treatment in combination with bevacizumab until the first
progression
3. Positive or unknown HER2/neu status or for whom determination of HER2 status is not possible. In general, HER2-positive status will be identified by a FISH assay as evaluated at the institution, or, if FISH is unavailable, a 2+ or 3+ immunohistochemistry result.
4. Current, recent or planned participation in an experimental drug study - other than a bevacizumab breast cancer study.
5. Active malignancy, other than superficial basal cell and superficial squamous cell, or carcinoma in situ of the cervix or breast within the last 5 years
6. Any laboratory values at baseline as follows:
Hematology:
ANC <1.5x10E9/L or 1500/mm3
Platelet count <75x10E9/L
Hemoglobin <8 g/dL
Coagulation:
INR >1.5 except for patients on stable anticoagulant therapy
aPTT ≥1.5 times ULN or greater than the lower limit of the therapeutic range
Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of
Day 1,
Cycle 1.
Serum chemistry:
Total bilirubin >1.5 times ULN
AST or ALT >2 times ULN
ALP >2 times ULN
7. Inadequate renal function, defined as:
Creatinine clearance <50 mL/min Urine dipstick for proteinuria ≥2+ unless a 24-hour protein ≤1 g is demonstrated
8. Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would prevent the patient from meeting the study requirements
9. Serious active infection requiring i.v. antibiotics and/or hospitalization at study entry
10. Patients who are treated with any medicinal product that contraindicates the use of any of the study drugs, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatmentrelated
complications
Bevacizumab-specific exclusions
11. Inadequately controlled hypertension while receiving anti-hypertensive medication
12. Prior history of hypertensive crisis or hypertensive encephalopathy
13. Prior history of nephrotic syndrome
14. New York Heart Association (NYHA) Class II or greater congestive heart failure (CHF). Note: For those patients where it is indicated an ECHO/MUGA must be performed. The LVEF must be above the institutional lower limit of normal in order for the patient to be eligible.
15. History of myocardial infarction or unstable angina within 6 months prior to day 1
16. History of stroke or transient ischemic attack (TIA) within 6 months prior to day 1
17. Known CNS disease, except for treated brain metastases. Treated brain metastases are defined as: having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging during the screening period. Anticonvulsants are allowed.
Treatment for brain metastases may include whole brain radiotherapy, radiosurgery or a combination as deemed
appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 are excluded. A brain or MRI scan is required within 28 days prior to day 1 if the presence of untreated brain metastases is suspected.
18. Significant vascular disease within 6 months prior to day 1
19. Any previous venous thromboembolism > NCI-CTCAE Grade 3
20. History of hemoptysis within 1 month prior to day 1
21. Evidence of bleeding diathesis or significant coagulopathy.
22. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1, or
anticipation of need for major surgical procedure during the course of the study
23. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to day 1
24. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to day 1
25. Serious, non-healing wound, active ulcer, or untreated bone fracture
26. Known hypersensitivity to any component of bevacizumab or any of the study drugs
27. Pregnant or lactating females.
28. Chronic, daily treatment with high-dose aspirin or clopidogrel
29. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of bevacizumab or any of the study drugs that may affect the interpretation of the results or render the patient at high risk for treatment complications. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Second-line progression-free survival (PFS), defined as the time from randomization to the first documented disease progression or death from any cause, whichever occurs first. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from randomization to the first documented disease progression or death from any cause, whichever occurs first. |
|
E.5.2 | Secondary end point(s) |
1) 3rd-line PFS
2) 2nd- and 3rd-line PFS
3) 2nd-line PFS in stratified subgroups
4) 2nd-line overall response rate (ORR), overall survival (OS), one-year survival, QoL. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 3rd-line PFS is defined as the time from the start of 3rd-line treatment to the documented 3rd-line disease progression or death from any cause, whichever occurs first.
2) 2nd- and 3rd-line PFS is the time from randomization to the documented disease progression in 3rd-line treatment or death from any cause, whichever occurs first.
3) Time from randomization to the first documented disease progression or death from any cause, whichever occurs first.
4) ORR timepoint will be similar to the primary endpoint.
OS is defined as the time from randomization to death from any cause.
1-year survival is defined as the number of patients alive at 12 months after randomization.
QOL is assessed at the time of primary endpoint |
|
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 | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Dynamic biomarkers; Quality of life |
|
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.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 135 |
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 | No |
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 |
Argentina |
Austria |
Brazil |
Croatia |
France |
Germany |
Greece |
Hungary |
Italy |
Spain |
Israel |
Slovakia |
Switzerland |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
End of study will occur when all patients have been followed up for at least 24 months after randomization, unless they have been lost to follow-up, withdrawn consent, or died, or if the trial is prematurely terminated by the Sponsor, whichever occurs first |
|
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 |