| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patient with early and locally advanced triple negative (ER, PgR and HER2 negative) breast cancer |
|
| 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 | 10006187 |
|
| 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 assess the activity of this regimen in terms of pathological complete remission (pCR) rate |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of the combination
• To evaluate the percentage of breast conservative surgery
• To assess the objective response rate (clinical complete response plus partial response)
• To estimate the time to disease progression and the overall survival
• To assess the changes in Ki-67 index , EGFR pathway inhibition, and the effect of therapy on other markers characterizing triple negative disease diseases
• To study the gene expression profile predicting pathological complete response and the change in gene expression profile with therapy
• To study the correlation of VEGF genotype (SNPs) with response, toxicity outcome
• To study the possibility of early response assessment with contrast-enhanced dynamics MRI. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age 18 years and <75 years
Pre- or post-menopausal women with histologically proven, previously untreated, primary breast cancer stage II-IIIC
ER (< 1% by IHC) and PgR (< 1% by IHC) negative
HER2/neu not overexpressed (Fish negative, or IHC score 0-1+ , or IHC score 2+ AND FISH negative)
Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as 20 mm with conventional techniques
Availability of tumor tissue suitable for biological and molecular examination before starting primary treatment
ECOG performance status < 2 (Karnofsky 60%)
Normal organ and marrow function (leukocytes 3,000/uL, absolute neutrophil count 1,500/ul, platelets 100,000/uL, total bilirubin within normal institutional limits, AST(S-GOT)/ALT(S-GPT) <2.5 x institutional upper limit of normal, creatinine within normal institutional limits or creatinine clearance 60 mL/min
Cardiac ejection fraction within normal institutional limits defined as LVEF not below the institutional lower limit of normal by either echocardiogram or MUGA
Urine dipstick for proteinuria <2+. Patient discovered to have >2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demostrate < 1 g of protein/24hr
Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation
Ability to understand and the willingness to sign a written informed consent document. |
|
| E.4 | Principal exclusion criteria |
Presence of distant metastases
Patients receiving any others investigational agents
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, or minor surgical procedures within 24 hours prior to randomization
History of allergic reactions attributed to compounds of similar chemical or biologic composition used in the study
Uncontrolled intercurrent illness including, but not limited, to uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg)ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, symptomatic peripheral neuropathy, or psychiatric illness/social situations that would limit compliance with study requirements
Serious non-healing wound, peptic ulcer, or bone fracture
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of randomization
Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects of agents included in this trial. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding must be discontinued. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The pathological Complete Response, defined by complete absence of infiltrating tumor cells in the breast and in lymph nodes, will be evaluated according to the criteria of Miller and Payne.
Miller-Payne scale:
Grade 1 No change or some alteration to individual malignant cell, but no reduction in
overall cellularity
Grade 2 A minor loss in tumor cells (up to 30%)
Grade 3 Between an estimated 30 and 90% reduction in tumor cells
Grade 4 Marked disappearance of tumor cells, with only small cluster or dispersed cell
remaining (more than 90% loss)
Grade 5 No malignant identifiable cells. DCIS may be present.
To assess the safety profile, nature, incidence and severity of adverse events (AEs) and serious adverse events (SAEs) will be collected. Incidence of and reasons for study drug dose interruption or reduction and discontinuation will be collected
The rate of conservative surgery will be calculated as the percent difference between the number of conservative surgical procedures feasible at study entry and the number of the conservative procedures performed after primary therapy
The objective response rate (clinical complete response plus partial response) will be evaluated according to Recist criteria
The time to disease progression will be calculated as the interval between the randomization and the occurrence of local tumor progression (including ipsilateral and contra-lateral breast) or distant tumor progression
The overall survival will be calculated as the interval between the randomization and the death from any cause or the last date the patient was known to be alive
The percentage of inhibition of intermediate biomarkers of proliferation and apoptosis will be calculated as the difference between the staining scores before and after treatment. The association between the gene expression profiles and clinical/biological response will be evaluated.
The role of breast MRI in early prediction of response after a single dose bevacizumab will be evaluated by comparing the enhancement before, after 1 dose of single agent bevacizumab, and at the end of therapy. |
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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