| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High risk triple negative (ER negative, PR negative, HER2 negative) breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 Avelumab ability to improve “disease free survival rates”, compared to receiving no treatment, for patients with a diagnosis of high-risk triple negative breast cancer who have already completed treatment with curative intent including surgery and chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives are:
To determine whether avelumab improves overall survival (OS) compared to observation in patients with high-risk primary triple negative breast cancer.
To determine whether avelumab improves “disease free survival rates”, compared to receiving no treatment, for patients that have a diagnosis of high-risk triple negative breast cancer who also have a particular marker (PD-L1) on their tumour cells and have already completed treatment with curative intent including surgery and chemotherapy.
The safety objective is to assess the overall safety of avelumab administered in patients with high-risk primary triple negative breast cancer.
Exploratory objectives are to explore biomarkers (including, but not limited to, CD8, Foxp3, MHC-I, PD-L2, gene expression, circulating tumour DNA, cytokines and intestinal microbiota composition), in tumour tissue, plasma and faecal samples that may be relevant to the mechanism of action of, or efficacy, or resistance |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Male/female aged>18 years
-Signed informed consent
-ECOG performance status 0/1
-Non-metastatic histologically confirmed primary invasive breast carcinoma
-Normal organ & marrow function
-Highly effective contraception for male & female subjects (from 28 days prior to trial treatment to at least 60 days after stopping trial treatment)
- FFPE block containing tumor tissue or at least 7 unstained tumor slides
Specific Stratum A:
-TNBC: hormone receptor (ER<10% & PgR<10%) & HER2 negative (IHC0/1+ or ISH non-amplified). If discordance between pre-operative core-biopsy & surgical sample, receptor assessment on surgical sample has to be considered for inclusion criteria evaluation
-Completed treatment with curative intent including surgery & adjuvant chemotherapy
-Adequately excised: have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy. Margins of resected specimen should be free of invasive tumor & ductal carcinoma in situ (CIS). In the case of breast-conserving surgery patients with margins positive for lobular CIS are eligible without additional resection. Patients who undergo mastectomy or with a microscopic positive deep margin are eligible, provided radiotherapy on chest wall is planned.
-Had axillary lymph node (LN) dissection for evaluation of pathologic nodal status. Must meet 1 of:
a. if 4 or more metastatic LN, any pT
b. if 1 to 3 metastatic LN, pT>2cm
c. if no metastatic LN, pT>5cm
-Had adjuvant chemotherapy after surgery. Adjuvant treatment should have included at least 3courses of an anthracycline agent & 3courses of a taxane agent. Patients who cannot complete all planned treatment cycles for any reason are considered high risk & therefore are eligible for the study. Patients who received dose-dense regimens & those who received carboplatin as part of the adjuvant treatment are eligible
-No more than 10weeks may elapse between the completion adjuvant chemotherapy&randomization
Specific Stratum B:
-TNBC: hormone receptor negative (ER < 10% & PgR < 10%) & HER2 negative (IHC 0/1+ or ISH non-amplified), as defined by the local pathology laboratory. In case of discordance between the pre-treatment diagnostic core-biopsy and the surgical sample, the receptor assessment performed on the surgical sample has to be considered for inclusion criteria evaluation.
-Patients must have completed treatment with curative intent including: neoadjuvant chemotherapy & surgery
-Adequately excised: patients should have undergone adequate tumor excision after preoperative chemotherapy, which means surgical removal of all clinically evident disease in the breast & LN’s
a. Must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy. Margins of resected specimen should be free of invasive tumor & ductal CIS. In the case of breast-conserving surgery patients with margins positive for lobular CIS are eligible without additional resection. Patients who undergo mastectomy, patients with a microscopic positive deep margin are eligible, provided radiotherapy on chest wall is planned
b. LN surgery:
-Axillary dissection without sentinel node evaluation is permitted after preoperative therapy
-If positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy(SNB) performed prior to preoperative therapy, additional surgical evaluation of the axilla following preoperative therapy is required
-If SNB performed before preoperative therapy was negative, no additional surgical evaluation of the axilla is required after preoperative therapy
-Sentinel node after preoperative therapy is allowed if no evidence of axillary node involvement was documented by ultrasonography at diagnosis. If SNB after preoperative therapy is negative, no further additional surgical evaluation of the axilla is required. If SNB performed after preoperative therapy is positive, additional surgical evaluation of the axilla is recommended
-Pathologic evidence of residual invasive carcinoma in the breast &/or axillary LN’s on the surgical specimen obtained after preoperative therapy (ypT1micN0, ypT1micN0i+, ypT0N0i+ will be excluded)
-Clinical stage at presentation: T1–4,N0–3,M0 (T1a/bN0 tumors will not be eligible)
-Completed neoadjuvant chemotherapy before surgery. Neoadjuvant treatment should have included at least 3 courses of an anthracycline agent & 3 courses of a taxane agent. Patients who cannot complete all planned cycles are considered high risk & therefore are eligible. Patients who received dose-dense regimens & those who received carboplatin as part of the adjuvant treatment are eligible
-No more than 10 weeks may elapse between the surgery & randomization. If positive margins after first intervention requiring additional resection, interval of 10 weeks will be calculated from date of last surgery
|
|
| E.4 | Principal exclusion criteria |
1. Metastatic breast cancer.
2. Synchronous bilateral breast cancer, unless both tumors confirmed triple negative disease.
3. History of non-breast malignancies within the 5 years prior to study entry, except for the following: Carcinoma in situ (CIS) of the cervix, CIS of the colon, Basal cell and squamous cell carcinomas of skin.
4. Prior organ transplantation, including allogeneic stem-cell transplantation.
5. Prior or concomitant treatment with any other investigational agents.
6. Prior therapy with any antibody / drug targeting T-cell coregulatory proteins (immune
checkpoints) such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4 (CTLA-4).
7. Concurrent anticancer treatment (e.g. cytoreductive therapy, immune therapy, cytokine therapy except for erythropoietin). If indicated, radiotherapy to the operated breast/chest wall/locoregional lymph nodes is admitted
8. Concomitant treatment with all herbal (alternative) remedies with immunostimulating properties (for example, mistletoe extract) or known to potentially interfere with major organ function (e.g. hypericin)
9. Major surgery for any reason, within 4 weeks of randomization and / or if the subject has not fully recovered from the surgery within 4 weeks of randomization
10. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs before initiation of the trial treatment (with the exception of subjects with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, equivalent to ≤ 10 mg prednisone daily)
11. Significant acute or chronic infections including, among others:
a. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
b. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
12. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent:
a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
b. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or equivalent prednisone per day
13. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
14. Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the daily dose after 14 days will be ≤ 10 mg per day of equivalent prednisone
15. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
16. Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident /stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication
17. All other significant diseases (for example, inflammatory bowel disease), which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment
18. Any psychiatric condition that would prohibit the understanding or rendering of informed consent
19. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines)
20. Known alcohol or drug abuse
21. Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03 (however, alopecia, grade 2 neuropathy and any other grade 2 not constituting a safety risk based on investigator’s judgement are acceptable)
22. Current pregnancy and/or lactation. Refusal to adopt adequate contraception methods
Criteria specific for Stratum A :
1. Patients in any of the following stage categories are not eligible:
- 1 to 3 metastatic axillary lymph nodes and pT<2cm;
- 0 metastatic axillary lymph nodes and pT<5cm. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma diagnosed within 10 years
Criteria specific for Stratum B :
1. No invasive residual disease in the breast and axilla at pathological examination after neoadjuvant chemotherapy. ypT1micN0, ypT1micN0i+, ypT0N0i+ will also be excluded
2. History of any prior (ipsi- and/or contralateral) invasive breas |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure for this study is disease-free survival (DFS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| DFS will be calculated as the time interval between randomization and any of the following events, whichever first: local, regional and distant recurrence; second primary breast cancer, excluding in situ carcinoma; other second primary cancer (excluding in-situ cancers); death before recurrence or second primary cancer. |
|
| E.5.2 | Secondary end point(s) |
Efficacy objective: Overall survival (OS) in all patients, and DFS in PD-L1 positive patients.
Safety objective: Assess the overall safety of Avelumab
Exploratory objective: Explore the molecular, soluble and microbiological biomarkers (including, but not limited to, CD8, Foxp3, MHC-I, PD-L2, gene expression, circulating tumor DNA,cytokines and intestinal microbiota composition), that may be relevant to the mechanism of action of, or efficacy/resistance to Avelumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: The OS will be calculated as the time-interval between randomization and patient death or last follow-up.
Safety: Assessed at all study visits and analysed at the end of the study.
Exploratory: When final patients submits last sample. |
|
| 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 | 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) | No |
| 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
| 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.8.6 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 | No |
| 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 occurs when all of the following criteria have been satisfied:
1. The trial is mature for the analysis of the primary/co-primary endpoints as defined in the protocol
2. The database has been fully cleaned and frozen for analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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