Adjuvant Treatment for High-risk Triple Negative Breast Cancer Patients With the Anti-PD-l1 Antibody Avelumab
Adjuvant Treatment for High-risk Triple Negative Breast Cancer Patients With the Anti-PD-l1 Antibody Avelumab
Phase III randomized trial of the anti-PD-L1 antibody avelumab as adjuvant or
 post-neoadjuvant treatment for high-risk triple negative breast cancer patients. The overall
 protocol-defined patient population will include the following two strata of patients:

 -  Stratum A - Patients who have completed treatment with curative intent including surgery
 of the primary tumor followed by adjuvant chemotherapy .

 -  Stratum B - Patients who have completed treatment with curative intent including
 neoadjuvant chemotherapy followed by surgery of the primary tumor and (if indicated)
 further adjuvant chemotherapy.
-  to determine whether 1 year of adjuvant Avelumab improves disease-free survival (DFS)
 compared to observation in patients with high-risk primary triple negative breast cancer
 who have completed treatment with curative intent including surgery of the primary tumor
 and neo- or adjuvant chemotherapy (Stratum A [surgery of the primary tumor followed by
 adjuvant chemotherapy] and Stratum B [neoadjuvant chemotherapy followed by surgery]
 combined).

 -  to determine whether 1 year of adjuvant Avelumab improves disease-free survival (DFS)
 compared to observation in patients with high-risk primary triple negative breast cancer
 who have completed treatment with curative intent including neoadjuvant chemotherapy
 followed by surgery (Stratum B).

 -  to determine whether Avelumab improves overall survival (OS) compared to observation in
 patients with high-risk primary triple negative breast cancer who have completed
 treatment with curative intent including surgery of the primary tumor and neo- or
 adjuvant chemotherapy.

 -  to determine whether 1 year of adjuvant Avelumab improves disease-free survival (DFS)
 compared to observation in PD-L1-positive (as determined by a companion diagnostic test
 under development) patients with high-risk primary triple negative breast cancer who
 have completed treatment with curative intent including surgery of the primary tumor and
 neo- or adjuvant chemotherapy.
Inclusion Criteria Stratum A (Adjuvant patients) & B (Post-neoadjuvant patients)

 1. Male or female subjects aged > 18 years

 2. Signed written informed consent before any trial-related procedure is undertaken that
 is not part of the standard patient management

 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

 4. Patients must have completed treatment with curative intent including: surgery and
 adjuvant chemotherapy.

 5. Patients must have completed adjuvant chemotherapy including at least 3 courses of an
 anthracycline agent and 3 courses of a taxane agent. Patients who received dose-dense
 regimens and those who received carboplatin as part of the adjuvant treatment are
 eligible.

 6. No more than 10 weeks may elapse between the completion of last adjuvant treatment
 (adjuvant chemotherapy or surgery) and randomization.

 8. Normal organ and marrow function

 1. White blood count (WBC) greater than or equal to 2.5 x109/L

 2. Absolute neutrophil count (ANC) greater than or equal to 1.5 x109/L

 3. Absolute lymphocyte count greater or equal to 0.5 x109/L

 4. Platelet count greater than or equal to 100 x109/L

 5. Hemoglobin greater than or equal to 9 g/dL

 6. Serum creatinine less or equal to 1.5 x the upper limit of laboratory normal range
 (ULN)

 7. Adequate hepatic function defined by a total bilirubin level less or equal to 1.5 x
 ULN range and AST and ALT levels less or equal than 2.5 x ULN for all subjects. For
 patients with known Gilbert's syndrome, total bilirubin levels less or equal than 2 x
 ULN range (with direct bilirubin less than ULN) will be accepted.

 9. Highly effective contraception (i.e. methods with a failure rate of less than 1 %
 per year) for both male and female subjects if the risk of conception exists (Note:
 The effects of the trial treatment on the developing human fetus are unknown; thus,
 women of childbearing potential and men must agree to use highly effective
 contraception, defined in Appendix A or as stipulated in national or local guidelines.
 Highly effective contraception must be used 28 days prior to first trial treatment
 administration, for the duration of trial treatment, and at least for 60 days after
 stopping trial treatment. Should a woman become pregnant or suspect she is pregnant
 while she or her partner is participating in this trial, the treating physician should
 be informed immediately).

 10. Ability to understand and willingness to sign a written informed consent.

 Inclusion Criteria Stratum A (Adjuvant patients)

 1. Non-metastatic, histologically confirmed primary invasive breast carcinoma

 2. Triple negative breast cancer: hormone receptor negative (ER < 10% and PgR < 10%) and
 HER2 negative (IHC 0/1+ or ISH non-amplified), as defined by the local pathology
 laboratory. In case of discordance between pre-operative core-biopsy and the surgical
 sample, the receptor assessment performed on the surgical sample has to be considered
 for inclusion criteria evaluation.

 3. Availability of a formalin-fixed, paraffin-embedded block containing tumor tissue or
 at least 7 unstained tumor slides.

 4. Adequately excised: patients must have undergone either breast-conserving surgery or
 mastectomy/nipple- or skin-sparing mastectomy. The margins of the resected specimen
 should be free of invasive tumor and ductal carcinoma in situ (no ink on tumor). In
 the case of breast-conserving surgery patients with margins positive for lobular
 carcinoma in situ (LCIS) are eligible without additional resection. For patients who
 undergo mastectomy, patients with a microscopic positive deep margin are eligible,
 provided they will receive radiotherapy on chest wall.

 5. Patients must have had axillary lymph node dissection for evaluation of pathologic
 nodal status. Only patients in one of the following stage categories will be eligible:

 -  if 4 or more metastatic lymph nodes, any pT

 -  if 1 to 3 metastatic lymph nodes, pT >2 cm

 -  if no metastatic lymph nodes, pT >5 cm

 Inclusion criteria:

 Stratum B (Post-neoadjuvant patients)

 1. Non-metastatic histologically confirmed invasive breast carcinoma.

 2. Triple negative breast cancer: hormone receptor negative (ER < 10% and PgR < 10%) and
 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.

 3. Adequately excised: patients should have undergone adequate tumor excision after
 preoperative chemotherapy, which means surgical removal of all clinically evident
 disease in the breast and lymph nodes.

 1. Breast surgery: patients must have undergone either breast-conserving surgery or
 mastectomy/nipple- or skin-sparing mastectomy. The margins of the resected
 specimen should be free of invasive tumor and ductal carcinoma in situ (no ink on
 tumor). In the case of breast-conserving surgery patients with margins positive
 for lobular carcinoma in situ (LCIS) are eligible without additional resection.
 For patients who undergo mastectomy, patients with a microscopic positive deep
 margin are eligible, provided they will receive radiotherapy on chest wall.

 2. Lymph node surgery:

 i. Axillary dissection without sentinel node evaluation is permitted after
 preoperative therapy.

 ii. In case of positive results from a fine-needle aspiration, core biopsy, or
 sentinel node biopsy performed prior to preoperative therapy, additional surgical
 evaluation of the axilla following preoperative therapy is required.

 iii. If sentinel node biopsy performed before preoperative therapy was negative, no
 additional surgical evaluation of the axilla is required after preoperative therapy.

 iv. Sentinel node after preoperative therapy is allowed if no evidence of axillary
 node involvement was documented by ultrasonography at diagnosis. If sentinel node
 biopsy after preoperative therapy is negative, no further additional surgical
 evaluation of the axilla is required. If sentinel node biopsy performed after
 preoperative therapy is positive, additional surgical evaluation of the axilla is
 recommended.

 4. Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph
 nodes on the surgical specimen obtained after preoperative therapy (ypT1micN0,
 ypT1micN0i+, ypT0N0i+ will be excluded).

 5. Clinical stage at presentation: T1-4, N0-3, M0 (Exception: Patients with T1a/bN0
 tumors at presentation will not be eligible).

 6. No more than 10 weeks may elapse between the date of last treatment (surgery or
 post-surgery chemotherapy if indicated) and the date of randomization. In case of
 positive margins after the first intervention requiring additional resection.

 7. Availability of a formalin-fixed, paraffin-embedded block containing tumor tissue or
 at least 7 unstained tumor slides (tumor sample from the diagnostic core-biopsy
 obtained before neoadjuvant chemotherapy). In case only 7 unstained slides from the
 bioptic sample will be available, the investigator must ensure that the sample
 contains tumor tissue by performing an hematoxylin and eosin staining.

 Exclusion criteria: Stratum A (Adjuvant patients) & B (Post-neoadjuvant patients)

 1. Stage IV breast cancer.

 2. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma diagnosed
 within 10 years.

 3. Synchronous bilateral breast cancer, unless both tumors confirmed as triple negative
 disease.

 4. 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 the skin.

 5. Prior organ transplantation, including allogeneic stem-cell transplantation.

 6. Prior or concomitant treatment with any other investigational agents.

 7. 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).

 8. Concurrent anticancer treatment (for example, cytoreductive therapy, immune therapy,
 or cytokine therapy except for erythropoietin)

 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. Concomitant treatment with all herbal (alternative) remedies with immunostimulating
 properties (for example, mistletoe extract) or known to potentially interfere with
 major organ function (for example, hypericin).

 11. 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).

 12. Significant acute or chronic infections including, among others:

 1. Known history of testing positive test for human immunodeficiency virus (HIV) or
 known acquired immunodeficiency syndrome.

 2. 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).

 13. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
 agent:

 1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease
 not requiring immunosuppressive treatment are eligible.

 2. 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.

 3. Administration of steroids through a route known to result in a minimal systemic
 exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.

 14. Administration of steroids through a route known to result in a minimal systemic
 exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.

 15. 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.

 16. 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).

 17. Clinically significant (that is, active) cardiovascular disease: cerebral vascular
 accident /stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
 prior to enrollment), unstable angina, congestive heart failure (New York Heart
 Association Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia
 requiring medication.

 18. 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.

 19. Any psychiatric condition that would prohibit the understanding or rendering of
 informed consent.

 20. 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).

 21. Known alcohol or drug abuse.

 22. Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03 (except for
 grade 2 radiodermatitis and grade 2 neuropathy).

 23. Current pregnancy and/or lactation. Refusal to adopt adequate contraception methods.

 Stratum B (Postneoadjuvant patients)

 1. No invasive residual disease in the breast and axilla at pathological examination after
 neoadjuvant chemotherapy. ypT1micN0, ypT1micN0i+, ypT0N0i+ will also be excluded.