Amendment 1: The study protocol and informed consent form (ICF) were amended to implement substantial changes in the durvalumab investigator’s brochure (IB durvalumab Edition 9.0 [2016-01-22] which overruled Edition 8.0 [2015-09-01]). Mainly these changes related to the frequency of AEs in the so far 910 patients investigated within clinical studies. Moreover, the definition of progressive disease was corrected to 25% increase to reflect WHO criteria. Within the laboratory requirements for inclusion, the endocrinologic parameter T3 was removed since laboratories hardly used this parameter routinely due to a change the guidelines. Amendment 1 also contained changes in the translational research program: the investigation of xenograft tumor models was removed from the correlative science objectives. The biomaterial collection was amended to comprise mandatory additional blood samples for research projects on immunomonitoring and germline RNA analysis. The informed consent form was amended to depict the analysis of whole genome (exome) in tumor and normal cells. Patients who consented before amendment 1 was in force had to reconsent to this change.

Amendment 2: Following recommendation of the IDMC, the window of opportunity phase in which durvalumab/placebo was given as monotherapy for the first two weeks (part 1) was removed and the protocol and ICF amended accordingly in all parts. The IDMC considered the time interval from diagnostic biopsy to start of chemotherapy inadequate and strongly recommended to terminate the window part of the study. Three inclusion criteria were changed. The mandatory sizes of tumor lesions were removed and instead tumor lesions in the breast or the nodes had to be measurable in two dimensions, preferably by sonography. The definition of PgR negative was changed from <1% stained cells to <10% stained cells. Breast imaging could be performed by ultrasound and either bilateral mammography or breast MRI, instead of a mandatory imaging with all methods. In the exclusion criteria, patients with uncontrolled or poorly controlled arterial hypertension were re-defined as having blood pressure >140 / 90 mm Hg under treatment with at maximum two antihypertensive drugs. Amendment 2 also clarified that, while sex hormones were not allowed and prior treatment had to be stopped before study entry, the use of GnRH- analogues for ovarian protection was permitted. Due to recruitment being faster than expected, the number of safety interim analyses was reduced to 4: after the first 10 patients and the first 20 patients having completed part 2 of the study and after the first 10 patients and the first 30 patients having completed part 3 of the study. After amendment 2, administration of durvalumab via port was permitted. Furthermore, the ICF was amended to implement substantial changes in the durvalumab IB (Durvalumab Edition 10.0 [2016-12-12] which overruled Edition 9.0 [2016-01-22]).

Amendment 3: substantial amendment of the ICF only, due to changes in the safety profile of durvalumab (IB Durvalumab Edition 11.0 [2017-04-28] which overruled Edition 10.0 [2016-12-12].

Amendment 4: The study protocol and ICF were amended to implement substantial changes in the durvalumab IB (Durvalumab Edition 12.0 [2017-11-03] which overruled Edition 11.0 (2017-04-28)). Changes mainly related to the update on side effects and had an impact on the toxicity management guidelines for immune-related AEs associated with durvalumab. In the protocol section “Evaluation during chemotherapy before and after surgery”, the analysis of ‘planned therapy after surgery’ was inserted. Moreover, the sequence of analyses in this section was improved. The description of the analysis of ‘progression during neoadjuvant treatment’ was clarified in such that it was not considered as an event for the analyses of IDFS, LRFS, LRRFS, and EFS. However, progression of disease that precluded surgery was considered an event in the analysis of EFS. The ICF was additionally amended to contain a paragraph on the planned follow-up data collection and procedures.