This amendment was made prior to first patient recruitment. Key provisions introduced by this amendment included (1) the trial was changed from Phase III to Phase II and associated changes were made in the number of trial sites, countries, patient numbers, statistical analyses, and biomarker sampling; (2) language was added to allow for seamless expansion to a Phase III trial if criteria were met; and (3) the patient reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaire was added to examine patient perception of adverse events (AEs).

The protocol was amended based on feedback from investigators and to provide needed clarification. Key aspects of this amendment included (1) revised inclusion criterion 3 to state that biopsies could not be performed after consent for the purpose of the trial and that archival biopsy samples had to be provided to the sponsor; (2) exclusion criteria 22 was updated to include a washout period for any restricted medications; (3) withdrawal from trial treatment updated to state that if a patient required palliative radiotherapy, the patient would need to stop the trial; (4) screening period was increased from 14 to 28 days to allow additional time for screening procedures; (5) third party blinding added due to visual difference in appearance of placebo versus xentuzumab; (6) management of stomatitis/mucosal inflammation section updated to provide guidance regarding dexamethasone-containing mouthwashes; (7) addition of language that MD Anderson criteria would also be used in selection of target and or non-target lesions in the bone; (8) safety laboratory parameters section updated to include fasting requirements and to clarify that safety labs could be taken on the day before infusion as long as they were within clinical trial protocol (CTP) specified visit windows; (9) due to change in trial design (Phase III to Phase II), the interim analysis was removed, text was added stating that if the trial was seamlessly expanded to Phase III then end of Phase II would be considered as an interim analysis, and that the null hypothesis for primary analysis PFS was at end of Phase III.

Key provisions of this amendment included: (1) inclusion/exclusion criteria adapted to allow use of original histology report if archival tissue not available, include premenopausal women on ovarian suppression and birth control rather than just post-menopausal women, to allow enrolment of patients with blastic lesions only, and to allow for additional prior therapy options including some endocrine therapies, Phosphatidylinositol 3-kinase (PI3K) therapy, and one line of chemotherapy; (2) menopause status was added as a stratification factor; and (3) given the inclusion of premenopausal women, ovarian suppression and monitoring was also included. Additionally, because the use of Ev/Ex in premenopausal women on ovarian suppression might be considered off-label in some countries, clarified that Ev/Ex are not considered as investigational in this trial; however, where local regulatory requirements mandate it, then it may be considered as Investigational medicinal product (IMP) and would be provided as labelled product to the sites.

Key changes introduced by this amendment included: (1) increase in number of patients who could be recruited to a maximum of 100 to help achieve the required number of events; (2) inclusion/exclusion criteria updated to reflect amended contraception requirements for xentuzumab for women of childbearing potential, increased flexibility of study visits for patients who discontinued xentuzumab/placebo in order to help patient retention, and allowance of plasma to be used for biochemistry tests, if appropriate, in place of serum; and (3) updated language to allow for analysis of the Phase II trial without 40 progression-free survival (PFS) events with the condition that the trial would not be considered to have met criteria for seamless transition to Phase III.

This amendment was introduced after unblinded top-line data review. Because the benefit-risk ratio was no longer favourable due to lack of xentuzumab efficacy, this amendment recommended xentuzumab/placebo discontinuation and an associated decrease in visits/assessments, retaining only those necessary for patient safety. A new patient visit/assessment flow chart was provided.