Protocol amendment 1 dated 05-DEC-2013 introduced the following changes: •The recruitment timeline and assumed duration of the study were adapted. • The FACT GOG-Ntx questionnaire was added. • Minor clarifications to the flowchart were made. • The DLT definition of thrombocytopenia was re-worded to make it clearer without changing the criteria. • More emphasis was put on the recommendation to conduct further unscheduled visits if AEs were still ongoing at study end. • The number of cases with SAEs and the cut-off date to determine this number of cases in the benefit-risk evaluation section of the protocol (Section 12.5.2) were updated, on the basis of data updates from other ongoing studies with BT062. • The option to have CD138 assessed on historic biopsies, while a fresh biopsy still remained mandatory, was added. • Wording saying CA 15-3 and carcinoembryonic antigen (CEA) levels in breast cancer patients were to be assessed at baseline in addition to screening was removed to correct a discrepancy with the flow chart. • The description on optimal biomarker time points was corrected to match the flowchart. • It was further clarified that biological samples to be used for PK analysis consisted of sodium heparin plasma samples. • Blood gas analyses were removed from the clinical chemistry panel as it had been included in error. • A reminder on the limitations of the Cockcroft-Gault equation in showing the true glomerular filtration rate was included. • It was further clarified in the statistical section of the protocol that further recruitment was to be stopped if insufficient efficacy was found. The term ‘disease control or better’ was corrected into ‘disease control’ because disease control also included the best possible outcome CR.

The major changes: • Estimated end dates of enrollment and data cut-off were updated. • Enrollment of subjects who were scheduled to continue an ongoing denosumab treatment as concomitant medication during treatment with BT062 was permitted under certain restrictions and denosumab PK-specific time points were added to the description of the study visits. • Collection of denosumab PK samples and instructions for administering BT062 and denosumab as co-medication were added. In addition, all screening results had to be completed before the first dose of BT062 and it was explained that informed consent and biopsy collection could take place even before screening period. • In breast cancer subjects who failed more than 2 treatment regimens, the requirement to be eligible for the current study was that no PD was observed earlier than 9 weeks of the start of the last unsuccessful treatment. Treatments of a short duration < 9weeks due to insufficient tolerability or other reasons, with absence of disease progression did not have to lead to exclusion of a subject. • In case participation ended for a reason other than PD and the subject had received at least 2 cycles of BT062, the first tumor staging data from routine diagnostics after discontinuation were to be captured in the eCRF. • Previous chemotherapies, including adjuvant therapies, sequential regimens, and in-situ therapies were provided. • Guidance on the timing of written informed consent was provided. • Guidance on the timing of the 30-day follow-up depending on the reason of study discontinuation was provided. • A brief description of extravasation as a potential source of risk or discomfort was added. • A more detailed description of molecular parameters related to PK was added to clarify the aim to also analyze potential BT062 metabolites. • suspicion of a technical complaint or product complaint in a Biotest product which caused an infection in a subject, represented an IRAE.

Protocol amendment 3, dated 02-JUN-2016 introduced the following changes: • It was clarified that disease control observation was done during the first 3 cycles. • The ITT population and subsequently also the subject replacement section were adapted according to RECIST criteria. Every subject treated with BT062 who had 1 post-treatment tumor staging or DLT/intolerabilities was to be included in the ITT population. Subjects, who discontinued the treatment before the first post-dose tumor staging and for whom no DLT or other sign of insufficient tolerability was observed, needed to be replaced. In case of SD, the minimum time interval between baseline tumor staging and first post-dose tumor staging was defined as 6 weeks. • It was clarified that tumor staging was planned after every third treatment cycle, but could be performed at any time during the study, if clinically indicated. • The number of PK parameters analyzed was reduced for Phase I of the study. • Certain other sections were amended for clarification.