Following Changes were made: Text in schema was updated as OS follow-up every 2 months until 18 months after PFS cut-off date; Updated tumor assessment schedule, bone scan schedule, tumor specimen/biopsy schedule; Cut-off date for the presentation of TED14856 results updated from 22 October 2018 to 29 May 2019; Amcenestrant benefit information updated to align with the updated Investigator’s Brochure as number of subjects with stable disease updated from 7 to 8; number of subjects with long-term stable disease updated from 3 to 7; clinical benefit observed in 8 subjects; Amcenestrant safety information updated as treatment-emergent adverse event results from TED14856 study Part A included; Remaining information removed and referred to the Investigator’s Brochure; exploratory endpoint updated as to align with the updated schedule for ESR1 analysis and with the updated tumor specimen/biopsy schedule; Updated pharmacokinetic information related to Amcenestrant obtained from healthy volunteers and subjects was included, updates to exclude subjects with high thromboembolic risk; Clarified screen failures; Clarified dispensing and shipping procedures for IMP in case of direct to subject shipment of IMPs; Clarified recall procedures; Clarified dose modifications and management of amcenestrant toxicities; Clarified bone scan procedures when no lesions detected at screening; Clarified AE collection procedures; text updated to comply with the Sponsor standard procedures in Biomarker section; Clarified the statistical hypotheses; clarified the PFS censoring procedures; Clarified the DOR censoring procedures; clarified consenting procedures; Consistent updates made in appendices with the protocol amendment.

Following Changes were made: Protocol title, short title updated; The NCT number included NCT04059484; Updated synopsis & schema for clarity, Screening assessment for follicle-stimulating hormone & estradiol assessment for premenopausal women was added; New assessments were added to the schedule of activities: Estradiol, Genetic sampling for drug metabolising enzymes & transporters (amcenestrant treatment arm only); Updated to include the most up to date information on potential amcenestrant risks anticipated in humans; Overall survival was relocated as the first secondary objective; Clarified that men were included in study; Updates made to align with possible dosing regimens for tamoxifen, as per label; COD projections updated following newly added futility interim analysis for PFS & the inclusion of OS as key secondary endpoint; COD definitions updated for clarity; Recruitment period for Chinese population extended after sample size was revised for this population; Contraceptive guidance for male subjects was included; subjects with bone-only metastasis were allowed in this study; clarified to include all potential UGT inhibitors; Time window for amcenestrant dosing added; Updates that subjects that were benefiting from the medication to continue treatment after a delay longer than 2 weeks; Clarified concomitant administration of strong and moderate CYP3A4 inducers and moderate CYP2C8 inducers was not to be permitted in subjects receiving amcenestrant, since they may decrease amcenestrant exposure; Estradiol assessments included to explore the possible influence of circulating levels of estradiol on the efficacy of amcenestrant; A new section included for investigation of allelic variants of drug metabolising enzymes and/or drug transporters; clarified statistical hypotheses for the key secondary endpoint (OS); Sample size calculation updated in accordance with newly added futility interim analysis for PFS. Improvement in median PFS was corrected from 35 to 53%.

Following changes were made: Introduced of study name AMEERA 3; Updates to allow some flexibility in the assessment of the vital signs following the first intake of the IMP; updates to specify Estradiol sampling at predose; Contingency measures for a regional or national emergency information added; potential risk related to amcenestrant added as risk of severe rash; tertiary/exploratory objective and endpoint have were updated to indicate that the biopsies were optional; updates to clarify the scope of Data Monitoring Committee (DMC) responsibility - as the interim analyses on Overall Survival will happen at the time of final Progression Free Survival, treatment would be unblinded and thus there was no need for DMC at that time; Updates to specify that the previous treatment with a CDK 4/6 inhibitor and the limitation to the number of subjects naïve to CDK4/6 inhibitors does not apply to the subjects of the extension study; Clarified and harmonised the definition of Human epidermal growth factor receptor (HER) non over-expressing tumors; Updates to mark biopsy procedures was categorised as optional; definition of secondary endocrine resistance updated; definition of a “sexually active male” clarified; duration of avoiding the natural or artificial sunlight exposure updated; the assessment of the estrogen receptor degradation with the biopsies, updated as optional; harmonised the wording of the samples’ storage with the informed consent form.

Following changes were made: The definitions of Disease Control Rate (DCR) and Clinical Benefit Rate (BCR) have been updated to add the “Non-Complete Response/Non-Progressive Disease” in the endpoint’s descriptions; Texts updated to take in account that Estradiol levels can be high due to Fulvestrant intake; Added clarification on bone scans schedule; Risk of male infertility was added; Updated exclusion criteria with new data available on drug interactions (BCRP substrates, CYP3A and CYP2C8 inducers); Revised the futility analysis; to add risk minimisation strategies for pregnancy, osteoporosis induced by endocrine therapies, hepatic toxicity, and photosensitivity; Adverse events of special interests (AESI) section updated to provide guidance in case of an ALT increase; deleted a section which could be misunderstood in the AEs/SAEs reporting process; Clarification added on PROs schedule, to take in account that end of treatment (EOT) visit can be performed before 30 days following last IMP (if further therapy is started); Text added to allow remote-monitoring when allowed by local regulations, if on-site monitoring is not possible; Clarified that renal function calculation needed on top of the creatinine level for all subjects; Updates in collection of pregnancy information; List of CYP sensitive substrates were updated; Added a copy of the following PROs English-language questionnaires: EORTC QLQ-C30, EORTC BR-23 (for female and male subjects) and EQ-5D-5L.

Following changes were made: Updates to clarify that after COD for final PFS analysis, data collected would be limited to exposure data, reason of EOT, and safety events and its related information when adverse event is serious or related to IMP; For planned cutoff date (previously database lock date) for the Chinese subjects, sentence removed i.e., approximately 18 months after the PFS analysis of the global study; Exclusion criterion was adjusted to remove sensitive substrates of P-gp and BCRP and add sensitive substrates of OATP1B1/B3. And a note was added under this exclusion criteria to refer to FDA website; Sensitive substrates of P-gp and BCRP related information was removed, sensitive substrates of OATP1B1/B3 related information added to concomitant therapy section; Text removed to update caution to be taken with the proton pump inhibitors; Clarified the responsibilities for the monitoring, as a commitment to Belgium Health Authority requirement; Clarified that only amcenestrant is in scope of this ‘recommended dose modification’ table; Updated the required PK samples of the “full-PK” population in China, when sampling is difficult for subjects; Clarified that specificities regarding exploratory endpoints in China per local regulations apply also for subjects from China enrolled in the global part of the study; Clarified the sample size determination section, and to clarify the current definition of the COD rule for the Chinese population; Clarified that subjects who agree to have samples taken for the full PK assessments were required to sign a separate section of the ICF rather than a separate ICF; Correction of typographical errors and minor inconsistencies across different sections, and clarifications were aligned with latest protocol template.

Following updates were made: The definition of the COD for the final PFS and OS analysis was changed; The definition of the censoring and event scheme for the PFS analysis was changed; text added to clarify that SAEs are in scope of data to be collected post-COD, even if not related to IMP.