The design was changed from a ~350- to ~400-site study. This amendment also included new baseline assessments, changes to inclusion critiera, tumor assessment requirements flow chart, prohibited concomitant treatment, concomitant medication guidelines, ECG schedule, guidelines for evaluating liver function test (LFT) changes and pneumonitis/interstitial lung disease, guidelines for blood collection, new patient monitoring and dose adjustment guidelines, Instructions for laboratory determination, reportable liver function test information. Guidelines for PK sampling for patients with LFT changes and details on determination of neratinib and its metabolite plasma concentrations were also added.

The design changed from a 1,200-patient Phase 3 study to a 480-patient Phase 2 study. Analysis of p95 ERBB2 levels with an antibody-based assay was added to biomarkers evaluation. Guidelines for diarrhea management and dose adjustments for diarrhea were revised. Use of patient diaries and distribution of patient diarrhea management cards were made mandatory for all patients enrolled in the neratinib arm. Primary prophylactic use of antidiarrheal medication was mandated. The requirement to collect health outcomes questionnaires was discontinued. Adverse event and SAE reporting procedures were revised to reflect process changes at the Sponsor. Other changes and clarifications were made relative to guidelines of LVEF calculations and selection of lymph node as target vs non-target lesions at screening.

The Sponsor was changed to Puma. Updates were made to biomarker sample collection. Overall survival was removed from the secondary endpoints. As a result, the study no longer included a long-term follow-up for survival period. Other updates included the frequency of tumor assessment, discontinuation of PK sample collection, and exapansion of the scenario for possible use of locally supplied trastuzumab and paclitaxel.

Treatment Extension Period was added in order to provide study subjects who continue to derive benefit from investigational product (IP) the opportunity to continue to receive study drug with a reduced number of protocol required assessments. Additional changes included tumor assessments performed at the investigator’s discretion; required safety procedures for patients receiving neratinib were limited to reporting of all SAEs and non-serious adverse events leading to drug discontinuation or withdrawal from the trial; adverse event collection for patients who were not receiving neratinib was discontinued.