• Phase 1 eligibility criteria were changed to include no limit on the number of lines of prior therapy • Clarified that prior treatment and progression on lapatinib is not a requirement for eligibility • Definition of triple-negative disease in the eligibility criteria was changed to <5% estrogen receptor and progesterone receptor expression

• Included Wyeth-Pfizer merger; Wyeth is now Wyeth Pharmaceuticals, Inc., a Pfizer Company • Changed drug supply; Wyeth will be providing neratinib in 240-mg and 80-mg capsules and 40-mg tablets.

• A third dose cohort to Phase 1 (15 mg of temsirolimus and 240 mg of neratinib) was added. • The maximum number of patients needed to determine the MTD was increased to 18 patients.

• Shari Goldfarb, MD, was added as an investigator; this amendment was not submitted to the IND.

• The MTD from Phase 1 was determined to be 8 mg temsirolimus/240 mg neratinib. • Pathological nodes must be ≥15 mm by the short axis to be considered measurable.

• Signed informed consent and medication list must be obtained within 1 month prior to starting therapy instead of 2 weeks. • If patients have received at least 6 months of therapy, they can be seen monthly (Day 1 of each cycle) by the MD instead of biweekly.

• As of 2/10/12, the Triple-negative cohort was closed to accrual. This change in study design was not a result of safety concerns. After assessing the data of the Triple-negative patients, there was no indication that therapy with weekly temsirolimus (8 mg) and daily neratinib (240 mg) shows efficacy in terms of the ORR (CR + PR) as determined by RECIST 1.1 criteria. • Added that complete or partial responses will be confirmed with a repeat CT scan after 4 weeks. Radiographic assessments (CT and Bone or PET scan) may then be completed 8 weeks ±7 days from the confirmatory CT scan.

• Study sponsorship was changed from Memorial Sloan Kettering Cancer Center (MSKCC) to Puma Biotechnology, Inc. (Puma); contact information was revised accordingly. • Subjects who were unable to complete 1 week of therapy will not be included in the analysis for toxicity or response; however, they will be followed for safety. Subjects not completing 1 week of therapy may be replaced by a new subject. • A new section “Follow-up Visits” was added stating that subjects will be followed for overall survival after the treatment phase is complete.

• Two new sites in the US, in addition to MSKCC, were activated: Weill Cornell Medical College and University of Southern California. • Inclusion Criterion for Phase 2 HER2–Amplified Cohort was revised to allow enrollment of patients with no restriction on the number of prior chemotherapy regimens received. • The enrollment period was extended from 2 years to approximately 3 years. • To mitigate or reduce the incidence of diarrhea that generally occurs in the initial treatment cycle, a revised diarrhea management plan with mandatory prophylactic use of high-dose loperamide was implemented. This allowed for patients to take a maximum dose of 12 mg of loperamide for the first 3 days, followed by 6-8 mg of loperamide per day thereafter.

• 16 patients added in Phase 2 HER2-positive cohort. If these patients tolerated the starting dose of neratinib 240 mg/day + temsirolimus 8 mg/week in the first cycle of therapy, intra-patient dose-escalation of temsirolimus to 15 mg/week was allowed. • Patient enrollment in Phase 2 portion of study revised to minimum of 19 patients and maximum of approximately 79 patients (50 HER2+ patients). • Study expanded to centers in Spain, United Kingdom, France, and Hong Kong. • Total duration of study increased to approximately 48 months with 10 centers. • Final analysis revised: “The final analysis of the primary endpoint will occur when disease progression is reported for all patients in the Phase 2 HER2-positive cohort (first 34 patients without dose-escalation).” • End of study (EOS) stated to occur when disease progression is reported for all patients on study, or when EOS is declared early once the primary endpoint has been met. • Phase 2 secondary objectives revised to determine progression-free survival, duration of response, clinical benefit rate, and overall survival, and estimate the efficacy and safety assessment of dose escalation to 240 mg neratinib plus 15 mg temsirolimus with revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients. • Inclusion and Exclusion criteria revisions regarding informed consent for procedures. • Inclusion criterion for contraception while on study revised. • Exclusion criterion removed: Unable to consent to biopsy of metastatic disease or for whom a biopsy would be medically unsafe. • Exclusion criterion added: Previous treatment with any strong inhibitor and/or inducer of CYP3A4 enzyme or sensitive P glycoprotein. • Section “10 Patient Withdrawal and Replacement” added to clarify conditions for discontinuing IP administration and reasons for study withdrawal. • Section “12 Statistical Methods” revised to clarify all statistical analyses and methods.

• Number of patients in the HER2+ dose escalation cohort increased to approximately 100 and the number of centers to approximately 15 in order to expand the safety and efficacy data for the neratinib 240 mg/day plus temsirolimus 15 mg/week combination. • Minimum and maximum number of patients enrolled in Phase 2 increased from 19 to 119, and from 79 to 163, respectively. Maximum total sample size for study increased from 97 to 181 patients. • Statistical methods section and text throughout protocol revised to indicate that single-stage design was used to estimate sample size for HER2+ dose-escalation cohort. • Primary Phase 2 objective added to estimate the ORR for patients with dose escalation to 240 mg neratinib plus 15 mg, temsirolimus with a revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients. • Secondary Phase 2 objective revised to assess only safety (because the efficacy evaluation for this Phase 2 cohort was moved under primary objectives: to assess the safety of dose escalation to 240 mg neratinib plus 15 mg temsirolimus with a revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients. • Interim analysis for Phase 2 HER+ cohort added to determine if study continuation was warranted based on Simon 2-stage optimal design. • Text clarified, “final analysis of the primary endpoint will occur when disease progression is reported for all HER2-positive patients enrolled in the Phase 2 portion of study.” • Text added to clarify that efficacy analyses performed on the Efficacy Evaluable population, defined as “all patients who are enrolled into the study and have completed at least one week of treatment.” • Table added to clarify endpoints for laboratory assessments. • Definition of study termination clarified, “The end of study (EOS) is defined as the last visit of the last patient or the completion of any/all follow-up monitoring and data collection described in the protocol (ie, survival)."