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8.3.1. health outcomes assessments

The exploratory endpoint of patient-reported health outcomes will be assessed by the EuroQol EQ-5D-5L and by the FACT-B questionnaires (for patients enrolled starting with Amendment 2) and the RSCL (for patients enrolled starting with Amendment 6.1).  
Health outcomes will be assessed by patient-reported responses to the EQ-5D-5L multidimensional health status questionnaire (Appendix 7) and by the FACT-B (Appendix 8), and by the RSCL (Appendix 11). These assessments will be administered in accordance with the Schedule of Procedures (Appendix 1). The patient-reported assessments are for the purpose of exploring the subject's own perceptions about their symptoms and health-related quality of life and thus a proxy (ie, a caregiver or study personnel) should not complete the questionnaires. Additionally, the investigator must not influence the subject's assessments. Every effort should be made to maintain an unbiased assessment. Questionnaires should be administered before any other study procedures on the day of the study visit. If questionnaires can only be completed after the study visit, they should be administered no later than 5 days from the visit. Both assessments need to be completed on the same day. On the day of treatment discontinuation, it is acceptable for questionnaires to be performed after study procedures. If assessments were completed within the previous 7 days at a regularly scheduled visit, assessments do not need to be administered at the EOT visit.
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eq-5d-5l

The EQ-5D-5L is a standardized instrument for use as a measure of general health states preferences and provides a simple descriptive profile and index value for health status and measures 5 dimensions of health including mobility, self-care, usual activities, pain/discomfort, anxiety, and general health is measured via a vertical visual analog scale. Applicable to a wide range of health conditions and treatments, it provides a simple descriptive profile and a single index value for health status.
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fact-b

The FACT-B (version 4) is a 37-item questionnaire with 5 subscales assessing physical, social, emotional, and functional well-being and additional concerns more specific to women with breast cancer. Subjects will be asked to indicate how true a statement had been for them over the past 7 days using a 5-point scale as follows: 0, not at all; 1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much. All items receive equal weighting. Rotterdam Symptom Checklist: The RSCL measures both physical and psychological aspects of quality of life (QOL) in cancer patients. The instrument assesses symptom-related distress among patients for physical symptoms, psychological symptoms, and activities of daily living. The 3 domains are assessed in a 4-point scale (not at all, a little, quite a bit, very much) for 38 items. Patients are asked to indicate the degree to which they have been bothered by the indicated symptoms in the past week.
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8.3.2. biomarkers

The exploratory endpoint of disease biomarkers will consist of biomarkers of disease recurrence (for patients enrolled starting with Amendment 2). cfDNA will be obtained from plasma samples collected several times during the study and at disease recurrence (if applicable), in accordance with the Schedule of Procedures (Appendix 1). cfDNA will undergo molecular profiling to identify biomarkers of disease recurrence
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8.3.3. disease recurrence

Clinical documentation of recurrence, including recurrence site, radiographic, and/or pathologic procedures will be collected at end-of-treatment.
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8.3.4. microbiome evaluation (for patients

At select study centers, a stool swab will be collected at Screening, C2D1, and C4D1 and/or at time of treatment discontinuation if earlier than C4D1 for possible future assessments of microbiome to assess the effect that neratinib has on the microbiome.
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8.4. protocol deviations

Protocol deviations should be reported to the Sponsor (or designee) as they occur or are discovered and should be captured in CRFs at the time of monitoring and medical review of data line listings.
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8.5. study drug accountability/patient diary

The study site must maintain accurate records documenting dates and quantities of medicinal product received from the Sponsor. On a per patient basis, records must be maintained documenting dates and quantities of medicinal product dispensed and returned at each study visit. Any medicinal product accidentally or deliberately destroyed must be documented. Throughout the study, reconciliation will be made between the amount of medicinal product supplied, dispensed, returned, and subsequently destroyed or returned to Sponsor. All medicinal products will be returned to Sponsor or its representative, or destroyed at the site in accordance with local standard operating procedures (SOPs), as specified in writing by the Sponsor.
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8.5.2. patient diary

A patient diary will be provided by the Investigator for the patient to record daily study medication intake for every cycle. The number of stools per day and the use of antidiarrheal treatment will also be required to be recorded in the patient diary during the first 2 treatment cycles. Individual patient dosing compliance should be reviewed at each study visit by study site staff. If patient non-compliance is noted, the patient should be re-instructed regarding proper dosing procedures in order to continue in the study. If repeated non-compliance is noted, additional steps may be taken, including withdrawal of the patient from the study. For the first 2 cycles, eDiaries will be implemented, either hand-held or web-based, to collect the number of daily bowel movements, neratinib self-administration (number of tablets taken), and anti-diarrheal intake (number of loperamide capsules or tablets, and as applicable, the number of doses of other anti-diarrheal medications). If the use of an eDiary, either hand-held or webbased, is not feasible, the alternative of a paper diary will be considered on a case-by-case basis.  
After 2 cycles, the hand-held or web-based diary will continue to be available to patients, or alternatively, they may switch to a paper diary to be completed on a daily basis and returned to the clinic (site) for review and evaluation at scheduled study visits.
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9. study conduct a schedule

In addition to the procedures listed below, unscheduled clinic visits and procedures should be performed at the Investigator's discretion to assess symptoms and concerns newly reported by the patient to rule out or confirm potential recurrence, or for the purpose of assessing the patient's safety.
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9.1. screening/baseline

Screening activities are to be conducted within 28 days prior to Cycle 1/Day 1, except for serum or urine pregnancy test for women of child-bearing potential (see Inclusion Criterion 9 in Section 5.1), which should be performed, both, at screening and within 72 hours prior to Cycle 1/Day 1. Documented HER2 overexpression or gene-amplified tumor by a validated approved method (Wolff et al, 2013) must be retrieved. The following information/assessments will be collected/recorded at Screening:
Medical history:  
Presence of chronic conditions and/or medical history of significance (include review of history of cardiac, pulmonary, and gastrointestinal disease) including relevant surgical procedures.  
Cancer history, including but not limited to, date of first diagnosis, nodal status
(based on pathologic assessment of nodes at the time of surgery, either before adjuvant chemotherapy or after completion of neoadjuvant chemotherapy), histology, tumor stage at diagnosis, previous chemotherapy/biotherapy/immunotherapy, previous adjuvant therapy, drug names, start and stop dates, reason for treatment discontinuation, previous radiation, and prior cancer related surgical therapies.  
Other previous and concomitant medication will be documented, as described in Section 7.  
Demography: date of birth, sex, ethnicity, and race (Asian, Black or African American, White, Other).  
Physical examination. Refer to Section 8.2.4.  
Vital signs, including height and weight. Refer to Section 8.2.3.  
ECG. Refer to Section 8.2.5. LVEF. Refer to Section 8.2.6. Laboratory tests. Refer to Section 8.2.2. Health outcomes assessments. Refer to Section 8.3.1
Biomarkers. Refer to Section 8.3.2.  
Microbiome evaluation. Refer to Section 8.3.4.  
Per standard of care, bone scan or positron emission tomography (PET) scan performed within 28 days prior to the date of enrollment; only required if ALP is ≥2x upper limit of normal (ULN) and/or there are symptoms of metastatic bone disease. A confirmatory imaging study is required if the results from the bone scan are questionable (see Section 5.1)
Per standard of care, computed tomography (CT), magnetic resonance imaging (MRI)
or ultrasound of the abdomen and chest performed within 28 days prior to the date of enrollment; only required if aspartate aminotransferase (AST)/ALT or ALP is ≥2x ULN (see Section 5.1)
Other radiologic assessments may be performed within 28 days prior to the date of enrollment, unless a CT scan has already been performed, to rule out underlying breast cancer recurrence if indicated and as per standard of care (for patients enrolled starting with Amendment 6.1).  
ECOG status will be assessed in accordance with the Schedule of Procedures
(Appendix 1). The ECOG categories are summarized in Appendix 3.
The Cycle 1/Day 1 physical examination and blood sample may be omitted if the screening values were obtained within 72 hours prior to initiation of treatment.
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9.2. active treatment phase neratinib

For patients enrolled under Amendment 3, the anti-inflammatory treatment budesonide will be administered for 1 cycle during Cycle 1 for patients in this treatment cohort. For patients enrolled under Amendment 4, colestipol will be administered for 1 cycle during Cycle 1 (colestipol + intensive loperamide prophylaxis), and colestipol will also be administered for patients enrolled under Amendment 5 (colestipol + PRN loperamide). All patients enrolled under Amendment 6 and Amendment 6.1 will be evaluated after receiving neratinib administered according to the following dose-escalation scheme: 120 mg neratinib for Week 1 (C1D1 - C1D7), followed by 160 mg neratinib for Week 2 (C1D8 - C1D14), followed by 240 mg neratinib for Week 3 and thereafter (C1D15 to EOS). All patients enrolled under Amendment 7 and Amendment 7.1 will be evaluated after receiving neratinib administered according to a second dose escalation scheme: 160 mg neratinib to be taken for the first 2 weeks (C1D1 - C1D14), followed by 200 mg neratinib to be taken for the next 2 weeks (C1D15 - C1D28), followed by 240 mg neratinib daily dose taken thereafter (C2D1 to EOT). Loperamide is to be administered on a PRN basis only. For both dose escalation regimens, the Investigator or research staff must call patients at the end of the first and second weeks of treatment (ie, Day 7 or Day 8, and Day 14 or Day 15) to confirm that the patient has increased the dose of neratinib from 120 mg to 160 mg, and from 160 mg to 240 mg, respectively. The following will be performed in accordance with the Schedule of Procedures (Appendix 1):
AE assessment. Refer to Section 13.  
Monthly serum or urine pregnancy testing. Refer to Inclusion Criterion 9 in Section 5.1 and Section 8.2.2. The Investigator or designee must contact patients on months that do not have a scheduled visit to confirm that the patient has performed the pregnancy test, is not pregnant, and this is noted in the clinical progress notes.  
Concomitant medication assessment. Refer to Section 7.  
Brief symptom-guided physical examination. Refer to Section 8.2.4.  
Vital signs, including weight. Refer to Section 8.2.3.  
ECG. Refer to Section 8.2.5.  
Laboratory tests. Refer to Section 8.2.2.  
Health outcomes assessments. Refer to Section 8.3.1.  
Biomarkers. Refer to Section 8.3.2. Microbiome evaluation. Refer to Section 8.3.4. Treatment compliance assessment. Refer to Section 6.6.  
Collect Patient Diary at C2D1 and at C3D1 visits, and at clinic visits when applicable.  
AE assessment. Refer to Section 13. Serum or urine pregnancy test. Refer to Inclusion Criterion 9 in Section 5.1.  
Concomitant medication assessment. Refer to Section 7. Physical examination. Refer to Section 8.2.4.  
Vital signs, including weight. Refer to Section 8.2.3.  
ECG. Refer to Section 8.2.5.  
LVEF. Refer to Section 8.2.6. Laboratory tests (hematology, chemistry, LFT). Refer to Section 8.2.2. Health outcomes assessments. Refer to Section 8.3.1 . Biomarkers. Refer to Section 8.3.2. Microbiome evaluation. Refer to Section 8.3.4.  
Disease recurrence as applicable. Refer to Section 8.3.3.  
Collect Patient Diary for treatment compliance assessment.
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9.3. treatment discontinuation or end-of-treatment

The EOT visit will occur within 5 business days of Cycle 13/Day 28. When a patient discontinues study treatment for reasons of toxicity, disease progression, or other reasons, an EOT visit will occur within 5 business days of last dose of neratinib. The following will be performed in accordance with the Schedule of Procedures (Appendix 1):
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9.4. safety follow-up visit

Patients who complete the active treatment phase or who discontinue due to unacceptable toxicity will be followed-up for 28 days after the last dose of neratinib to collect AESIs/SAEs and to obtain a serum or urine pregnancy test.
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9.6. end of study

The EOS is defined as the last safety follow-up visit of the last patient or the completion of any/all follow-up monitoring and data collection described in the protocol.  
In the event that end of study (EOS) is declared earlier, patients will be offered the opportunity to complete the 1-year course of treatment either through a treatment extension study or through a managed access program.
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10. patient withdrawal and replacement

Patients **must** be discontinued from **investigational product** under the following circumstances listed below and in Appendix 2, unless otherwise agreed with the Medical Monitor:
If the patient requires more than 2 dose reductions of neratinib (see Appendix 2).  
If neratinib is withheld due to a AESIs/SAEs for >28 days. Patients who are clinically benefiting from therapy with neratinib may be resumed on therapy after 28 days if approved in advance by the Sponsor.  
Disease recurrence.  
Initiation of alternative anti-cancer therapy. Any concurrent chemotherapy, radiotherapy (including palliative radiotherapy), surgery related to cancer, anticancer immunotherapy, or other anticancer treatments including other investigational agents (see Section 7.3).  
Pregnancy (see Section 13.4).  
Investigator request.  
Patient request (ie, withdrawal of consent for treatment).  
AEs/toxicity.
Withdrawal due to AE should be distinguished from withdrawal due to other causes, and recorded on the appropriate AE page of CRF. If a patient withdraws due to toxicity, even if discontinuation is not otherwise required per protocol guidelines, the withdrawal should be classified as withdrawal due to AE.
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10.2. withdrawal from the study

Patients may withdraw from the entire study including follow up at any time without penalty and for any reason without prejudice to his or her future medical care. Patients may be required to withdraw from the study after discussion with the Sponsor and/or Investigator (whenever possible) for the following reasons:
At the discretion of the Investigator.  
At patient's request (withdrawal of consent for the study) (see Section 10.3).  
Lost to follow-up (defined as after three attempts at contact by phone followed by one attempt by sending a certified letter).  
If the entire study is terminated prematurely as described in Section 11.
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory Authorities, or IRBs/IECs.
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10.3. procedures for investigational product

When a patient is withdrawn from the study, the Investigator will notify the Sponsor. In all cases, the reason(s) for premature discontinuation/withdrawal, and the primary reason, must be recorded on the CRF. If a patient is prematurely withdrawn from the investigational product or the study for any reason, the Investigator must make every effort to perform the evaluations described for the EOT visit (performed within 5 days of the last dose of investigational product as appropriate). If a patient discontinues due to an AE, he/she should be strongly encouraged to undergo the EOT assessments and continue to be under medical supervision until symptoms cease or the condition becomes stable. If a patient is lost to follow-up, or voluntarily withdraws from study participation, every effort should be made to determine why a patient is lost to follow-up or withdraws consent. This information, including the date, should also be recorded on the patient's conclusion of patient participation CRF. All patients will remain on active study treatment until a cause of early treatment discontinuation occurs; these include disease progression, unacceptable toxicity, and withdrawal of consent (Section 10), or until study closure.
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10.4. patient replacement

Patients who do not complete at least one week of study therapy will be replaced.
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11. premature termination of study

The Sponsor may suspend or terminate the study or part of the study at any time for any reason. Investigational product will be available to patients to complete the 1-year course of treatment as described in Section 4.2. If the Investigator suspends or terminates the study, the Investigator will promptly inform the Sponsor and the IRB/IEC and provide them with a detailed written explanation. The Investigator will also return all investigational products, investigational product containers, and other study materials to the Sponsor or have them destroyed locally according to Sponsor guidelines. Upon study completion, the Investigator will provide the Sponsor, IRB/IEC, and regulatory agency with final reports and summaries as required by regulations. For investigational new drug application studies, the Investigator must submit a written report to the Sponsor and the IRB/IEC
within 3 months after the completion or termination of the study.
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12. statistical methods

The statistical considerations summarized in this section outline the plan for data analysis of this study. Before database lock, a separate statistical analysis plan will be finalized, providing detailed methods for the analyses outlined below. Any deviations from the planned analyses will be described and justified in the final integrated study report.
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12.1. general considerations 12.1.1. subgroups/cohorts

Unless otherwise specified, all analyses will be done by the following cohorts: (1) the Original Protocol, (2) Amendment 1 or Amendment 2, (3) Amendment 3, (4) Amendment 4, (5) Amendment 5, (6) Amendment 6 and Amendment 6.1, or (7) Amendment 7 and Amendment 7.1 by treatment cohort.
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12.2. study patients 12.2.1. disposition

The number and percentage of patients entering and completing the study will be presented. Reasons for withdrawal will also be summarized.
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12.2.2. demographic data medical history

Demographic data, medical history, concomitant disease, and concomitant medication will be summarized by means of descriptive statistics for continuous variables (n, mean, standard deviation, median, minimum and maximum) and frequency tables for categorical variables.
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12.2.3. treatment compliance

Duration of treatment will be summarized. In addition, the cumulative dose, dose intensity (quantity per time unit) and the relative dose intensity (dose intensity/scheduled dose per time unit) will be summarized. The number of patients with dose holds or dose reductions will be tabulated.
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12.4. safety analysis

All patients who receive a dose of neratinib will be analyzed for safety.
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12.4.1. statistical methods

The primary endpoint is the incidence of Grade 3 or higher diarrhea. The accompanying Clopper-Pearson 2-sided 95% CIs will be computed. The primary endpoint will be estimated for the overall safety population and, if needed, for subgroups of patients with specific anti-diarrheal prophylaxis regimens per protocol.
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12.4.2. adverse events

AEs will be coded using the Medical Dictionary for Regulatory Activities MedDRA coding system and all AEs will be graded by the Investigator according to the NCI-CTCAE version 4.0. Incidence of AEs will be summarized by system organ class (SOC) and preferred term (PT), and will be summarized by grade. A patient who experiences the same AE more than once within a SOC or preferred term category will be counted only once, using the worst toxicity grade for that event. SAEs and AESIs will also be summarized. Serious AE and deaths will be provided in a listing. All AEs resulting in discontinuation, dose modification, dosing interruption, and/or treatment delay of investigational product will also be listed and tabulated by PT.
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12.4.3. laboratory results

Laboratory test results will be collected pretreatment through 28 days after the last dose of investigational product. Standard reference ranges will be used for missing or discrepant normal ranges. Mean change from baseline in laboratory test values at each visit will be provided. On-study laboratory test abnormalities will be summarized. Shifts in laboratory test values will also be summarized.
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12.5. exploratory endpoints analyses

Exploratory analyses will be conducted on all patients in the safety population who were enrolled starting under Amendment 2.
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12.5.1. health outcomes assessments

Patient-reported health outcomes data (scores on the EQ-5D-5L, FACT-B, and RSCL questionnaires) will be summarized and plotted over time. Analyses will be descriptive only; changes from baseline will be provided with both point estimates and CIs.
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12.5.2. biomarkers analyses

Exploratory analyses will be conducted to evaluate the relationship between disease biomarkers identified from molecular profiling and indications of clinical disease recurrence. No formal statistical analyses are planned, however, of biomarker data.
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12.5.3. microbiome analyses

Results of microbiome evaluation from participating sites, if available, will be summarized at baseline, C2D1, C4D1, and/or at time of treatment discontinuation if earlier than C4D1. No formal statistical analyses are planned of the microbiome data.
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12.6. interim analysis

An interim analysis is planned when approximately 120 patients enrolled under the Original protocol, Amendment 1, and Amendment 2, all patients have completed at least 2 cycles (56 days) of neratinib with loperamide prophylaxis. The interim analysis will only include those 120 patients enrolled under the Original Protocol, Amendment 1, and Amendment 2. Other additional analyses by cohort may be carried out as required.
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12.7. determination of sample size

The first 120 patients will be under the Original Protocol, Amendment 1, and Amendment 2. The incidence of Grade 3 or higher diarrhea is assumed to be 15% in this study. A sample size of 120 patients will ensure that the width of the 95% Clopper-Pearson CI of the incidence of Grade 3 or higher diarrhea is no more than 18.5%. For example, if 18 out of the 120 patients are observed to have Grade 3 or higher diarrhea, the incidence and its 95% (2-sided) CIs will be 15.0% (9.1%, 22.7%) where the width of the CI is 13.5%. In addition to the analyses of the overall safety population, anti-diarrheal prophylaxis regimen-specific subgroup analyses will be performed as needed. For patients enrolled under Amendment 3, the effect of anti-inflammatory treatment budesonide on the incidence, severity, and duration of diarrhea will be assessed. For patients enrolled under Amendment 4, the effect of a bile acid sequestrant colestipol was to be assessed, with either intensive loperamide prophylaxis, or loperamide given on a PRN basis (Amendment 5); for patients enrolled under Amendment 6/6.1, under Amendment 7/7.1, the effect of 2 different dose-escalation schemes of neratinib will be assessed. The incidence of Grade 3 or higher diarrhea will be evaluated. For each additional cohort, a sample size of 64 patients will ensure that the width of the 95% Clopper-Pearson CI of the incidence of Grade 3 or higher diarrhea is no more than 26%. For example, if 7 out of the 64 patients are observed to have Grade 3 or higher diarrhea, the incidence and its 95% (2-sided) CI will be 10.9% (4.5–21.2%) where the width of the CI is 17%. For each additional cohort, a sample size of 100 patients will ensure that the width of the 95% Clopper-Pearson CI of the incidence of Grade 3 or higher diarrhea is no more than 21%. For example, if 15 out of the 100 patients are observed to have Grade 3 or higher diarrhea, the incidence and its 95% (2-sided) CI will be 15.0% (8.7–23.5%) where the width of the CI is 15%.
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13. safety data collection recording

All observed or volunteered AEs regardless of treatment group or causal relationship to investigational product will be recorded on the AE page(s) of the CRF.
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13.1. definitions 13.1.1. adverse events

An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product, and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign
(including abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the medicinal product (definition per International Conference on Harmonisation [ICH] E2A and E6 R1). All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be recorded using medical terminology on the AE CRF page. Whenever possible, diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory infection"). All measures required for AE management must be recorded in the source document and reported according to Sponsor instructions. For all AEs, the Investigator must pursue and obtain information adequate to both determine the outcome of the AE and to assess whether it meets the criteria for classification as a SAE (see Section 13.3 on SAEs) requiring immediate notification to the Sponsor or its designated representative. For all AEs, sufficient information should be obtained by the Investigator to determine the causality of the AE. Interventions for pretreatment conditions (eg, elective cosmetic surgery) or medical procedures that were planned before study enrollment are not considered AE.
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13.1.2. abnormal laboratory results

The criteria for determining whether an abnormal laboratory test result should be reported as an AE are as follows:
Test result is associated with accompanying symptoms, and/or,  
Test result requires additional diagnostic testing or medical/surgical intervention
(merely repeating an abnormal test, in the absence of any of the above conditions, does not meet criteria for reporting an AE), and/or Test result leads to a change in study dosing or discontinuation from the study, significant additional concomitant drug treatment or other therapy, and/or Test result leads to any of the outcomes included in the definition of a SAE, and/or Test result is considered to be an AE by the Investigator or by the Sponsor
Any abnormal test result that is determined to be an error does not require reporting as an AE, even if it did meet one of the above criteria except for when the test result leads to any of the outcomes included in the definition of a SAE. Clinically significant laboratory results must be recorded in the patient's CRF.
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13.1.3. serious adverse events

An SAE is defined as any untoward medical occurrence that at any dose (ICH E2A and E6 R2):  
Results in death.  
Is life-threatening.  
This means that the patient is at risk of death at the time of the event; it does not mean that the event hypothetically might have caused death if it were more severe.  
Requires inpatient hospitalization or prolongation of existing hospitalization.  
Results in persistent or significant disability or incapacity.  
Is a congenital anomaly or birth defect.
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical event(s) that may not be immediately life-threatening or result in death or hospitalization but that may jeopardize the patient or require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse. Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms of clinical sequelae resulting from disease progression will be reported if they fulfill the SAE definition.
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13.1.4. hospitalization

Any inpatient hospital admission that includes a minimum of an overnight stay to a healthcare facility meets the criteria for 'hospitalization'. Admission also includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor to a coronary care unit, neurological floor to a tuberculosis unit). The following are not considered to be hospitalization:
Rehabilitation facilities.  
Hospice facilities.  
Respite care (eg, caregiver relief).  
Skilled nursing facilities. Nursing homes.  
Routine emergency room admissions.  
Same day surgeries (as outpatient /same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is not in itself a SAE. Examples include:  
Admission for treatment of a preexisting condition not associated with the development of a new AE or with a worsening of the preexisting condition (eg, for work-up of persistent pre-treatment lab abnormality).  
Social admission (eg, patient has no place to sleep).  
Administrative admission (eg, for yearly physical examination).  
Protocol-specified admission during a study (eg, for a procedure required by the study protocol).  
Optional admission not associated with a precipitating clinical AE (eg, for elective cosmetic surgery).  
Hospitalization for observation without a medical AE.  
Pre-planned treatments or surgical procedures should be noted in the baseline documentation and/or for the individual patient.  
Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be reported as AEs. However, the medical condition for which the procedure was performed should be reported if it meets the definition of an AE. For example, an acute appendicitis that begins during the AE reporting period should be reported as the AE, and the resulting appendectomy should be recorded as treatment of the AE.
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13.1.5. suspected unexpected serious adverse

Suspected Unexpected Serious Adverse Reactions (SUSAR) are events which are serious as per the above criteria, the nature or severity of which is not consistent with the applicable product information (eg, IB Version 5.0) and are judged by the Investigator or by the Sponsor to be related to investigational product. For a non-Sponsored investigational product (eg, a comparator product) with a marketing authorization, the expectedness of an AE will be determined by whether or not it is listed in the package insert/SmPC.
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13.1.6. severity assessment

Adverse events will be graded by the Investigator according to the NCI CTCAE v.4.0 (Publish Date: May 28, 2009, http://ctep.cancer.gov/reporting/ctc.html), according to the following general categories:  
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.  
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental activities of daily living.  
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.  
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE. Note the distinction between the severity and the seriousness of an AE. A severe event is not necessarily a serious adverse event. For example, a headache may be severe (interferes significantly with patient's usual function) but would not be classified as serious unless it meets one of the criteria for SAEs, listed above.
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13.1.7. causality assessment

The Investigator's assessment of causality must be provided for all AEs (serious and non-serious); the Investigator must record the causal relationship in the CRF and report such an assessment in accordance with the serious adverse reporting requirements, if applicable. A suspected adverse reaction means any AE for which there is a reasonable possibility that the investigational product caused the AE. An Investigator's causality assessment is the determination of whether there exists a reasonable possibility that the investigational product caused or contributed to an AE; generally the facts (evidence) or arguments to suggest a causal relationship should be provided. If the Investigator does not know whether or not the investigational product caused the event, then the event will be handled as "related to investigational product" for reporting purposes, as defined by the Sponsor (see Section 13.2). If the Investigator's causality assessment is "unknown but not related to investigational product", this should be clearly documented on study records. For all AEs, sufficient information should be obtained by the Investigator to determine the causality of the AE (eg, investigational product or other illness). The relationship of the AE to the study treatment (investigational product, comparator or placebo [as applicable]) will be assessed following the definitions below:  
'No' (unrelated): Any event that does not follow a reasonable temporal sequence from administration of investigational product AND is likely to have been produced by the patient's clinical state or other modes of therapy administered to the patient.  
'Yes' (related): Any reaction that follows a reasonable temporal sequence from administration of investigational product AND follows a known response pattern to the suspected investigational product AND recurs with re-challenge, AND/OR is improved by stopping the investigational product or reducing the dose.
In addition, if the Investigator determines an AE is associated with study procedures, the Investigator must record this causal relationship on the AE CRF page and report such an assessment in accordance with the SAE reporting requirements, if applicable.
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13.1.8. special reporting situations

Safety events of interest on the Sponsor's investigational product that may require expedited reporting and/or safety evaluation include, but are not limited to:  
Overdose of an investigational product.  
Suspected abuse/misuse of an investigational product. Inadvertent or accidental exposure to an investigational product.  
Medication error that may result from the administration or consumption of the wrong drug, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Suspected transmission via an investigational product of an infectious agent.
Special reporting situations should be recorded on the AE CRF page. Any special reporting situation that meets the criteria of a SAE should be recorded on the SAE form and reported as required (see Section 13.3).
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13.2. reporting adverse events

For serious and non-serious AEs, the reporting period to the Sponsor (or its designated representative) begins from the time that the patient provides informed consent, which is obtained prior to the patient's participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through 28 calendar days after the last administration of the investigational product. For all AEs with causal relationship to the investigational product, follow-up by the Investigator may be required until the event or its sequelae resolve or stabilize at the level acceptable to the Investigator, and the Sponsor concurs with that assessment. If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at the time the new treatment is started. Death must be reported if it occurs during the SAE reporting period after the last dose of investigational product, irrespective of any intervening treatment. The Sponsor will evaluate any safety information that is spontaneously reported by an Investigator beyond the time frame specified in the protocol.
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13.3. reporting serious adverse events

All SAEs, irrespective of relationship to investigational product, must be reported within 24 hours of discovery or notification of the event to the Sponsor or designated representative using the SAE form. The SAE form must be signed by the Investigator. In particular, if the SAE is fatal or life-threatening, notification to the Sponsor must be made immediately, irrespective of the extent of available AE information. This timeframe also applies to follow-up information on previously forwarded SAE reports as well as to the initial and follow-up reporting of exposure during pregnancy and exposure via breast feeding cases. For SAE reporting information, please refer to the Study Contact List which is provided as a separate document. Relevant medical records should be provided to the Sponsor or its designated representative as soon as they become available; autopsy reports should be provided for deaths if available. Should an Investigator be made aware of any SAEs occurring any time after the reporting period that may be causally related to neratinib's administration, it should be promptly reported. All SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation of the patient's participation in the study, must be followed until any of the following occurs:  
The event resolves. The event stabilizes. The event returns to baseline, if a baseline value/status is available. The event can be attributed to agents other than the investigational product or to factors unrelated to study conduct.  
It becomes unlikely that any additional information can be obtained (patient or health care practitioner refusal to provide additional information, lost to follow-up after demonstration of due diligence with follow-up efforts).
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13.4. pregnancy

All initial reports of pregnancy must be reported to the Sponsor by the investigational staff within 24 hours of their knowledge of the event using the appropriate Exposure In Utero (EIU) form. For investigational products and for marketed products used as investigational product in neratinib studies, an exposure during pregnancy occurs if:  
A female becomes, or is found to be, pregnant either while receiving or having been directly exposed (eg, environmental exposure) to the investigational product, or the female becomes or is found to be, pregnant after discontinuing and/or being directly exposed to the investigational product (maternal exposure) for 28 days after last dose of or exposure to neratinib.  
A male partner of a pregnant female has been exposed to the investigational product, either due to treatment or environmental exposure, within 3 months prior to the time of conception and/or is exposed during his partner's pregnancy (paternal exposure).
If any study patient or study patient's partner becomes or is found to be pregnant during the study patient's treatment with the investigational product or exposure as defined above, the Investigator must submit this information on an EIU form to the Sponsor (or its designated representative). In addition, the Investigator must submit information regarding environmental exposure to an investigational product in a pregnant woman (eg, a patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) using the EIU form. This must be done irrespective of whether an AE has occurred and within 24 hours of awareness of the pregnancy. The information submitted should include the anticipated date of delivery (see following information related to induce termination of pregnancy). Follow-up is conducted to obtain pregnancy outcome information on all exposure during pregnancy reports with an unknown outcome. The Investigator will follow the pregnancy until completion or until pregnancy termination (eg, induced abortion) and then notify the Sponsor or its designated representative of the outcome as a follow-up to the initial EIU form. In the case of a live birth, the structural integrity of the neonate can be assessed at the time of birth. In the event of a termination, the reason(s) for termination should be specified and, if clinically possible, the structural integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and the findings are reported). If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [including that in a live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the Investigator should follow the procedures for reporting SAEs. Additional information about pregnancy outcomes that are classified as SAEs follows:
"Spontaneous abortion" includes miscarriage and missed abortion.  
All neonatal deaths that occur within 1 month of birth should be reported, without regard to causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs when the Investigator assesses the infant's death as related to exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested by the Investigator. Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be required.
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13.5. sponsor reporting requirements to

The Sponsor assumes responsibility for reporting of AEs including SUSARs according to local and international regulations, as appropriate. The Investigator (or the Sponsor where required) must report these events to the appropriate IRB/IEC that approved the protocol unless otherwise required and documented by the IRB/IEC.
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14. ethical legal and administrative

The Sponsor of this study may delegate some administrative aspects of this study to a duly authorized representative including, but not limited to, study initiation, monitoring, and management of SAE reports.
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14.1. data collection processing and

All data captured for the study is planned to be electronic using the Electronic Data Capture system. However, if necessary and only if requested by the Sponsor, data capture may be performed using paper CRFs. eCRFs will be provided by the Sponsor or its representative and should be handled in accordance with the instructions provided by the Sponsor or designated representative. The Investigator is responsible for maintaining adequate and accurate eCRFs which have been designed to record all observations and other data pertinent to the clinical investigation. Visit data should be entered into the eCRFs within 5 business days. Each eCRF should be completed by the Investigator or delegate as stated in the Site Delegation List. The site will perform data entry of all eCRFs as per source documents. Completion Instructions for eCRFs will be provided for the Study Coordinator's use. The data should be reviewed, signed and dated by the Investigator electronically for accuracy and completeness. Once the site monitor has verified the contents of the completed eCRF pages against the source data, queries may be raised if the data are unclear or contradictory. These queries must be addressed by the Investigator and verified by the clinical research associate (CRA). After all the data issues are resolved, these eCRFs may be locked to prevent any further data changes.
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14.1.2. study monitoring and access

To ensure compliance with relevant regulations, data generated by this study must be available for inspection upon request by representatives of the US Food and Drug Administration (FDA),
the European Medicines Agency (EMA), other national authorities (eg, the United Kingdom Medicines and Healthcare products Regulatory Agency, the German Federal Institute for Drugs and Medical Devices, and local health authorities as applicable, the Sponsor and representatives, and the IRB/IEC for each study site. The Investigator will permit authorized representatives of the Sponsor, the respective national or local health authorities, and auditors to inspect facilities and records relevant to this study. The Sponsor or representative's monitor is responsible for verifying the CRFs at regular intervals throughout the study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence to local regulations on the conduct of clinical research. Source data to be reviewed during this study will include, but is not restricted to: patient's medical file, patient's diary cards (if applicable), and original laboratory test, histology, and pathology reports. All key data must be recorded in the patient's hospital notes. Auditors, IRB/IEC and/or regulatory inspectors will also have access to the CRFs and source documents. The ICF will include a statement by which the patient allows the monitor/auditor/inspector from the IRB/IEC or regulatory authority access to source data (eg, patient's medical file, appointment books, original laboratory test reports, X-rays, etc.) that substantiate information in the CRFs. These personnel, bound by professional secrecy, will not disclose any personal information or personal drug information.
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14.1.3. data quality assurance

During and/or after completion of the study, quality assurance auditor(s) named by the Sponsor or the regulatory authorities may wish to perform on-site audits. The Investigators will be expected to cooperate with any audit and provide assistance and documentation (including source data) as requested. The Sponsor's representatives are responsible for contacting and visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the various records of the clinical study (eg, CRFs and other pertinent data) provided that patient confidentiality is respected. The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the course of these monitoring visits, including delays in completing CRFs, are resolved. In accordance with ICH E6 Good Clinical Practice (GCP) and the Sponsor's audit plans, this study may be selected for audit by representatives from the Sponsor's (or designee's) Quality Assurance Department. Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) and review of study-related records will occur to evaluate the study conduct and compliance with the protocol, ICH GCP (ICH E6), US Investigational Drugs (21 CFR§50, §54, §56, and §312), EU Clinical Studies Directive (Directive 2001/20/EC), and applicable regional regulatory requirements.
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14.1.4. data processing

All data will be entered by site personnel into the electronic data capture system/CRF (as detailed in Section 14.1.1). The data-review and data-handling document will include specifications for consistency and plausibility checks on data and will also include data-handling rules for obvious data errors. Query/correction sheets for unresolved queries will be sent to the study monitors for resolution with the Investigator. The database will be updated on the basis of signed corrections. Previous and concomitant medications will be coded using the World Health Organization Drug Reference List, which employs the Anatomical Therapeutic Chemical (ATC) classification system. Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The versions of the coding dictionaries will be provided in the Clinical Study Report (CSR).
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14.1.5. retention of data and

As described in the ICH GCP Guidelines, 'essential documents', including CRFs, source documents, ICFs, laboratory test results, and drug inventory records, should be retained by the Investigator until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period; however, if required by the applicable regulatory requirements or by agreement with the Sponsor. The Investigator should obtain written permission from the Sponsor prior to the destruction of any study document. These records should be made available at reasonable times for inspection and duplication, if required, by a properly authorized representative of the US FDA in accordance with 21 CFR §312.68 or other National Regulatory Authorities.
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14.2. ethical aspects 14.2.1. good

This protocol accords with the principles of the World Medical Association Declaration of Helsinki as set forth at the 18th General Assembly (World Medical Association Declaration of Helsinki, Helsinki, Finland, 1964) and amendments thereto. The most current amended version will be in effect. The procedures set out in this study protocol are also designed to ensure that the Sponsor and Investigator abide by the principles of the GCP guidelines of the ICH and in keeping with local legal requirements.
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14.2.2. informed consent responsibilities

It is the responsibility of the Investigator to obtain written informed consent from the patient or patient's legal representative. If informed consent has not been obtained, then no protocol required procedures are to be performed on the patient and no patient data are to be transferred to the Sponsor. Documentation of informed consent must be recorded in the source documents for each patient. The study will be discussed with the patient, and the patient will receive written information and an explanation of what the study involves, ie, the objectives, potential benefits and risk, inconveniences and the patient's rights and responsibilities. If applicable, the information will be provided in a certified translation of the local language. A signed, IRB/IEC approved ICF must be obtained from patient before any study specific procedures can occur. Confirmation of the patient's informed consent and the informed consent process must also be documented in the patient's medical record. Signed ICFs must remain in each patient's study file and must be available for verification by study monitors at any time. A copy of the fully signed ICFs will be given to the patient. If the IRB/IEC requires modification of this form, the documentation supporting this requirement must be provided to the Sponsor, along with the new version. The Sponsor reserves the right to reject these modifications, should they not cover the minimum information required by ICH GCP. A patient wishing to participate must also provide Authorization for Use and Release of Health and Research Study Information prior to any study-related procedures or change in treatment. If a patient is not physically or mentally competent to understand and to give their informed consent to participate in the study (eg, is blind or illiterate), a legally acceptable representative or impartial witness as applicable, may sign the ICF on behalf of the patient. It remains the responsibility of the principal Investigator to assure that the patient is suitable for inclusion in this study and will be able to adhere to all study procedures throughout the course of the study. The explicit wish of a minor, or mentally incapacitated adult, who is capable of forming an opinion and assessing the study information, to refuse participation in or to be withdrawn from the study at any time will be respected by the Investigator. If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the protocol. If the consent form is revised, it must be reviewed and approved by the appropriate IRB/IEC, and signed by all patients subsequently enrolled in the study as well as those currently enrolled in the study.
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14.3. other study administrative aspects

The protocol (approved by the Sponsor or its representative) will be submitted to the IRB/IEC for review and it must be approved before the study is initiated. Prior to implementing changes in the study, the Sponsor will produce a protocol amendment and the IRB/IEC must also approve any amendments to the protocol. Any change in the study plan requires a protocol amendment. An Investigator must not make any changes to the study without IRB/IEC and Sponsor approval except when necessary to eliminate apparent immediate hazards to the patients. A protocol change intended to eliminate an apparent immediate hazard to patients may be implemented immediately, but the change must then be documented in an amendment, reported to the IRB/IEC within 5 working days, and submitted to the appropriate regulatory agency in the required time frame. All protocol amendments must be reviewed and approved, by the Sponsor and the Investigator.
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14.3.2. investigator responsibilities

The Investigator undertakes to perform the study in compliance with the protocol, ICH Guidelines per GCP and the applicable regulatory requirements. A copy of the guidelines will be available in the Investigator Site File. It is the Investigator's responsibility to ensure that adequate time and appropriate resources are available at the investigational site prior to commitment to participate in this study. The Investigator should also be able to demonstrate a potential for recruiting the required number of suitable patient within the agreed recruitment period. The Investigator will maintain a list of appropriately qualified persons to whom the Investigator has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the Investigator and sub-Investigator(s) will be provided to the Sponsor (or its representative) before starting the study. If the patient has a primary physician, the Investigator should, with the patient's consent, inform the primary physician of the patient's participation in the study. Agreement with the final CSR will be documented by the signed and dated signature of the principal or coordinating Investigator (Lead Investigator of the study) in compliance with ICH E3.  
The Investigator must adhere to the protocol as detailed in this document. The Investigator will be responsible for enrolling only those patients who have met protocol eligibility criteria. The Investigators will be required to sign an Investigator agreement to confirm acceptance and willingness to comply with the study protocol. It is the Investigator's responsibility to communicate with their local IRB/IEC to ensure accurate and timely information is provided at all phases during the study. In particular, the appropriate approvals must be in place prior to recruitment, notification of any SAEs during the study must take place and the IRB/IEC must be informed of study completion. It is the responsibility of the Investigator to submit this protocol, the final approved informed consent document (approved by the Sponsor or its representative), relevant supporting information, all types of patient recruitment or advertisement information (approved by the Sponsor or its representative), and any other written information to be provided to the patient to the IRB/IEC for review and these must be approved before the study is initiated. Prior to implementing changes in the study, the Sponsor will produce a protocol amendment and the IRB/IEC must also approve any amendments to the protocol. On the approval letter, the study (title, protocol number and version), the documents reviewed (protocol, informed consent material, amendments) and the date of review should be clearly stated. Investigational product supplies will not be released and the patient recruitment will not begin until this written approval has been received by the Sponsor or its designee. The Investigator is responsible for keeping the IRB/IEC apprised of the progress of the study and of any changes made to the protocol as deemed appropriate, and at least once a year. The Investigator must also keep the IRB/IEC informed of any serious and significant AEs.
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14.3.3. patient responsibilities

Data collected during this study may be used to support the development, registration or marketing of neratinib. All data collected during the study will be controlled by the Sponsor (or designee) and the Sponsor will abide by all relevant data protection laws. After a patient has consented to take part in the study, their medical records and the data collected during the study will be reviewed by representatives of the Sponsor and/or the company organizing the research on the Sponsor's behalf to confirm that the data collected are accurate and for the purpose of analyzing the results. These records and data may additionally be reviewed by auditors or by regulatory authorities. The patient's name, however, will not be disclosed outside the hospital. They will be known by a unique patient number. The results of this study may be used in other countries throughout the world that have ensured an adequate level of protection for personal data. Written authorization (United States [US] sites only) or written informed consent in accordance with current data protection regulations (EU sites only) is to be obtained from each patient prior to enrollment into the study, and/or from the patient's legally authorized representative in accordance with the applicable privacy requirements (eg, the Health Insurance Portability and Accountability Act of 1996 Standards for Privacy of Individually Identifiable Health Information ("HIPAA"), General Data Protection Regulation (EU) 2016/679("GDPR") and any other state privacy requirements). If the patient is under the legal age of consent, the Authorization must be signed by the legally authorized representative in accordance with the applicable privacy requirements and other state privacy requirements.
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14.3.4. financial disclosure

The Investigator will be required to disclose any financial arrangement whereby the value of the compensation for conducting the study could be influenced by the outcome of the study; any significant payments of other sorts from the Sponsor, such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria; any proprietary interest in neratinib; any significant equity interest in the Sponsor, as defined in the US Code of Federal Regulations (21 CFR §54.2(b)). In consideration of participation in the study, the Sponsor will pay the Investigator, study site or nominated payee the sums set out in the payment schedule attached to the Investigator Agreement.
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14.3.5. publication policy

The Sponsor encourages publication of results derived from the clinical research it sponsors. Publications include a paper in a peer reviewed medical journal, abstract submission with a poster or oral presentation at a scientific meeting, or making results public by some other means. The Sponsor will retain the right to review all material prior to presentation or submission for publication and neither institution(s) nor Study Co-chairs/Principal Investigator(s) are permitted to publish/present the results of the study, in part or in their entirety, without the written authorization of the Sponsor. The review is aimed at protecting the Sponsor's pre-existing propriety information and commercial interests.
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first publication

The results of the entire multicenter study shall be presented in a first publication upon completion of the entire multicenter study (data lock), with authorship being determined by the Sponsor and Study Investigators using the criteria defined by the International Committee of Medical Journal Editors. At least two Sponsor representatives will also be included as coauthors on the first publication of the results of the entire multicenter study to allow recognition of the Sponsor's involvement in the design and execution of the study.
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subsequent publications

Results from data subsets should not be published in advance of the first publication, and must make reference to it. Publications must include at least 2 Sponsor authors to allow recognition of the Sponsor's involvement. In all publications, the study is to be identified as PUMA-NER-6201. The Study Principal Investigator(s) shall be free to publish or present, subject to the timing described in the Clinical Study Agreement.
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15. reference list

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2011;10:2019.  
Saini KS, Azim HA, Metzger-Filho O, et al. Beyond trastuzumab: New treatment options for HER2-positive breast cancer. *The Breast* 2011;20:S20-S27. Saura C, Garcia-Saenz JA, Xu B, et al. Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. *J Clin Oncol* 2014;32. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J and Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. *Cancer Res* 2009;69:9330-9336. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. *Science*. 1987;235:177-182. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. *Science* 1989;244:707-712. Swain SM, Kim S, Cortes J, et al. Final overall survival (OS) analysis from the CLEOPATRA study of first-line (1L) pertuzumab (Ptz), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). Presented at: ESMO 2014 Congress; 26-30 September, 2014; Madrid, Spain, Abstract 350O_PR. Tatro, DS. Drug Interaction Facts: The Authority on Drug Interactions. St. Louis, MI: Wolters Kluwer Health; 2012.  
Uceris® (budesonide) extended release tablets [Package Insert]. US Prescribing Information, Uceris® (budesonide extended release tablets). Santarus, Inc., Raleigh, NC 27615. Available at:
www.accessdata.fda.gov/ scripts/cder/drugsatfda, accessed on 10-NOV-2016. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. *N Engl J Med* 2012;367:1783-91. Erratum in *N Engl J Med* 2013;368:2442.  
Vermeij J, Teugels E, Bourgain C, et al. Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers. *BMC Cancer*. 2008;8:3. Widdison WC, Wilhelm SD, Cavanagh EE, et al. Semisynthetic maytansine analogues for the targeted treatment of cancer. *J Med Chem* 2006;49:4392-4408. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. *J Clin Oncol* 2013;31:3997-4013 Xia W, Liu LH, Ho P and Spector NL. Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. *Oncogene* 2004;23:646-653. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. *Nat Rev Mol Cell Biol*. 2001;2:127-137. Zaczek A, Brandt B and Bielawski KP. The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol Histopathol 2005;20:1005-1015.  
Zhang H, Berezov A, Wang Q, et al. ErbB receptors: from oncogenes to targeted cancer therapies. *J Clin Invest* 2007;117:2051-2058.
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16. signature pages declaration of

Title of Study: An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide.
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study number puma-ner-6201

I have read and approve this protocol. My signature, in conjunction with the signature of the Investigator, confirms the agreement of both parties that the clinical study will be conducted in accordance with the protocol and all applicable laws, regulations, and guidelines, including, but not limited to, the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the United States Code of Federal Regulations (CFR), the Directives of the European Union, the ethical principles that have their origins in the Declaration of Helsinki, and applicable privacy laws. _____________________________________ Signature _____________________________________ _____________________ Name (Printed) Date _____________________________________ Title
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declaration of principal investigator

Title of Study: An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide.
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study number puma-ner-6201

I have read and approve this protocol. My signature, in conjunction with the signature of the Sponsor, confirms the agreement of both parties that the clinical study will be conducted in accordance with the protocol and all applicable laws, regulations, and guidelines, including, but not limited to, the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the United States Code of Federal Regulations (CFR), the Directives of the European Union, the ethical principles that have their origins in the Declaration of Helsinki, and applicable privacy laws. The study will not be commenced without the prior written approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). No changes will be made to the study protocol without the prior written approval of the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the patients. Nothing in this document is intended to limit the authority of a physician to provide emergency medical care under applicable regulations. _____________________________________ Signature _____________________________________ ______________________________ Name (Printed) Date _____________________________________ ______________________________
Title Institution (block letters) and site number
_____________________________________ ______________________________ Address Phone number
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schedule of procedures appendix 1.

| Table A1.1.                              |  Schedule of Study Procedures                           | Safety        |       |       |        |     |     |    |      |
|------------------------------------------|---------------------------------------------------------|---------------|-------|-------|--------|-----|-----|----|------|
| Active Treatment a                       |                                                         |               |       |       |        |     |     |    |      |
| Screening                                | Follow-up                                               |               |       |       |        |     |     |    |      |
| Study Procedures                         | Cycle / Day (C/D)                                       | Visit         |       |       |        |     |     |    |      |
| Days                                     | C13/D28 / End of                                        | 28 Days After |       |       |        |     |     |    |      |
| C1/D1                                    | C2/D1                                                   | C3/D1         | C4/D1 | C7/D1 | C10/D1 |     |     |    |      |
| -28 to -1                                | Treatment Visit®                                        | Last Dose     |       |       |        |     |     |    |      |
| Study visit window in Days               | 0                                                       | -3 b          | ±5    | ±10   | ±10    | ±14 | ±14 | ±5 | ($5) |
| Informed consent 9                       | X                                                       |               |       |       |        |     |     |    |      |
| Medical/Cancer history/Demography        | X                                                       |               |       |       |        |     |     |    |      |
| ERBB2 status documentation d             | x                                                       |               |       |       |        |     |     |    |      |
| X                                        |                                                         |               |       |       |        |     |     |    |      |
| ECOG performance status                  |                                                         |               |       |       |        |     |     |    |      |
| Serum or urine β-hCG°                    | X                                                       | X             | X     | X     | X      | X   | X   | X  | X    |
| Physical examination                     | X                                                       | X             |       |       |        |     |     |    |      |
| Targeted physical examination"           | x                                                       | x             | X     | X     | x      | x   |     |    |      |
| Vital signs®                             | X                                                       | X             | X     | X     | X      | X   | X   | X  |      |
| Complete blood count plus differential h | X                                                       | X             | x     | x     | x      | x   | x   | X  |      |
| Serum chemistry 1                        | X                                                       | x             | X     | X     | x      | X   | x   | X  |      |
| Liver function tests                     | X                                                       | X             | X     | X     | X      | X   | X   | X  |      |
| Biomarkers"                              | X                                                       | X             | X     |       |        |     |     |    |      |
| Stool swab for microbiome evaluation¹    | X                                                       | X             | X     |       |        |     |     |    |      |
| MUGA or ECHO™                            | x                                                       | x             |       |       |        |     |     |    |      |
| ECG (12-lead)                            | X                                                       | X             | X     | X     | X      | X   |     |    |      |
| Bone scan or PET scan"                   | X                                                       |               |       |       |        |     |     |    |      |
| CT scan or MRI or ultrasound of the      | X                                                       |               |       |       |        |     |     |    |      |
| abdomen and chest"                       |                                                         |               |       |       |        |     |     |    |      |
| Health outcomes assessments P            | X                                                       | X             | X     | X     | X      | X   |     |    |      |
| Concomitant medications or treatments 9  | x                                                       | x             | x     | x     | x      | x   | x   | X  | x    |
| Neratinib administration'                | Continuous once-daily dosing (pill count at each visit) |               |       |       |        |     |     |    |      |
| For loperamide dosing                    |                                                         |               |       |       |        |     |     |    |      |
| during C1 & C2, see                      |                                                         |               |       |       |        |     |     |    |      |
| Loperamide administration'               | As needed                                               |               |       |       |        |     |     |    |      |
| Footnote "I"                             |                                                         |               |       |       |        |     |     |    |      |
| (pill count at each visit)               |                                                         |               |       |       |        |     |     |    |      |  
Amendment 7.1  
| Protocol: PUMA-NER-6201                                                                                                                         | Amendment 7.1     |               |       |       |        |     |    |     |
|-------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|---------------|-------|-------|--------|-----|----|-----|
| Safety                                                                                                                                          |                   |               |       |       |        |     |    |     |
| Active Treatment®                                                                                                                               |                   |               |       |       |        |     |    |     |
| Screening                                                                                                                                       | Follow-up         |               |       |       |        |     |    |     |
| Study Procedures                                                                                                                                | Cycle / Day (C/D) | Visit         |       |       |        |     |    |     |
| Days                                                                                                                                            | C13/D28 / End of  | 28 Days After |       |       |        |     |    |     |
| C1/D1                                                                                                                                           | C2/D1             | C3/D1         | C4/D1 | C7/D1 | C10/D1 |     |    |     |
| -28 to -l                                                                                                                                       | Treatment Visit"  | Last Dose     |       |       |        |     |    |     |
| -3 b                                                                                                                                            |                   |               |       |       |        |     |    |     |
| Study visit window in Days                                                                                                                      | 0                 | ±5            | ±10   | ±10   | ±14    | ±14 | ±5 | (5) |
| Anti-inflammatory or colestipol                                                                                                                 | X                 |               |       |       |        |     |    |     |
| administration 2                                                                                                                                | X--               | x             |       |       |        |     |    |     |
| Adverse events'                                                                                                                                 | --X               |               |       |       |        |     |    |     |
| Phone calls to patient after first dosen                                                                                                        | x                 |               |       |       |        |     |    |     |
| Abbreviations: β-liCG=beta-human chorionic gonadotropin; C=cycle; CT = computed tomography; D=day; ECG= electrocardiogram; ECHO=echocardiogram; |                   |               |       |       |        |     |    |     |  
ECOG=Eastern Collaborative Oncology Group; ERBB2=human epidermal growth factor receptor 2; MRI = magnetic resonance imaging; MUGA=multiple-gated acquisition scan; PET = positron emission tomography. A treatment cycle is defined as 28 days.  The Cycle 13/Day 28 Visit (EOT Visit) will be performed as soon as possible, but no later than 5 business days after the last dose and before start of new anticancer regimen.  If patient discontinues study treatment for reasons of toxicity or disease progression, all activities indicated for the EOT Visit should be conducted within 5 business days of last dose of neratinib.  All visit dates are calculated from the date of first dose.  If a visit occurs before or after a scheduled visit date, the next visit is still expected to occur on the date initially calculated for this visit, and is not shifted due to an earlier or later prior visit.  
Screening procedures and enrollment may occur on one day, however, enrollment must not be done before all screening procedures have been completed and results confirming eligibility have been reviewed.  
Informed consent must be obtained before any protocol required assessments are performed.  Certain procedures done prior to informed consent as part of the standard work-up are acceptable, as long as they have been performed within 28 days from the date of enrollment.  Acceptable procedures are: complete blood count (with differential), serum chemistry, MUGA/ECHO, ECGs, CT scan/MRI/ultrasound of abdomen and chest, and bone scan or PET scan. When obtaining the patient's informed consent, the Investigator must review with the patient the Patient Instructions for the Management of Diarrhea and the Patient Diary for the patient's daily recording of neratinib dose, (for patients starting with Amendment 7, this will be for every cycle of the study), any adverse reactions, number of loose stools and use of loperamide and/or other antidiarrheals (for patients starting under Amendment 7, adverse reactions, stools, and antidiarrheals are to be documented only for the first 2 cycles [36 days]). Both the patient and the Investigator must sign the patient instructions for the management of diarrhea. Copies of both documents are handed to the patient before she leaves the site with neratinib and loperamide on Cycle 1/Day 1. The Investigator must also complete and sign the Investigator Checklist by Cycle 1/Day 1.  
Documentation of locally assessed ERBB2-amplified status by fluorescence in situ hybridization (FISH) (>2.2) or ERBB2 overexpression by immunohistochemistry (IHC) (3+) must be retrieved.  
For women of childbearing potential; to be performed both at screening and within 72 hours prior to Cycle 1/Day 1, and monthly, including at the End-of-
Treatment Visit and at the Safety Follow-up Visit. The Investigator or research staff must contact patients on months that do not have a scheduled visit to confirm that the patient has performed the pregnancy test. In addition, a pregnancy test may be done at any time during the study at the discretion of the investigator if a subject misses a period or has unusual menstrual bleeding.  
During treatment, brief symptom-guided physical examinations will be done on Day 1 of Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 7, and Cycle 10.  
g Vital signs will be measured after resting in a seated position for 5 minutes, prior to dosing, and will include: blood pressure (systolic and diastolic; mmHg),
resting heart rate (beats per minute), body temperature (°C), respiration rate, weight (kg), height (screening only).  
h Complete blood count (CBC) to include hematocrit (Hct), hemoglobin (Hb), platelet count, red blood cell (RBC) count, and white blood cell (WBC) count plus differential. CBCs must be tested at screening and on Day 1 of Cycle 1 (-3 days), Cycle 2 (±5 days), Cycle 3 (±10 days), Cycle 4 (±10 days), Cycle 7
(±14 days), Cycle 10 (±14 days), as well as on Day 28 of Cycle 13/EOT Visit (±5 days), and as clinically indicated. Visits for CBC testing should be aligned with LFT testing and other routine study visits when possible. The Cycle 1/Day 1 tests do not need to be performed, if the screening tests were done within 72 hours of enrollment.  
i Serum chemistry tests include sodium, potassium, chloride, calcium, magnesium, blood urea nitrogen (BUN) or urea, serum creatinine, albumin, lactate dehydrogenase (LDH), phosphorus, and glucose (non-fasting). The Cycle 1/Day 1 tests do not need to be performed, if the screening tests were done within 72 hours of enrollment. For Amendment 4 and Amendment 5 patients who will be receiving colestipol, a baseline (occurring at Screen or C1D1) and C2D1 fasting lipid panel is required to assess total cholesterol, HDL-C, and triglycerides.  
j Liver function tests (LFTs) must include total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST).  
LFTs must be tested at screening, and on Day 1 of Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 7, and Cycle 10, as well as on Day 28 of Cycle 13/EOT Visit (±5 days), and as clinically indicated. Visits for LFT testing should be aligned with CBC testing and other routine study visits when possible. LFTs should also be tested in patients experiencing Grade 3 or higher diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia. During the evaluation of potential hepatotoxicity, bilirubin should be fractionated and prothrombin time should be measured. Also, liver imaging should be obtained for patients with any signs or symptoms of hepatotoxicity and/or Grade 3 or higher LFT elevations, or as clinically indicated. Refer to the guidelines for the management of LFT changes in the main section of the protocol (see Appendix 2).  
k For patients enrolled starting with Amendment 2 only: cfDNA will be obtained from plasma samples collected at screening, C7D1, C13D28, and/or at time of treatment discontinuation and at disease recurrence; cfDNA will undergo molecular profiling to identify biomarkers of disease recurrence.  
l At selected centers, a small stool swab from toilet paper, inserted into a tube that is provided, will be collected by the patient at Screening, C2D1, and C4D1 or at time of treatment discontinuation if earlier than C4D1 for possible future assessments of microbiome. The tube is to be inserted into a bag then labeled for return in packaging.  
m During trial participation, ECHO or MUGA will be performed at Screening and on Day 28 of Cycle 13/EOT Visit. It is strongly recommended to use the same method of measurement for the same patient throughout the duration of the study.  
n Per standard of care, bone scan or positron emission tomography (PET) scan performed within 28 days prior to the date of enrollment; only required if alkaline phosphatase (ALP) is ≥2x upper limit of normal (ULN) and/or there are symptoms of metastatic bone disease. A confirmatory imaging study is required if the results from the bone scan are questionable (see Section 5.1).  
o Per standard of care, computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound of the abdomen and chest performed within 28 days prior to the date of enrollment; only required if aspartate aminotransferase (AST)/alanine aminotransferase (ALT) or ALP is ≥2x ULN (see Section 5.1).  
p For patients enrolled starting with Amendment 2 only: Health outcomes assessments consist of the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) and the EQ-5D-5L questionnaires. For patients enrolled starting with Amendment 6.1: the Rotterdam Symptom Checklist (RSCL) will be added to the health outcomes questionnaires that the patient will complete. Questionnaires should be completed before any other study procedures on the day of the study visit. At the final or EOT visit, it is acceptable for questionnaires to be completed after study procedures. Questionnaires are to be completed by the patient at C1D1, C2D1, C4D1, C7D1, C10D1, and C13D28.  
q Concomitant medications and concomitant nonpharmacologic treatments/therapies are recorded from 30 days before signing of the informed consent form until the Safety Follow-up Visit.  
r Patients enrolled starting with Amendment 6 will receive neratinib at a starting dose of 120 mg/day with dose escalation (ie, total dose 120 mg daily for the first week, 160 mg daily for the Week 2, and 240 mg daily for Week 3 and thereafter, until EOT. For patients receiving budesonide, loperamide is to be administered daily for two (2) 28-day cycles and then as needed (PRN). For patients in Amendment 4, loperamide is to be administered for one 28-day cycle and then as needed (PRN) thereafter. For patients enrolled under Amendment 5, Amendment 6, Amendment 6.1, Amendment 7, and Amendment 7.1, loperamide is to be administered as needed (PRN) for the entire study. Patients are asked to document administration of neratinib and loperamide on a diary on a daily basis (for patients starting with Amendment 6.1, this will be for the first 2 cycles (56 days) of the study; for patients starting with Amendment 7, after 2 cycles only neratinib administration is to be recorded, until EOT), and to return this diary to the site at appropriate visits (for patients starting with Amendment 6.1, the diary will be collected at C3D1, or at EOT if earlier). Individual patient dosing compliance should be reviewed at each study visit by study site staff. Investigators must ensure that patients have loperamide on hand when starting to take neratinib. Loperamide and neratinib will be dispensed directly by the study sites on or before Cycle 1/Day 1 and during subsequent visits as needed. Loperamide is the recommended standard therapy to treat diarrhea in this study. If alternative antidiarrheal medication is used, the reason must be documented in the source documents. Acceptable reasons are non-tolerance of loperamide or lack of efficacy.  
s The effect of anti-inflammatory treatment (for patients enrolled under Amendment 3 and a bile acid sequestrant, colestipol, (for patients enrolled under Amendment 4 and Amendment 5) on the incidence and severity of Grade 3 or higher diarrhea will be investigated in 3 sequential patient cohorts. The first treatment cohort will receive budesonide + intensive loperamide prophylaxis, the next cohort will receive colestipol + intensive loperamide prophylaxis, and the subsequent cohort will receive colestipol + loperamide on a PRN only basis.  
t From the signing of the informed consent form to 28 days after the last dose, adverse events (AEs) and serious adverse events (SAEs) are monitored continuously and recorded in the electronic case report form (eCRF) at every visit. Patients must be instructed to contact the site to report and discuss the severity of diarrhea and the appropriate course of treatment. Patients must use the diary to document any episodes of diarrhea for the first 2 cycles (56 days) of the study. On this diary, patients also record the baseline number of stools per day, and in case of diarrhea, the number of loose stools per day and use of loperamide and/or other antidiarrheals, if applicable. Patients are asked to return this diary to the site at each visit. Patient instructions for the management of diarrhea are reviewed with the patients and handed to the patient at the time of enrollment. Should an Investigator be made aware of any SAEs occurring any time after the reporting period that may be causally related to neratinib's administration, it should be promptly reported.  
u The Investigator or research staff must call the patients 1, 2, and 3 days after the first dose of neratinib (i) to inquire about potential adverse events, including diarrhea; (ii) to provide guidance to the patients for immediate and appropriate management of AEs, including diarrhea as specified in this protocol; (iii) to confirm that the patients have loperamide available, in case needed; (iv) to inquire about the first date of neratinib intake; the Investigator/research staff must update the eCRF within 3 days of receipt of this information. In addition, for patients enrolled under Amendment 6, the Investigator or research staff must call patients at the end of the first and second weeks of treatment (ie, Day 7 or Day 8, and Day 14 or Day 15) to confirm that the patient has increased the dose of neratinib from 120 mg to 160 mg, and from 160 mg to 240 mg, respectively, as required by the protocol. For patients enrolled under Amendment 7 and Amendment 7.1, the Investigator or research staff must call patients at the end of the first 2 weeks of treatment (ie, Day 14 or Day 15) and at the end of Cycle 1 (C1D28 or C2D1) to confirm that the patient has increased the dose of neratinib from 160 mg to 200 mg, and from 200 mg to 240 mg, respectively, as required by the protocol.These phone calls are mandatory and must be recorded in the study chart together with response from the patient and action taken
(See Section 7.2).
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appendix 2. investigational product dose

Recommended dose reductions for the -1 and -2 dose levels of neratinib are listed in Table 3 in Section 6.1.1.  
For patients enrolled starting with Amendment 6, during the dose escalation phase (240 mg neratinib), for any patient who experiences Grade ≥2 AE(s) leading to neratinib dose interruption which do not resolve to Grade ≤ 1, a review of the patient and the patient's adverse event profile must occur with the Sponsor's Medical Monitor to determine whether the patient should be allowed to continue in the study.
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2. toxicities requiring investigational product

The guidelines for general toxicities are shown in Table A2.1.  
| Table A2.1.                                                                                   | General Toxicities Requiring Dose Adjustment of Neratinib                                                                                                                                                                                                                                    |
|-----------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| NCI CTCAE v.4.0                                                                               | Action                                                                                                                                                                                                                                                                                       |
| Grade 2 adverse reaction   1st appearance                                                    |  Hold neratinib until event resolves to Grade ≤1; then resume neratinib at the  starting dose level.                                                                                                                                                                                        |
|  2nd appearance                                                                              |  Hold neratinib until event resolves to Grade ≤1; then resume neratinib at  160 mg.                                                                                                                                                                                                         |
|  3rd appearance                                                                              |  Hold neratinib until event resolves to Grade ≤1; then resume neratinib at 120  mg.                                                                                                                                                                                                         |
|  4th appearance                                                                              |  Discontinue neratinib permanently.                                                                                                                                                                                                                                                         |
| Grade 3 adverse reaction  1st appearance                                                     |  Hold neratinib until event resolves to Grade ≤1; then resume neratinib at  160 mg.                                                                                                                                                                                                         |
|  2nd appearance                                                                              |  Hold neratinib until event resolves to Grade ≤1; then resume neratinib at  120 mg.                                                                                                                                                                                                         |
|  3rd appearance                                                                              |  Discontinue neratinib permanently.                                                                                                                                                                                                                                                         |
| Grade 4 adverse reaction  1st appearance                                                     |  Discontinue neratinib permanently OR if Investigator deems it to be in the  patient's best interest to continue, hold neratinib until resolved to Grade ≤1;  then resume neratinib at 160 mg.  If the event occurs again despite one dose reduction, permanently discontinued  neratinib. |
| Based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 |                                                                                                                                                                                                                                                                                              |
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gastrointestinal toxicity

Guidelines for adjusting doses of neratinib in the event of gastrointestinal toxicity diarrhea are shown in Table A2.2.
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table a2.2. gastrointestinal toxicities requiring

| NCI CTCAE V4.0                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Action                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Grade 1 Diarrhea [Increase of <4 stools per                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| day over baseline; mild increase in ostomy output  compared to baseline.] OR  Grade 2 Diarrhea [Increase of 4-6 stools per  day over baseline; moderate increase in ostomy  output compared to baseline;] lasting <5 days OR  Grade 3 Diarrhea [Increase of ≥7 stools per  day over baseline; incontinence; hospitalization  indicated; severe increase in ostomy output  compared to baseline limiting self-care activities  of daily living (ADL)] lasting ≤2 days |  Adjust anti-diarrheal treatment, as per the guidelines for  management of diarrhea at the first onset of diarrhea  Continue neratinib at full dose.   Instruct patient to follow dietetic recommendations in the  guidelines for management of diarrhea.  Fluid intake of ~2L should be maintained to avoid  dehydration.  Once the event resolved to ≤ Grade 1 or baseline, start  loperamide 4 mg with each subsequent neratinib administration.                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Persisting and intolerable Grade 2 Diarrhea                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| lasting ≥5 days despite being treated with optimal  medical therapy, or associated with fever,  dehydration, or Grade 3-4 neutropenia OR  Grade 3 Diarrhea lasting > 2 days despite  being treated with optimal medical therapy, or  associated with fever, dehydration, or Grade 3-4  neutropenia OR  Any Grade 4 diarrhea [Life-threatening  consequences; urgent intervention indicated]                                                                          |  Adjust anti-diarrheal treatment, as per the guidelines for  management of diarrhea at the first onset of diarrhea.  Hold neratinib until recovery to ≤ Grade 1 or baseline.  Instruct patient to follow dietetic recommendations of the  guidelines for management of diarrhea.   Fluid intake of ~2L should be maintained, intravenously if  needed.  If recovery occurs:  o ≤1 week after withholding treatment, resume same dose of  neratinib.  o Within 1-4 weeks after withholding treatment, reduce  neratinib dose to the next lower dose level.   If event occurs a 2nd time and the neratinib dose has not  already been decreased, reduce neratinib dose to the next  lower dose level.  If subsequent events occur, reduce neratinib dose to the next  lower dose level.   Once the event resolved to ≤ Grade 1 or baseline, start  loperamide 4 mg with each subsequent neratinib  administration. |
| Based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
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pulmonary toxicity

Guidelines for adjusting doses of neratinib in the event of pulmonary toxicities are shown in Table A2.3. Interstitial lung disease, which can sometimes be fatal, has been reported with other oral tyrosine kinase inhibitors that target EGFR ±HER2 (*ERBB2*), including lapatinib, gefitinib, and erlotinib. Rare cases of pneumonitis (0.6%) and lung infiltration (0.4%) have been reported in patients treated with neratinib monotherapy, and considered drug-related. Patients receiving neratinib should be monitored for acute onset or worsening of pulmonary symptoms such as dyspnea, cough, and fever and treated appropriately.  
| Table A2.3.                                                                                                                                                                                                  | Pulmonary Toxicities Requiring Dose Adjustment of Neratinib  NCI CTCAE V4.0 Action  Hold neratinib until recovery to ≤ Grade 1 or baseline.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|
|  Grade 2 Pneumonitis/Interstitial Lung Disease  [Symptomatic; medical intervention indicated;  limiting instrumental ADL]                                                                                   |  Reduce neratinib to 160 mg or discontinue neratinib as per Investigator's best medical judgment.  Discontinue neratinib permanently.        |
|  Grade 3 Pneumonitis/Interstitial Lung Disease  [Severe symptoms; limiting self-care ADL; oxygen  indicated] Based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 |                                                                                                                                                |
untitled h1
liver toxicity

Guidelines for adjustment of neratinib in the event of liver toxicity are shown in Table A2.4. Abnormal values in ALT concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in the absence of other causes of liver injury are considered potential cases of drug-induced liver injury (potential Hy's Law cases) and should always be considered important medical events. Patients who experience ≥Grade 3 diarrhea requiring IV fluid treatment or any signs or symptoms of hepatotoxicity such as worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia should be evaluated for changes in liver function tests. Fractionated bilirubin and prothrombin time must also be collected during hepatotoxicity evaluation. Table A2.4. Liver Function Test Abnormalities Requiring Dose Adjustment of Neratinib  
| NCI CTCAE V4.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Action                                                                                                                                                                                                                                                |                                                                                                                                                  |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 3 ALT (>5 - 20x ULN) OR  Grade 3 bilirubin (>3-10x ULN)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                      | Hold neratinib until recovery to ≤ Grade 1 for patients  with ALT ≤ Grade 1 at baseline OR ≤ Grade 2 for patients  with Grade 2 ALT at baseline. |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Evaluate alternative causes.                                                                                                                                                                                                                          |                                                                                                                                                  |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | For patients with ALT ≤ Grade 1 at baseline: Resume  neratinib at the next lower dose level if recovery to  ≤Grade 1 occurs within 4 weeks. If Grade 3 ALT or  bilirubin occurs again despite one dose reduction,  permanently discontinue neratinib. |                                                                                                                                                  |
| Grade 4 ALT (>20x ULN) OR Grade 4 Bilirubin (>10x ULN)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                      | Permanently discontinue neratinib.                                                                                                               |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Evaluate alternative causes.                                                                                                                                                                                                                          |                                                                                                                                                  |
| ALT >3x ULN AND Total bilirubin >2x ULN AND Alkaline phospatase <2x ULN (potential Hy's law indicators of drug-induced liver  damage)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                      | Hold neratinib.                                                                                                                                  |
| The patient should return to the investigational site and be  evaluated as soon as possible, preferably within 48 hours  from awareness of the abnormal results. This evaluation  should include laboratory tests, detailed history and  physical assessment and for oncology studies, the  possibility of hepatic neoplasm (primary or secondary)  should be considered. In addition to repeating AST and  ALT, laboratory tests should include albumin, total  bilirubin, direct bilirubin, PT and alkaline phosphatase. A  detailed history, including relevant information, such as  review of ethanol, concomitant medications, recreational  drug and supplement consumption, family history, sexual  history, travel history, history of contact with a jaundiced  patient, surgery, blood transfusion, history of liver or  allergic disease, and work exposure, should be collected.  Further testing for acute hepatitis A, B, or C infection and  liver imaging (eg, biliary tract) may be warranted. All cases  confirmed on repeat testing as meeting the criteria  mentioned above (i.e., ALT > 3 x ULN associated with  bilirubin >2 x ULN and alkaline phosphatase <2 x ULN),  with no other cause for liver function test abnormalities  identified at the time should be considered potential Hy's  Law cases, irrespective of availability of all the results of  the investigations performed to determine etiology of the  abnormal liver function tests. |                                                                                                                                                                                                                                                       |                                                                                                                                                  |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Contact the Sponsor immediately to discuss next steps,  including evaluation of alternative causes, and  management of investigational product.                                                                                                       |                                                                                                                                                  |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | These events must be reported as SAEs.                                                                                                                                                                                                                |                                                                                                                                                  |
| NOTE: During evaluation of hepatotoxicity, bilirubin must be fractionated, prothrombin time must be measured, and  liver imaging should be considered.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                       |                                                                                                                                                  |
untitled h1
eastern cooperative oncology group (ecog)

| Description                                                                          | Grade   |
|--------------------------------------------------------------------------------------|---------|
| Fully active, able to carry on all pre-disease performance without restriction.      | 0       |
| Restricted in physically strenuous activity, but ambulatory and able to carry out    | 1       |
| work of a light or sedentary nature, ie, light house work, office work.              |         |
| Ambulatory and capable of all self-care but unable to carry out any work activities. | 2       |
| Up and about more than 50% of waking hours.                                          |         |
| Capable of only limited self-care, confined to bed or chair more than 50% of         | 3       |
| waking hours.                                                                        |         |
| Completely disabled. Cannot carry on any self-care. Totally confined to bed or       | 4       |
| chair.                                                                               |         |
| Dead                                                                                 | S       |
untitled h1
appendix 4. inhibitors and inducers

| P450 ISOENZYMES                                                                                           |                       |                 |
|-----------------------------------------------------------------------------------------------------------|-----------------------|-----------------|
| CYP3A4 Inducers                                                                                           |                       |                 |
| Carbamazepine                                                                                             | Macrolide antibiotics | Rifabutin       |
| Efavirenz                                                                                                 | Phenobarbital         | Rifampin        |
| Glucocorticoids:                                                                                          | Phenylbutazone        | Rifapentine     |
| Dexamethasone                                                                                             | Phenytoin             | St. John's Wort |
| Prednisone                                                                                                | Primidone             | Sulfinpyrazone  |
| CYP3A4 Inhibitors                                                                                         |                       |                 |
| Amprenavir                                                                                                | Grapefruit juice      | Paroxetine      |
| Anastrozole                                                                                               | Indinavir             | Propranolol     |
| Cimetidine                                                                                                | Itraconazole          | Quinidine       |
| Clarithromycin                                                                                            | Ketoconazole          | Quinine         |
| Clotrimazole                                                                                              | Mibefradil            | Ranitidine      |
| Danazol                                                                                                   | Miconazole            | Ritonavir       |
| Delavirdine                                                                                               | Mirtazapine (weak)    | Saquinavir      |
| Diethyldithiocarbamate                                                                                    | Nefazodone            | Sertraline      |
| Sildenafil (weak)                                                                                         |                       |                 |
| Diltiazem                                                                                                 | Nelfinavir            |                 |
| Erythromycin                                                                                              | Nevirapine            | Troglitazone    |
| Fluconazole                                                                                               | Norfloxacin           | Troleandomycin  |
| Fluoxetine                                                                                                | Norfluoxetine         | Zafirlukast     |
| Fluvoxamine                                                                                               | CYP3A5-7 Inducers     |                 |
| Phenobarbital                                                                                             | Primidone             | Rifampin        |
| Phenytoin                                                                                                 |                       |                 |
| Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health 2012. |                       |                 |  
| (P-GP)                                                                                                    |                               |                                |
|-----------------------------------------------------------------------------------------------------------|-------------------------------|--------------------------------|
| P-glycoprotein Substrates                                                                                 |                               |                                |
| Amiodarone (eg, Cordarone)                                                                                | Fluphenazine (eg, Prolixin)   | Progesterone (eg, Prometrium)  |
| Chlorpromazine (eg, Thorazine)                                                                            | Hydrocortisone (eg, Cortef)   | Promethazine (eg, Phenergan)   |
| Clarithromycin (eg, Biaxin)                                                                               | Indinavir (Crixivan)          | Quinidine                      |
| Cyclosporine (eg, Neoral)                                                                                 | Itraconazole (eg, Sporanox)   | Reserpine                      |
| Dactinomycin (Cosmegen)                                                                                   | Ketoconazole (eg, Nizoral)    | Ritonavir (Norvir)             |
| Daunorubicin (eg, Cerubidine)                                                                             | Lidocaine (eg, Xylocaine)     | Saquinavir (eg, Fortovase)     |
| Dexamethasone (eg, Decadron)                                                                              | Loperamide (eg, Imodium)      | Sirolimus (Rapamune)           |
| Digoxin (eg, Lanoxin)                                                                                     | Lovastatin (eg, Mevacor)      | Tacrolimus (Prograf)           |
| Diltiazem (eg, Cardizem)                                                                                  | Mifepristone (Mifeprex)       | Tamoxifen (eg, Nolvadex)       |
| Doxorubicin (eg, Adriamycin)                                                                              | Mitoxantrone (Novantrone)     | Teniposide (Vumon)             |
| Erythromycin (eg, Ery-Tab)                                                                                | Nelfinavir (Viracept)         | Testosterone Delatestryl)      |
| Estradiol (eg, Estrace)                                                                                   | Nicardapine (eg, Cardene)     | Trifluoperazine                |
| Etoposide (eg, Vepesid)                                                                                   | Nifedipine (eg, Procardia)    | Verapamil (eg, Calan)          |
| Felodipine (Plendil)                                                                                      | Ondansetron (Zofran)          | Vinblastine (eg, Velban)       |
| Fexofenadine (Allegra)                                                                                    | Paclitaxel (eg, Taxol)        | Vincristine (eg, Vincasar PFS) |
| P-glycoprotein Inhibitors                                                                                 |                               |                                |
| Amiodarone (eg, Cordarone)                                                                                | Indinavir (Crixivan)          | Quinidine                      |
| Atorvastatin (Lipitor)                                                                                    | Itraconazole (eg, Sporanox)   | Reserpine                      |
| Chlorpromazine (eg, Thorazine)                                                                            | Ketoconazole (eg, Nizoral)    | Ritonavir (Norvir)             |
| Clarithromycin (eg, Biaxin)                                                                               | Lidocaine (eg, Xylocaine)     | Saquinavir (eg, Fortovase)     |
| Cyclosporine (eg, Neoral)                                                                                 | Mifepristone (Mifeprex)       | Tacrolimus (Prograf)           |
| Diltiazem (eg, Cardizem)                                                                                  | Nelfinavir (Viracept)         | Tamoxifen (eg, Nolvadex)       |
| Erythromycin (eg, Ery-Tab)                                                                                | Nicardipine (eg, Cardene)     | Testosterone (Delatestryl)     |
| Felodipine (Plendil)                                                                                      | Nifedipine (eg, Procardia)    | Trifluoperazine                |
| Fluphenazine (eg, Prolixin)                                                                               | Progesterone (eg, Prometrium) | Verapamil (eg, Calan           |
| Hydrocortisone (eg, Cortef)                                                                               | Propranolol (eg, Inderal)     |                                |
| Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health 2012. |                               |                                |
untitled h1
substrates and inhibitors of p-glycoprotein

| PROLONGATION LEADING TO TORSADE DE POINTES   |                                         |                      |
|----------------------------------------------|-----------------------------------------|----------------------|
| Drugs Reported to Prolong QT Interval        |                                         |                      |
| Analgesics                                   |                                         |                      |
| Celecoxib (Celebrex)                         | Methadone (eg, Dolophine, Methadose)    |                      |
| Anesthetic agents                            |                                         |                      |
| Enflurane (eg, Ethrane)                      | Halothane                               |                      |
| Isoflurane (eg, Forane)                      |                                         |                      |
| Antiarrhythmic agents                        |                                         |                      |
| Class IA                                     | Class III                               |                      |
| Disopyramide (eg, Norpace)*                  | Amiodarone (eg, Cordarone)* 6           |                      |
| Procainamide (eg, Procanbid)*                | Bretylium*                              |                      |
| Quinidine*                                   | Dofetilide (Tikosyn)* 6                 |                      |
| Class IC                                     | Ibutilide (Corvert)* b                  |                      |
| Flecainide (eg, Tambocor)*ª                  | Sotalol (eg, Betapace)* 6               |                      |
| Propafenone (eg, Rythmol)* b                 |                                         |                      |
| Anticonvulsants                              |                                         |                      |
| Felbamate (Felbatol)*                        | Fosphenytoin (Cerebyx)                  |                      |
| Antiemetics                                  |                                         |                      |
| Dolasetron (Anzemet) 6                       | Droperidol (eg, Inapsine)*®             | Ondansetron (Zofran) |
| Antihistamines                               |                                         |                      |
| Desloratadine (Clarinex) b (overdose)        | Fexofenadine (Allegra)                  |                      |
| Diphenhydramine (eg, Benadryl)               | Hydroxyzine (Atarax)                    |                      |
| Anti-infectives                              |                                         |                      |
| Amantadine (eg, Symmetrel)*                  | Macrolides and related antibiotics      |                      |
| Antimalarials                                | Azithromycin (eg, Zithromax)            |                      |
| Mefloquine (eg, Lariam) b                    | Clarithromycin (eg, Biaxin)* 6          |                      |
| Quinine*                                     | Erythromycin (eg, Ery-Tab, EES)* 6      |                      |
| Antivirals                                   | Telithromycin (Ketek) b                 |                      |
| Efavirenz (Sustiva)*                         | Troleandomycin                          |                      |
| Azole antifungal agents                      | Pentamidine (eg, Pentam 300, Nebupent)* |                      |
| Fluconazole (eg, Diflucan)* 6                | Quinolones                              |                      |  
| Protocol: PUMA-NER-6201                   | Amendment 7.1                                     |                           |
|-------------------------------------------|---------------------------------------------------|---------------------------|
| Drugs Reported to Prolong QT Interval     |                                                   |                           |
| Itraconazole (eg, Sporanox)               | Gatifloxacin (eg, Tequin)* 6                      |                           |
| Ketoconazole (eg, Nizoral)                | Levofloxacin (eg, Levaquin)*², b                  |                           |
| Voriconazole (Vfend) b                    | Moxifloxacin (eg, Avelox) b                       |                           |
| Chloroquine (eg, Aralen)*                 | Ofloxacin (eg, Floxin)* b                         |                           |
| Clindamycin (eg, Cleocin)                 | Sparfloxacin (Zagam) b                            |                           |
| Foscarnet (Foscavir)                      | Trimethoprim/sulfamethoxazole (eg, Bactrim)*      |                           |
| Antineoplastics                           |                                                   |                           |
| Arsenic trioxide (Trixenox)* b            | Doxorubicin (eg, Adriamycin)                      | Tamoxifen (eg, Nolvadex)  |
| Bronchodilators                           |                                                   |                           |
| Albuterol (eg, Proventil) 6               | Salmeterol (Serevent) b                           |                           |
| Formoterol (Foradil)®                     | Terbutaline (eg, Brethine) 6                      |                           |
| Isoproterenol (eg, Isuprel)               |                                                   |                           |
| Calcium channel blockers                  |                                                   |                           |
| Isradipine (DynaCirc)                     | Nicardipine (eg, Cardene)                         |                           |
| Contrast media                            |                                                   |                           |
| Ionic contrast media*                     | Non-ionic contrast media: Iohexol (Omnipaque)     |                           |
| Corticosteroids                           |                                                   |                           |
| Prednisolone (eg, Prelone)                | Prednisone (eg, Deltasone)*                       |                           |
| Diuretics                                 |                                                   |                           |
| Furosemide (eg, Lasix)                    | Indapamide (eg, Lozol)                            |                           |
| Gastrointestinal agents                   | Famotidine (eg, Pepcid)*                          |                           |
| Cisapride (Propulsid)* 64                 |                                                   |                           |
| Immunosuppressants                        |                                                   |                           |
| Tacrolimus (Protopic)* b (postmarketing)  |                                                   |                           |
| Miscellaneous                             |                                                   |                           |
| Levomethadyl                              | Papaverine (eg, Pavaden three times daily [TID])* |                           |
| Moexipril/Hydrochlorothiazide (Uniretic)  | Probucol (Lorelco)*                               |                           |
| Octreotide (Sandostatin) 6                | Vasopressin (eg, Pitressin)*                      |                           |
| Oxytocin (eg, Pitocin; intravenous bolus) |                                                   |                           |
| Psychotropics                             |                                                   |                           |
| Droperidol (eg, Inapsine)*                | Primozide (Orap)* 6.                              | Trazodone (eg, Desyrel)   |
| Haloperidol (eg, Haldol)*                 | Quetiapine (Seroquel) 6                           | Tricyclic antidepressants |  
| Protocol: PUMA-NER-6201                                     | Amendment 7.1                 |                            |
|-------------------------------------------------------------|-------------------------------|----------------------------|
| Drugs Reported to Prolong QT Interval                       |                               |                            |
| Lithium (eg, Eskalith)*                                     | Risperidone (Risperdal) 6     | Amitriptyline*             |
| (overdose)                                                  |                               |                            |
| Maprotiline*                                                | Serotonin Reuptake Inhibitors | Clomipramine (eg,          |
| (SRIs)                                                      | Anafranil)                    |                            |
| Phenothiazines                                              | Citalopram (eg, Celexa)*      | Desipramine (eg,           |
| Norpramin)*                                                 |                               |                            |
| Chrlorpromazine (eg,                                        | Fluoxetine (eg, Prozac)*²     | Doxepin (eg, Sinequan)*    |
| Thorazine)*                                                 |                               |                            |
| Fluphenazine (eg,                                           | Paroxetine                    | Imipramine (eg, Tofranil)* |
| Prolixin)*                                                  | (eg, Paxil)*                  |                            |
| Perphenazine                                                | Nortriptyline (eg, Pamelor)   |                            |
| Sertraline (Zoloft)*a.b                                     |                               |                            |
| (postmarketing)                                             |                               |                            |
| Thioridazine (Mellaril)* 6                                  | Venlafaxine (Effexor) b       |                            |
| (postmarketing)                                             |                               |                            |
| Trifluopherazine                                            |                               |                            |
| Serotonin 5-HT¹ agonists                                    |                               |                            |
| Naratriptan (Amerge)                                        | Sumatriptan (Imitrex) 6       | Zolmitriptan (Zomig) 6     |
| Skeletal muscle relaxants                                   |                               |                            |
| Tizanidine (eg, Zanaflex) b (animals)                       |                               |                            |
| Drugs for which Torsades de Pointes has also been reported. |                               |                            |  
Association unclear b QT, QTc, and/or Torsades de Pointes association listed in FDA-approved product labeling Source: Tatro, DS. Drug-induced Prolongation of the QT Interval and Torsades de Pointes. Drug Interaction Facts.  
The Authority on Drug Interactions. Wolters Kluwer Health 2012.
appendix 7. euroqol 5d-5l health
substrates and inhibitors of p-glycoprotein

Under each heading, please tick the ONE box that best describes your health TODAY.  
MOBILITY l have no problems in walking about l have slight problems in walking about  
| l have slight problems in walking about           |
|---------------------------------------------------|
| l have moderate problems in walking about         |
| l have severe problems in walking about           |
| l am unable to walk about                         |
| SELF-CARE                                         |
| l have no problems washing or dressing myself     |
| I have slight problems washing or dressing myself |  
I have slight problems washing or dressing myself I have moderate problems washing or dressing myself I have severe problems washing or dressing myself  
| I have severe problems washing or dressing myself        |
|----------------------------------------------------------|
| I am unable to wash or dress myself                      |
| USUAL ACTIVITIES (e.g. work, study, housework, family or |
| leisure activities)                                      |
| l have no problems doing my usual activities             |
| l have slight problems doing my usual activities         |
| I have moderate problems doing my usual activities       |
| l have severe problems doing my usual activities         |
| I am unable to do my usual activities                    |
| PAIN / DISCOMFORT                                        |
| l have no pain or discomfort                             |
| l have slight pain or discomfort                         |
| l have moderate pain or discomfort                       |
| l have severe pain or discomfort                         |
| l have extreme pain or discomfort                        |
| ANXIETY / DEPRESSION                                     |
| l am not anxious or depressed                            |
| l am slightly anxious or depressed                       |  
l am moderately anxious or depressed  
| l am severely anxious or depressed   |
|--------------------------------------|
| I am extremely anxious or depressed  |  
o o n  
  
D
D
o
→
�
D
UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group Amendment 7.1
.. .  
.  
.  
.  
  
3 UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group
appendix 7. euroqol 5d-5l health
appendix 8. functional assessment of

FACT-B (Version 4)
Below is a list of statements that other people with your illness have said are important. By circling one (1) number per line, please indicate how true each statement has been for you during the past 7 days.  
Very much 4 4 4 4 4 4 4 Very much 4 4 4 4 4 4 4 ol es o es e o er on ot OR
GM ol  
| PHYSICAL WELL-BEING                                         | Not      | A little   | Some   | Quite   |
|-------------------------------------------------------------|----------|------------|--------|---------|
| at all                                                      | bit      | what       | a bit  |         |
| I have a lack of energy                                     | o        | l          | 2      | 3       |
| I have nausea.                                              | o        | l          | 2      | 3       |
| Because of my physical condition, I have trouble            |          |            |        |         |
| meeting the needs of my family                              | o        | l          | 2      | 3       |
| I have pain.                                                | o        | l          | 2      | 3       |
| I am bothered by side effects of treatment                  | 0        | l          | 2      | 3       |
| I feel ill                                                  | o        | l          | 2      | 3       |
| I am forced to spend time in bed .                          | l        | 2          | 3      |         |
| 0                                                           |          |            |        |         |
| SOCIAL/FAMILY WELL-BEING                                    | A little |            |        |         |
| Not                                                         | Some     | Quite      |        |         |
| at all                                                      | bit      | what       | a bit  |         |
| I feel close to my friends .                                | o        | l          | 2      | 3       |
| I get emotional support from my family                      | 0        | l          | 2      | 3       |
| I get support from my friends                               | o        | l          | 2      | 3       |
| My family has accepted my illness.                          | o        | l          | 2      | 3       |
| I am satisfied with family communication about my           |          |            |        |         |
| illness                                                     | o        | l          | 2      | 3       |
| I feel close to my partner (or the person who is my         |          |            |        |         |
| main support)                                               | o        | l          | 2      | 3       |
| Regardless of your current level of secual activity, please |          |            |        |         |
| answer the following question. If you prefer not to answer  |          |            |        |         |
| it, please check this box I and go to the next section.     |          |            |        |         |
| I am satisfied with my sex life…………                         | o        | l          | 2      | 3       |  
18 In 1991, 1991
appendix 7. euroqol 5d-5l health
fact-b (version 4)

By circling one (1) number per line, please indicate how true each statement has been for you during the past 7 days.  
00 GE
GER
GH GES
GH  
| EMOTIONAL WELL-BEING                                              | Not   | A little   | Some-   | Quite   | Very   |
|-------------------------------------------------------------------|-------|------------|---------|---------|--------|
| at all                                                            | bit   | what       | a bit   | much    |        |
| I feel sad                                                        | 2     | 3          |         |         |        |
| 0                                                                 | i     | 4          |         |         |        |
| I am satisfied with how I am coping with my illness .......       | 2     |            |         |         |        |
| 0                                                                 | l     | 3          | 4       |         |        |
| I am losing hope in the fight against my illness ................ | 0     | i          | 2       | 3       | 4      |
| I feel nervous .                                                  | 0     | 1          | 2       | 3       | 4      |
| I wony about dying .                                              | o     | 1          | 2       | 3       | 4      |
| I wony that my condition will get worse.                          | 0     | 1          | 2       | 3       | 4      |  
| FUNCTIONAL WELL-BEING                                                  | Not   | A little   | Some-   | Quite   | Very   |
|------------------------------------------------------------------------|-------|------------|---------|---------|--------|
| at all                                                                 | a bit |            |         |         |        |
| bit                                                                    | what  | m much     |         |         |        |
| I am able to work (include work at home).............................  | 0     | 1          | 2       | 3       | 4      |
| My work (include work at home) is fulfilling .                         | 0     | 2          |         |         |        |
| i                                                                      | 3     | 4          |         |         |        |
| I am able to enjoy life                                                | 0     | 2          | 3       |         |        |
| l                                                                      | 4     |            |         |         |        |
| I have accepted my illness .                                           | 0     | i          | 2       | 3       | 4      |
| I am sleeping well .                                                   | o     | i          | 2       | 3       | 4      |
| I am enjoying the things I usually do for fun......................... | 0     | i          | 2       | 3       | 4      |
| I am content with the quality of my life right now ............        | 2     |            |         |         |        |
| 0                                                                      | 1     | 3          | 4       |         |        |  
G
e Gi i d 108 References FACT-B (Version 4)
By circling one (1) number per line, please indicate how true each statement has been for you during the past 7 days.  
| ADDITIONAL CONCERNS                                                   | Not   | A little   | Some-   | Quite   | Very   |
|-----------------------------------------------------------------------|-------|------------|---------|---------|--------|
| a bit                                                                 |       |            |         |         |        |
| at all                                                                | bit   | what       | much    |         |        |
| I have been short of breath.                                          | 0     | l          | 2       | 3       | 4      |
| I am self-conscious about the way I dress ........................... | 0     | 3          |         |         |        |
| l                                                                     | 2     | 4          |         |         |        |
| One or both of my arms are swollen or tender .                        | o     | l          | 2       | 3       | 4      |
| I feel sexually attractive                                            | 0     | 1          | 2       | 3       | 4      |
| I am bothered by hair loss                                            | 0     | i          | 2       | 3       | 4      |
| I wony that other members of my family might                          | 2     |            |         |         |        |
| someday get the same illness I have                                   | 0     | i          | 3       | 4       |        |
| I worry about the effect of stress on my illness                      | 0     | l          | 2       | 3       | 4      |
| I am bothered by a change in weight .                                 | 0     | l          | 2       | 3       | 4      |
| I am able to feel like a woman.                                       | o     | l          | 2       | 3       | 4      |
| I have certain parts of my body where I experience                    | o     | 3          |         |         |        |
| significant pain .                                                    | l     | 2          | 4       |         |        |  
81 2 83 ist as la as 28 2 72 100 International
appendix 7. euroqol 5d-5l health
appendix 9. contraindications warnings and

Budesonide Contraindications Known hypersensitivity to budesonide or any of the ingredients in budesonide tablets  
| Warnings and Precautions   |
|----------------------------|  
Hypercorticism and adrenal suppression- since budesonide is a glucocorticosteroid, follow general warnings concerning glucocorticoids:
When glucocorticoids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticoids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since budesonide is a glucocorticosteroid, general warnings concerning glucocorticosteroids should be followed.  
Transferring patients from systemic glucocorticoids: Risk of impaired adrenal function when transferring from glucocorticoid treatment with higher systemic effects to glucocorticoid treatment with lower systemic effects, such as budesonide. Taper patients slowly from systemic corticosteroids if transferring to budesonide.  
Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as budesonide, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop.  
Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.  
Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral or parasitic infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients.  
Patients who are on drugs that suppress the immune system are more susceptible to infection that healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.  
| disease and/or prior glucocorticoid treatment to the risk is also not known. If exposed,  therapy with varicella zoster immune globulin (VZIG) or pooled intravenous  immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles,  prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. See  prescribing information for VZIG and IG. If chicken pox develops, treatment with  antiviral agents may be considered.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Protocol: PUMA-NER-6201   | Amendment 7.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
|---------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Budesonide                | Contraindications  Glucocorticosteroids should be used with caution, if at all, in patients with active or  quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic  infections.  Replacement of systemic glucocorticosteroids with budesonide tablets may unmask  allergies (e.g., rhinitis and eczema), which were previously controlled by systemic drug.  Reduced liver function affects the elimination of glucocorticosteroids, and increased  systemic availability of oral budesonide has been demonstrated in patients with liver  cirrhosis.  Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis,  peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or  with any other condition where glucocorticosteroids may have unwanted effects. |
appendix 7. euroqol 5d-5l health
appendix 10. contraindications warnings and

Colestipol Contraindications  
| Known hypersensitivity to micronized colestipol hydrochloride tablets or any of the  ingredients in the tablets   |
|-------------------------------------------------------------------------------------------------------------------|  
Warnings and Precautions Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat absorptions and thus may reduce absorption of folic acid and fat soluble vitamins such a, D, and K.  
Chronic use of colestipol hydrochloride may be associated with an increased bleeding tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral administration of vitamin K1.  
Serum cholesterol and triglyceride levels should be determined periodically based on NCEP guidelines to confirm a favorable initial and adequate long-term response.  
| Micronized colestipol hydrochloride tablets may produce or severely worsen pre-existing  constipation. The dosage should be increased gradually in patients to minimize the risk of  developing fecal impaction. In patients with pre-existing constipation, the starting dose  should be 2 grams once or twice a day. Increased fluid and fiber intake should be  encouraged to alleviate constipation and a stool softener may occasionally be indicated. If  the initial dose is well tolerated, the dose may be increased as needed by a further 2 to 4  grams/day (at monthly intervals) with periodic monitoring of serum lipoproteins. If  constipation worsens or the desired therapeutic response is not achieved at 2 to 16  grams/day, combination therapy or alternate therapy should be considered. Particular  effort should be made to avoid constipation in patients with symptomatic coronary artery  disease. Constipation associate with micronized colestipol hydrochloride tablets may  aggravate hemorrhoids. While there have been no reports of hypothyroidism induced in individuals with normal  thyroid function, the theoretical possibility exists, particularly in patients with limited  thyroid reserve.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Since colestipol hydrochloride is a chloride form of an anion exchange resin, there is a possibility that prolonged use may lead to the development of hyperchloremic acidosis. Potential for Drug-drug Interactions  
Since colestipol is an anion exchange resin, this effect may be related to a strong affinity  
for anions other than the bile acids. In vitro studies have indicated that colestipol binds a  
number of drugs. Repeated doses of colestipol given prior to a single dose of propranolol in human trials have been reported to decrease propranolol absorption. Patients on propranolol and  
possibly other beta-blockers should be monitored when colestipol is added or deleted from  
Colestipol Contraindications  
| the therapeutic regimen. Effects of the absorption of other beta-blockers have not been  determined. Studies in humans show that the absorption of chorothiazide as reflected in urinary  excretion is markedly decreased even when administered one hour before colestipol. The  absorption of tetracycline, furosemide, penicillin G, hydrochlorothiazide, and gemfibrozil  was significantly decreased when given simultaneously with colestipol. These drugs were  not tested to determine the effect of administration one hour before colestipol. No lowering effect on blood levels in humans was noted when colestipol was administered  with any of the following drugs: aspirin, clindamycin, clofibrate, methyldopa, nicotinic  acid (niacin), tolbutamide, phenytoin or warfarin. Particular caution should be observed  with digoxin preparations since ther are conflicting results for the effect of colestipol on  the availability of digoxin and digitoxin. The potential for binding of these drugs if given  concomitantly is present. Discontinuing colestipol could pose a hazard to health if a  potentially toxic drug that is significantly bound to the resin has been titrated to a  maintenance level while the patient was taking colestipol. Bile acid bind resins such as coletipol may also interfere with the absorption of oral  phosphate supplements and hydrocortisone. A study has shown that cholestyramine binds bile acids and reduces mycophenolic acid  exposure. As colestipol also binds bile acids, colestipol may reduce mycophenolic acid  exposure and potentially reduce efficacy of mycophenolate mofetil.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Information for Patients Micronized colestipol hydrochloride tablets may be larger than pills you have taken before. If you have had swallowing problems or choking with food, liquids or other tablets or capsules in the past, you should discuss this with your doctor before taking micronized colestipol hydrochloride tablets.  
It is important that you take micronized colestipol hydrochloride tablets correctly:
Always take on tablet at a time and swallow promptly Swallow each tablet whole. Do not cut, crush, or chew the tablets Micronized colestipol hydrochloride tablets much be taken with water or another liquid that you prefer. Swallowing the tablets will be easier if you drink plenty of liquid as you swallow each tablet.  
Difficulty swallowing and temporary obstruction of the esophagus (the tube between your mouth and stomach) have been rarely reported in patients taking micronized colestipol hydrochloride tablets. If a tablet does get stuck after you swallow it, you may notice pressure or discomfort. If this happens to you, you should contact your doctor. Do not take micronized colestipol hydrochloride tablets again without your doctor's advice.  
If you are taking other medications, you should take them at least one hour before or four hours after taking micronized colestipol hydrochloride tablets.  
Adverse Reactions  
| Gastrointestinal   |
|--------------------|  
| The most common adverse reactions are confined to the gastrointestinal tract.  Constipation is the major single complaint and at times is severe. Most instances of   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Colestipol Contraindications  
| constipation are mild, transient, and controlled with standard treatment. Increased fluid  intake and inclusion of additional dietary fiber should be the first step; a stool softener  may be added if needed. Some patients require decreased dosage or discontinuation of  therapy. Hemorrhoids may be aggravated.  Other less frequent gastrointestinal complaints consist of abdominal discomfort  (abdominal pain and cramping) intestinal gas (bloating and flatulence), indigestion and  heartburn, diarrhea and loose stools, and nausea and vomiting. Bleeding hemorrhoids and  blood in the stool have been infrequently reported. Peptic ulceration, cholecystitis, and  cholelithiasis have been rarely reported in patients receiving colestipol hydrochloride  granules, and are not necessarily drug related.  Difficulty swallowing and transient esophageal obstruction have been rarely reported in  patients taking micronized colestipol hydrochloride.  Transient and modest elevations of aspartate aminotransferase (AST, SGOT), alanine  aminotransferase (ALT, SGPT) and alkaline phosphatase were observed on one or more  occasions in various patients treated with colestipol hydrochloride. Cardiovascular Chest pain, angina, and tachycardia have been infrequently reports and are comparable to  placebo rates in trials Hypersensitivity Rash has been infrequently reported. Urticaria and dermatitis have been rarely noted in  patients receiving colestipol hydrochloride granules. Musculoskeletal  Musculoskeletal pain, aches, and pains in the extremities, joint pain and arthritis, and  backache have been reported.  Neurologic Headache, migraine headache, and sinus headache have been reported. Other infrequently  reported complaints include dizziness, light-headedness, and insomnia.  Miscellaneous Anorexia, fatigue, weakness, shortness of breath, and swelling of the hands or feet, have  been infrequently reported.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Source: Colestid (colestipol) US Package Insert.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
appendix 7. euroqol 5d-5l health
rotterdam checklist

A number of activities are listed below. We do not want to know whether you actually do these, but only whether you are able to perform them presently. Would you please circle the number per line that applies most to your condition of the past week?  
| only with           | without help,                       | without         |      |    |    |
|---------------------|-------------------------------------|-----------------|------|----|----|
| unable              |                                     |                 |      |    |    |
| Activities          | help                                | with difficulty | help |    |    |
| (1)                 | (2)                                 | (4)             |      |    |    |
| (3)                 |                                     |                 |      |    |    |
| R1                  | care for myself (wash etc.).        | 1               | 2    | 3  | 4  |
| 2                   |                                     |                 |      |    |    |
| R2                  | walk about the house                | 1               | 3    | 4  |    |
| R3                  | light housework/household jobs..... | 1               | 2    | 3  | 4  |
| climb stairs....... |                                     |                 |      |    |    |
| R4                  | 1                                   | 2               | 3    | 4  |    |
| R5                  | heavy housework/household jobs...   | 1               | 2    | 3  | 4  |
| walk out of doors.  | 1                                   | 2               | 3    | 4  |    |
| R                   |                                     |                 |      |    |    |  
  
2- good 6--- poor  
  
1- excellent 5- Prather poor
4 4  
  
Document Name: protocol-6201-amend-7.1.docx Document Title: Protocol 6201 Amendment 7.1 Document Version: 1.0 Document State: Approved for Submission Page Number: 1 of 1
appendix 7. euroqol 5d-5l health
signed by

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