untitled h1
15. references

Ahn ER and Vogel CL. Dual HER2-targeted approaches in HER2-positive breast cancer. *Breast* Cancer Res Treat 2012;131:371-383. Awada A, Dirix L, Manso Sanchez L, et al. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. *Ann Oncol* 2013;24:109-116. Badache A and Goncalves A. The ErbB2 signaling network as a target for breast cancer therapy. J Mammary Gland Biol Neoplasia 2006;11:13-25. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9:463-475. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. *J Clin Oncol* 2010;28:13011307. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. *Lancet Oncol* 2016;17:367-377. Chow LW, Xu B, Gupta S, et al. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. *Br J Cancer* 2013;108:1985-1993. Cockcroft DW and Gault MH. Prediction of creatinine clearance from serum creatinine. *Nephron* 1976;16:31-41. Cornolti G, Ungari M, Morassi ML, et al. Amplification and overexpression of HER2/neu gene and HER2/neu protein in salivary duct carcinoma of the parotid gland. Arch Otolaryngol Head Neck Surg. 2007;133:1031-1036.  
Edge SB and Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. *Ann Surg Oncol* 2010;17:1471-1474. Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. *Mol Cell*. 2003;11:507-517. Garrett JT, Arteaga CL. Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications. *Cancer Biol Ther*. 2011;11:793-800. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. *N Engl J Med* 2006;355: 2733-43. Ginsburg O, Bray F, Coleman MP, et al. The global burden of women's cancers: a grand challenge in global health. *The Lancet*. 2017; 389:847-860.  
Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. *EMBO J*. 1997;16:1647-1655.  
Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. *Ann Intern Med* 1999;130(6):461-70.  
Martin M, Bonneterre J, Geyer C, et al. A phase 2, randomized, open-label, study of neratinib (HKI-272) vs lapatinib plus capecitabine for 2nd/3rd-line treatment of HER2+ locally advanced or metastatic breast cancer. Presented at the 34th Annual San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, TX. S5-7 (abst). Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebocontrolled, phase 3 trial. *Lancet Oncol* 2017;18:1688-1700.  
Mosesson Y and Yarden Y. Oncogenic growth factor receptors: implications for signal transduction therapy. *Semin Cancer Biol* 2004;14:262-270. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. *EMBO J*. 2000;19:3159-3167. Ottini L, Capalbo C, Rizzolo P, et al. HER2-positive male breast cancer: an update. Breast Cancer (Dove Med Press) 2010;2:45-58.  
Pardi DS. Diagnosis and Management of Microscopic Colitis. *Am J Gastroenterol* 2017;112:7885. Rabindran SK, Discafani CM, Rosfjord EC, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. *Cancer Res*. 2004;64:3958-3965. Rampaul RS, Pinder SE, Nicholson RI, Gullick WJ, Robertson JF and Ellis IO. Clinical value of epidermal growth factor receptor expression in primary breast cancer. *Adv Anat Pathol* 2005;12:271-273. Rosen LS, Ashurst HL, Chap L. Targeting signal transduction pathways in metastatic breast cancer: a comprehensive review. *Oncologist*. 2010;15:216-235.  
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;32:3626-3633. Secombe KR, Ball IA, Shirren J, et al. Budesonide Reduces Neratinib-Induced Gastrointestinal Injury and Diarrhea in Rats. Presented at: 44th Clinical Oncology Society of Australia Annual Scientific Meeting (2017 COSA ASM); November 13-15, 2017; Sydney, Australia, Asia-Pac J
Clin Oncol 13:60-105, abstr 40. Secombe KR, Ball IA, Shirren J, et al. Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model. *Cancer Chemother Pharmacol* 2019;83:531-543.  
Singh H, Walker AJ, Amiri-Kordestani L, et al. U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early Stage HER2-Positive Breast Cancer. Clin Cancer Res 2018;24:3486-3491.  
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. Tatro, DS. Drug Interaction Facts: The Authority on Drug Interactions. St. Louis, MI: Wolters Kluwer Health; 2012. Ustaris F, Saura C, Di Palma J, et al. Effective Management and Prevention of Neratinib-Induced Diarrhea. *Am J Hematol Oncol* 2015;11:13-22. 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.  
Waks AG and Winer EP; Breast cancer Treatment: A review. *J Am Med Assoc*. 2019; 321: 288300. 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.  
Wong KK, Fracasso PM, Bukowski RM et al. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. *Clin* Cancer Res 2009; 15: 2552-8. 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. Xu BH, Jiang ZF, Chua D, et al. Lapatinib plus capecitabine in treating HER2-positive advanced breast cancer: efficacy, safety and biomarker results from Chinese patients. *Chin J Cancer* 2011;30(5):327-35. Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. *Nat Rev Mol Cell Biol*.  
2001;2:127-137.  
Zaczek A, Brandt B, 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(3):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.
untitled h1
16. signature pages declaration of

Title of Study: An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast Cancer Treated With Neratinib Study Number: PUMA-NER-6203 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  
  
_ _____________________  
  
  
__ _______  
 Title
untitled h1
declaration of principal investigator

Title of Study: An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast Cancer Treated With Neratinib Study Number: PUMA-NER-6203 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
6000 University Commons 74 University Boulevard South _____________________________________ Univ South Alabama College of Medicine Title Institution (block letters) and site number  
 Mobile, Alabama 36688______________ +1 (251) 660-5555__________________  
 Address Phone number
untitled h1
17. appendices

APPENDIX 1. **SCHEDULE OF PROCEDURES**  
Table A1.1. Schedule of Study Procedures - **Neratinib Monotherapy in the Extended Adjuvant Setting**  
| Table A1.1.                                                                                                                                     | Schedule of Study Procedures - Neratinib Monotherapy in the Extended Adjuvant Setting  Screeninga Active Treatmentb   | Safety Follow-up  Visit                                                   |                         |                    |    |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|-------------------------|--------------------|----|----|
| Cycle / Day (C/D)                                                                                                                               |                                                                                                                       |                                                                           |                         |                    |    |    |
| Days                                                                                                                                            | (28-day cycle)                                                                                                        | Colonoscopy 2                                                             | Post-second colonoscopy |                    |    |    |
| C1/D1                                                                                                                                           | EOT Visit                                                                                                             | 28 Days After Last                                                        |                         |                    |    |    |
| -28 to -1                                                                                                                                       | Visit 1-2-3                                                                                                           | Dose                                                                      |                         |                    |    |    |
| Study visit window in Days                                                                                                                      | 0                                                                                                                     | -3 b                                                                      | +/-3                    | Every 3 months ±10 | ±5 | +5 |
| Informed consentc                                                                                                                               | X                                                                                                                     |                                                                           |                         |                    |    |    |
| Medical/Cancer history/Demographyd                                                                                                              | X                                                                                                                     |                                                                           |                         |                    |    |    |
| ERBB2 status documentatione                                                                                                                     | X                                                                                                                     |                                                                           |                         |                    |    |    |
| ECOG performance status                                                                                                                         | X                                                                                                                     |                                                                           |                         |                    |    |    |
| Serum or urine β-hCG f                                                                                                                          | X                                                                                                                     | X                                                                         |                         |                    |    |    |
| Physical examinationg                                                                                                                           | X                                                                                                                     | X                                                                         | X                       | X                  | X  |    |
| Vital signsh                                                                                                                                    | X                                                                                                                     | X                                                                         | X                       |                    |    |    |
| CBC plus differentiali                                                                                                                          | X                                                                                                                     | X                                                                         |                         |                    |    |    |
| Serum chemistryj                                                                                                                                | X                                                                                                                     | X                                                                         |                         |                    |    |    |
| Liver function testsk                                                                                                                           | X                                                                                                                     | X                                                                         | X                       |                    |    |    |
| INR                                                                                                                                             | X                                                                                                                     |                                                                           |                         |                    |    |    |
| ESR and CRPl                                                                                                                                    | X                                                                                                                     | X                                                                         |                         |                    |    |    |
| MUGA or ECHOm                                                                                                                                   | X                                                                                                                     |                                                                           |                         |                    |    |    |
| ECG (12-lead)                                                                                                                                   | X                                                                                                                     |                                                                           |                         |                    |    |    |
| Colonoscopyn                                                                                                                                    | X                                                                                                                     | X                                                                         |                         |                    |    |    |
| Fecal calprotein and fecal elastase                                                                                                             | X                                                                                                                     | X                                                                         |                         |                    |    |    |
| Concomitant medications or treatmentso                                                                                                          | X                                                                                                                     | X                                                                         | X                       | X                  |    |    |
| Neratinib administrationp                                                                                                                       | Continuous once-daily dosing (pill count at each visit)                                                               |                                                                           |                         |                    |    |    |
| Study Procedures                                                                                                                                | Loperamide                                                                                                            |                                                                           |                         |                    |    |    |
| Loperamide administrationq                                                                                                                      | dosing                                                                                                                | As needed                                                                 |                         |                    |    |    |
| during C1                                                                                                                                       |                                                                                                                       |                                                                           |                         |                    |    |    |
| Adverse eventsr                                                                                                                                 | X                                                                                                                     | X-----------------------------------------------------------------------X | X                       |                    |    |    |
| Abbreviations: β-hCG=beta-human chorionic gonadotropin; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; |                                                                                                                       |                                                                           |                         |                    |    |    |  
Abbreviations: β-hCG=beta-human chorionic gonadotropin; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; C=cycle; CBC=complete blood count; CRP = C-reactive protein; D=day; ECG= electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Collaborative Oncology Group; eCRF=electronic case report form; EOT = end of treatment; ESR = erythrocyte sedimentation rate; FISH =
fluorescence in situ hybridization ; Hb=hemoglobin; Hct=hematocrit; IHC=immunohistochemistry; INR = International Normalized Ratio; LFT=liver function test; LDH=lactate dehydrogenase; MUGA=multiple-gated acquisition scan; NP=nurse practioner; PA=physician's assistant; RBC=red blood cell; SAE=serious adverse event; TEAE=treatment-emergent adverse event; WBC=white blood cell.  
a 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.  
b Cycle 1 is defined as 28 days. The 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 neratinib 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.  
c 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: CBC (with differential), serum chemistry, MUGA/ECHO, and ECGs. 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, any adverse reactions, number of loose stools and use of loperamide and/or other antidiarrheals (adverse reactions, stools, and antidiarrheals are to be documented only for the first cycle [28 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.  
d Collect presence of chronic conditions and/or medical history of significance; include review of history of cardiac, pulmonary, and gastrointestinal disease including assessment of bowel movements experienced during the previous 28 days as well as those ongoing at the time of screening, any medical conditions that require medication, and therapies such as chemotherapy/biotherapy/immunotherapy.  
e Documentation of locally assessed ERBB2-amplified status by FISH (>2.2) or ERBB2 overexpression by IHC (3+) by a validated approved method must be confirmed.  
f For women of childbearing potential, serum or urine β-hCG test to be performed both at screening and repeated within 72 hours prior to Cycle 1/Day 1.  
bleeding.  
g Physical examination may be delegated and performed by a properly trained NP, PA or equivalent. During treatment, brief symptom-guided physical examinations including worsening of medical history conditions will be done approximately every 3 months. As per Section 12.3 beginning with Cycle 3 through the end of the study and during visits scheduled per standard of care, only SAEs will be reported.  
h 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).  
i CBC to include Hct, Hb, platelet count, RBC and WBC count plus differential. CBCs must be tested at screening and on Day 1 of Cycle 1 (-3 days), and as clinically indicated. The Cycle 1/Day 1 tests do not need to be performed, if the screening tests were done within 72 hours of enrollment.  
j Serum chemistry tests include sodium, potassium, chloride, calcium, magnesium, BUN or urea, serum creatinine, albumin, 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.  
k LFTs must include total bilirubin, ALT, ALP, and AST. LFTs must be tested at screening, on Day 1 of Cycle 1,and approximately every 3 months, 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.  
l ESR and CRP must be collected at the time of the Baseline colonoscopy or prior to initiation of neratinib in Cycle 1 and at the time of the second study colonoscopy procedure after the first 28-day cycle, i.e., Day 1 of Cycle 2 (+ 5 days). If Screening is to be performed within 72 hours of enrollment and the first colonoscopy, ESR and CRP testing may be performed at the time of screening.  
m During trial participation, ECHO or MUGA will be performed at Screening, and as clinically indicated. It is strongly recommended to use the same method of measurement for the same patient throughout the duration of the study.  
n Colonoscopy will be performed after eligibility has been confirmed, but prior to administration of the first dose of neratinib on Day 1 of Cycle 1, Andon Day 30 (± 3 days). Oral medications, including the morning dose of neratinib, will be withheld on the day of the colonoscopy as per local standard of care. In addition, biopsies will be collected as described in Section 8.2.2.  
o Concomitant medications and concomitant nonpharmacological treatments/therapies are recorded at screening from 28 days before signing of the informed consent form, on Day 1 of Cycle 1, on the day before and day of the second study colonoscopy procedure, and on Day 1 of Cycle 3.  
p Neratinib is to be self-administered as per instructions in Section 6.1.  
q Loperamide is to be self-administered as per instructions in Section Section 6.4.2. Patients are asked to document administration of neratinib and loperamide in a diary on a daily basis during the first cycle (28 days) of the study, and to return this diary to the site at appropriate visit. Individual patient dosing compliance should be reviewed by study site staff. Investigators must ensure that patients have loperamide on hand when starting to take neratinib. 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.  
r From the signing of the informed consent form through 28 days of neratinib monotherapy following the second study colonoscopy procedure in patients with stage 1 to 3c breast cancer treated in the extended adjuvant setting, and in and Cycle 2 in patients with mBC, TEAEs and SAEs will be monitored continuously and recorded in the eCRF. Patients must use the diary to document any episodes of diarrhea for the first cycle (28 days) of the study.  
r After the completion of Cycle 2 through 28 calendar days after the last administration of neratinib, only SAE data will be collected. Should an Investigator be made aware of any SAEs occurring any time after the reporting period that may be causally related to administration of neratinib, it should be promptly reported. All SAEs must be reported within 24 hours of awareness of the event using the SAE Report Form. Protocol: PUMA-NER-6203 Original  
| Table A1.2.                            | Schedule of Study Procedures - Neratinib In Combination with Capecitabine in Metastatic Breast Cancer  Screeningb Active Treatmenta Treatment  Safety Follow-up  Contact Cycle / Day (C/D)  Discontinuation   |                    |                 |               |     |
|----------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|-----------------|---------------|-----|
| Study Procedures                       | Days                                                                                                                                                                                                          | C1/D1 (28-         | (21-day)        | Colonoscopy 2 | C3+ |
| C2/D1                                  | 0-3 Days                                                                                                                                                                                                      | 28 Days After Last |                 |               |     |
| -28 to -1                              | day)                                                                                                                                                                                                          | (21-day)q,r        | After Last Dose | Dose          |     |
| Study visit window in Days             | 0                                                                                                                                                                                                             | -3 b               | ±5              | ±5            | ±5  |
| Informed consentc                      | X                                                                                                                                                                                                             |                    |                 |               |     |
| Medical/Cancer history/Demographyd     | X                                                                                                                                                                                                             |                    |                 |               |     |
| ERBB2 status documentatione            | X                                                                                                                                                                                                             |                    |                 |               |     |
| ECOG performance status                | X                                                                                                                                                                                                             |                    |                 |               |     |
| Serum or urine β-hCG f                 | X                                                                                                                                                                                                             | X                  |                 |               |     |
| Physical examination                   | X                                                                                                                                                                                                             | X g                | X g             | X g           | X g |
| Vital signsh                           | X                                                                                                                                                                                                             | X                  | X               | X             | X   |
| CBC plus differentiali                 | X                                                                                                                                                                                                             | X                  | X               | X             |     |
| Serum chemistryj                       | X                                                                                                                                                                                                             | X                  | X               | X             |     |
| Liver function testsk                  | X                                                                                                                                                                                                             | X                  | X               | X             | X   |
| INR                                    | X                                                                                                                                                                                                             |                    |                 |               |     |
| ESR and CRPl                           | X                                                                                                                                                                                                             | X                  |                 |               |     |
| MUGA or ECHOm                          | X                                                                                                                                                                                                             | X                  |                 |               |     |
| ECG (12-lead)n                         | X                                                                                                                                                                                                             | X                  | X               |               |     |
| Colonoscopyo                           | X                                                                                                                                                                                                             | X                  |                 |               |     |
| Fecal calprotein and fecal elastase    | X                                                                                                                                                                                                             | X                  |                 |               |     |
| Concomitant medications or treatmentsp | X                                                                                                                                                                                                             | X                  | X               | X             | X   |
| Neratinib administrationq              | Continuous once-daily dosing (pill count at each visit)                                                                                                                                                       |                    |                 |               |     |
| Capecitabiner                          | X                                                                                                                                                                                                             | X                  |                 |               |     |  
| Screeningb                                                                                                                                      | Active Treatmenta   | Treatment                                                                    | Safety Follow-up  Contact   |               |     |
|-------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------------------------------------------------------------|-----------------------------|---------------|-----|
| Cycle / Day (C/D)                                                                                                                               | Discontinuation     |                                                                              |                             |               |     |
| Study Procedures                                                                                                                                | Days                | C1/D1 (28-                                                                   | (21-day)                    | Colonoscopy 2 | C3+ |
| C2/D1                                                                                                                                           | 0-3 Days            | 28 Days After Last                                                           |                             |               |     |
| (21-day)q,r                                                                                                                                     |                     |                                                                              |                             |               |     |
| -28 to -1                                                                                                                                       | day)                | After Last Dose                                                              | Dose                        |               |     |
| b                                                                                                                                               | ±5                  | ±5                                                                           | ±5                          |               |     |
| Study visit window in Days                                                                                                                      | 0                   | -3                                                                           |                             |               |     |
| Loperamide                                                                                                                                      |                     |                                                                              |                             |               |     |
| Loperamide administrationq                                                                                                                      | dosing              | As needed                                                                    |                             |               |     |
| during C1                                                                                                                                       |                     |                                                                              |                             |               |     |
| Adverse eventss,t                                                                                                                               | X s                 | X t -----------------------------------------------------------------------X |                             |               |     |
| Abbreviations: β-hCG=beta-human chorionic gonadotropin; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; |                     |                                                                              |                             |               |     |  
Abbreviations: β-hCG=beta-human chorionic gonadotropin; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; C=cycle; CBC=complete blood count; CRP = C-reactive protein; D=day; ECG= electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Collaborative Oncology Group; eCRF=electronic case report form; EOT = end of treatment; ESR = erythrocyte sedimentation rate; FISH=
fluorescence in situ hybridization; Hb=hemoglobin; Hct=hematocrit; IHC=immunohistochemistry; INR = International Normalized Ratio; LFT=liver function test; LDH=lactate dehydrogenase; MUGA=multiple-gated acquisition scan; NP=nurse practioner; PA=physician's assistant; RBC=red blood cell; SAE=serious adverse event; TEAE=treatment-emergent adverse event; WBC=white blood cell.  
a Cycle 1, neratinib monotherapy, is defined as 28 days. Cycle 2 and all subsequent cycles are defined as 21 days. Cycle 2 will begin after the completion of the second study colonoscopy procedure. The Treatment Discontinuation Visit will be performed as soon as possible, but no later than 3 business days after the last dose and before start of new anticancer regimen. All visit dates are calculated from the date of first dose of neratinib. 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.  
b 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.  
c 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: CBC (with differential), serum chemistry, MUGA/ECHO, and ECGs. 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, any adverse reactions, number of loose stools and use of loperamide and/or other antidiarrheals (adverse reactions, stools, and antidiarrheals are to be documented only for the first cycle [21 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.  
d Collect presence of chronic conditions and/or medical history of significance (include review of history of cardiac, pulmonary, and gastrointestinal disease experienced during the previous 28 days as well as those ongoing at the time of screening, any medical conditions that require medication, and therapies such as chemotherapy/biotherapy/immunotherapy.  
e Documentation of locally assessed ERBB2-amplified status by FISH (>2.2) or ERBB2 overexpression by IHC (3+) by a validated approved method must be confirmed.  
f For women of childbearing potential, serum or urine β-hCG test to be performed both at screening and repeated within 72 hours prior to Cycle 1/Day 1.  
bleeding.  
g Physical examination may be delegated and performed by a properly trained NP, PA or equivalent. During treatment, brief symptom-guided physical examinations including worsening of medical history conditions will be done on Day 1 of each cycle. As per Section 12.3 beginning with Cycle 3 through the end of the study and during visits scheduled per standard of care, only SAEs will be reported.  
h 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), and height (screening only).  
i CBC to include Hct, Hb, platelet count, RBC and WBC count plus differential. CBCs must be tested at screening and on Day 1 of Cycle 1 (-3 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.  
j Serum chemistry tests include sodium, potassium, chloride, calcium, magnesium, BUN or urea, serum creatinine, albumin, 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.  
k LFTs must include total bilirubin, ALT, ALP, and AST, as well as serum lipase and serum amylase. LFTs must be tested at screening, on Day 1 of each treatment cycle, 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. Patients receiving neratinib and capecitabine on study should be monitored for signs or symptoms related to pancreatitis, including abdominal pain, especially epigastric pain radiating to the back and elevations in serum lipase and serum amylase. Severe pancreatitis can also be accompanied by ecchymotic discoloration of the periumbilical or flank regions, fever, hypotension, and hypoxemia. Serum lipase and (pancreatic) amylase should be measured at baseline and subsequently at any time if pancreatitis is suspected. If pancreatic enzymes are elevated, imaging should be performed in accordance with standard institutional protocols for investigation of acute pancreatitis.  
l ESR and CRP must be collected at the time of the Baseline colonoscopy or prior to initiation of neratinib in Cycle 1 and at the time of the second study colonoscopy procedure after the first 28-day cycle, ie, Day 1 of Cycle 2 (+ 5 days). If Screening is to be performed within 72 hours of enrollment and the first colonoscopy, ESR and CRP testing may be performed at the time of screening.  
m During trial participation, ECHO or MUGA will be performed at Screening, and should be repeated at Cycle 3/Day 1, Cycle 6/Day 1, Day 1 of every 6th subsequent cycle, as clinically indicated. It is strongly recommended to use the same method of measurement for the same patient throughout the duration of the study.  
n ECGs should be performed at Screening, and should be repeated at Cycle 3/Day 1, Cycle 6/Day 1, every 6th subsequent cycle during the active treatment phase, and as clinically indicated. ECG should also be performed at Treatment Discontinuation if not done during the previous 12 weeks. Patients using drugs known to cause QT/QTc prolongation should be monitored closed with serial ECGs at the Investigator's discretion. Refer to Appendix 6 for a summary of drugs known to have a risk of causing QT/QTc prolongation, potentially causing Torsade's de Pointes.  
o Colonoscopy will be performed after eligibility has been confirmed, but prior to administration of the first dose of neratinib on Day 1 of Cycle 1, and after the first 28-day cycle, i.e., Day 1 of Cycle 2 (+ 5 days). Oral medications, including the morning dose of neratinib on the day of the Day 1/Cycle 2 colonoscopy, will be withheld on the day of the colonoscopy as per local standard of care. In addition, biopsies will be collected as described in Section 8.2.2.  
p Concomitant medications and concomitant nonpharmacological treatments/therapies are recorded at screening from 28 days before signing of the informed consent form, on Day 1 of Cycle 1, on Day 1 of Cycle 2, on the day before and day of the second study colonoscopy procedure, and on Day 1 of Cycle 3.  
q Loperamide is to be administered as per instructions in Section 6.2. Patients are asked to document administration of neratinib and loperamide in a diary on a daily basis during the first cycle (28 days) of the study, and to return this diary to the site at appropriate visit. Individual patient dosing compliance should be reviewed by study site staff. Investigators must ensure that patients have loperamide on hand when starting to take neratinib. 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.  
r Capecitabine therapy will begin following the completion of the second study colonoscopy procedure and will be administered on Day 1-14 of each cycle. **Note:**
capecitabine cannot be administered until after the second study colonoscopy procedure is completed.  
s From the signing of the informed consent form through the end of Cycle 2 TEAEs and SAEs will be monitored continuously and recorded in the eCRF.  
Patients must use the diary to document any episodes of diarrhea for the first cycle (28 days) of the study.  
t After the completion of Cycle 2 through 28 calendar days after the last administration of neratinib, only SAE data will be collected. Should an Investigator be made aware of any SAEs occurring any time after the reporting period that may be causally related to administration of neratinib, it should be promptly reported. All SAEs must be reported within 24 hours of awareness of the event using the SAE Report Form.
untitled h1
appendix 2. investigational product dose

Recommended dose reductions for the -1 and -2 dose levels of **neratinib** and **capecitabine** are listed in Table 3 in Section 6.1.1 and in Table 6 in Section 6.3.1. 2. Toxicities Requiring Investigational Product Dose Adjustments
untitled h1
general toxicities

The guidelines for dose adjustments of **neratinib** and **capecitabine** for general toxicities due to the combination of **neratinib** plus **capecitabine** are shown in Table A2.1.  
| NCI CTCAE v.4.0                                                                                                                | Action                                                                                                                                                                                                                                                                                                                                                                       |
|--------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2 adverse reaction   1st appearance                                                                                     |  Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume  neratinib at the starting dose level.                                                                                                                                                                                                                                                       |
|  2nd appearance                                                                                                               |  Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume  neratinib at 160 mg and capecitabine at 1100 mg/m2 (550 mg/m2 BID).                                                                                                                                                                                                                         |
|  3rd appearance                                                                                                               |  Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume  neratinib at 120 mg and capecitabine at 750 mg/m2 (375 mg/m2 BID).                                                                                                                                                                                                                          |
|  4th appearance                                                                                                               |  Discontinue neratinib and capecitabine permanently.                                                                                                                                                                                                                                                                                                                        |
| Grade 3 adverse reaction  1st appearance                                                                                      |  Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume  neratinib at 160 mg and capecitabine at 1100 mg/m2 (550 mg/m2 BID).                                                                                                                                                                                                                         |
|  2nd appearance                                                                                                               |  Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume  neratinib at 120 mg and capecitabine at 750 mg/m2 (375 mg/m2 BID).                                                                                                                                                                                                                          |
|  3rd appearance                                                                                                               |  Discontinue neratinib and capecitabine permanently.                                                                                                                                                                                                                                                                                                                        |
| Grade 4 adverse reaction  1st appearance                                                                                      |  Discontinue neratinib and capecitabine permanently OR if Investigator deems  it to be in the patient's best interest to continue, hold neratinib and capecitabine until resolved to Grade ≤1; then resume neratinib at 120 mg and  capecitabine at 750 mg/m2 (375 mg/m2 BID).  If the event occurs again despite one dose reduction, permanently discontinued  neratinib. |
| Abbreviations: BID: twice daily; NCI CTCAE v4.0, National Cancer Institute Common Terminology for Adverse  Events Version 4.0. |                                                                                                                                                                                                                                                                                                                                                                              |
untitled h1
table a2.1. general toxicities requiring

Guidelines for adjusting doses of **neratinib** and **capecitabine** in the event of gastrointestinal toxicity diarrhea are shown in Table A2.2.
untitled h1
table a2.2. gastrointestinal toxicities requiring

| Capecitabine  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 (refer  to Section 6.2 and Section 7.2).  Continue neratinib and capecitabine at full dose.   Instruct patient to follow dietetic recommendations in the  guidelines for management of diarrhea (refer to  Section 7.2).   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.   Adjust anti-diarrheal treatment, as per the guidelines for  management of diarrhea at the first onset of diarrhea (refer  to Section 6.2 and Section 7.2).   Hold neratinib and capecitabine 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 and capecitabine.  o Within 1-4 weeks after withholding treatment, reduce  neratinib dose to the next lower dose level and maintain  the same dose of capecitabine.   If event occurs a 2nd time and the neratinib dose has not  already been decreased, reduce neratinib dose to the next  lower dose level and maintain the same dose of  capecitabine. If neratinib dose has already been reduced,  the reduce the dose of capecitabine to 1100 mg/m2a (550 mg/m2 BID) (maintain same dose of neratinib)  If subsequent events occur, reduce the dose of neratinib or capecitabine to the next lower dose level in an alternate  fashion (i.e., reduce capecitabine to 750 mg /m2 (375  mg/m2 BID) if neratinib was previously reduced, or reduce  neratinib to 120 mg if capecitabine was previously  reduced..   Once the event resolved to ≤ Grade 1 or baseline, start  loperamide 4 mg with each subsequent neratinib  administration. |
| Abbreviations: BID: twice daily; IV: intravenous; L: liter; NCI CTCAE v4.0: National Cancer Institute Common  Terminology Criteria for Adverse Events version 4.0.   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] |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
untitled h1
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.  
| NCI CTCAE V4.0                                                                                                             | Action                                                                                                                                                        |
|----------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|
|  Grade 2 Pneumonitis/Interstitial Lung Disease  [Symptomatic; medical intervention indicated;  limiting instrumental ADL] |  Hold neratinib until recovery to ≤ Grade 1 or baseline.   Reduce neratinib to 160 mg or discontinue neratinib as per Investigator's best medical judgment. |
|  Grade 3 Pneumonitis/Interstitial Lung Disease  [Severe symptoms; limiting self-care ADL; oxygen  indicated]             |  Discontinue neratinib permanently.                                                                                                                          |
| Abbreviations: NCI CTCAE v4.0: National Cancer Institute Common Terminology Criteria for Adverse Events                    |                                                                                                                                                               |  
Abbreviations: NCI CTCAE v4.0: National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
untitled h1
liver toxicity

Guidelines for adjustment of **neratinib** and **capecitabine** 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                                                                                                                                                                                                                                                                                                                                                       |                                                     |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Hold neratinib and capecitabine 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 (160 mg) and  capecitabine at the next lower dose level (1100 mg/m2 [550 mg/m2 BID])a if recovery to ≤Grade 1 occurs within  4 weeks. If Grade 3 ALT or bilirubin occurs again despite  one dose reduction, permanently discontinue neratinib  and capecitabine. |                                                     |
| Grade 3 ALT (>5 - 20x ULN) OR  Grade 3 bilirubin (>3-10x ULN)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                             | Permanently discontinue neratinib and capecitabine. |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Evaluate alternative causes.                                                                                                                                                                                                                                                                                                                                 |                                                     |
| Grade 4 ALT (>20x ULN) OR Grade 4 Bilirubin (>10x ULN)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                             | Hold neratinib and capecitabine.                    |
| 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.                                                                                                                                                                                                                                                                                                                       |                                                     |
| Abbreviations; ALT=alanine aminotransferase; AST: aspartate aminotransferase; BID: twice daily; PT: prothrombin  time; SAE: serious adverse event; ULN: upper limit of normal.  NOTE: During evaluation of hepatotoxicity, bilirubin must be fractionated, prothrombin time must be measured, and  ALT >3x ULN AND  Total bilirubin >2x ULN  AND  Alkaline phospatase <2x ULN  (potential Hy's law indicators of drug-induced liver  damage)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                              |                                                     |  
a Since capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose reduction(s) is rounded down to the nearest 500 mg or multiple of 150 mg for the BID dose. If the patient's body surface are is >2.0, the standard of care for the study center can be utilized for capecitabine mg/m2 dosing.
untitled h1
left ventricular ejection fraction toxicity

Guidelines for dose adjustments of neratinib in the event of abnormalities in LVEF are shown in Table A2.5. LVEF assessments will be performed according to the Schedule of Procedures (Appendix 1 ). It is strongly recommended to use the same method of cardiac evaluation (ECHO or MUGA) at each time point for each patient.  
Table A2.5: Left Ventricular Ejection Fraction (LVEF) Results Requiring Dose  
Adjustments of Neratinib  
| Adjustments of Neratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                            |                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|-----------------------------------|
| EVENT ON DAY OF SCHEDULED  TREATMENT                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Action                                                                                                     |                                   |
| A)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | If LVEF is below 40%: hold neratinib and seek  cardiology input OR continue neratinib with great  caution. |                                   |
| Initiate monthly monitoring of LVEF  If while monitoring monthly, LVEF remains <40%:  reconsider neratinib only if appropriate and after  cardiology consult.  If while monitoring monthly, LVEF increases to ≥40%:  continue neratinib, monitor LVEF every 12 weeks and  consider cardiac support with input from cardiologist  B) If LVEF is between 40% to 50%: continue neratinib with caution and surveillance. Initiate monthly monitoring of LVEF.  If while monitoring, LVEF falls to <40%: Follow bullet  point A instructions described above.  If while monitoring, LVEF remains ≥40%: continue  neratinib, monitor LVEF every 12 weeks and consider  cardiac support with input from cardiology. |                                                                                                            |                                   |
| Symptomatic cardiac failure                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                           | Neratinib should be discontinued. |
| Abbreviations: LVEF: left ventricular ejection fraction.  Asymptomatic absolute decline of LVEF ≥15%  from baseline OR absolute decline of LVEF ≥10%  ad below the lower limit of normal of 50%                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                            |                                   |  
If a patient has a second episode of asymptomatic decline in LVEF that meets either of the above criteria, permanently discontinue **neratinib**, repeat LVEF in 3-4 weeks and consider cardiology consult.  
Note that, for AEs other than symptomatic LVEF decline, if **neratinib** is held for >28 days, the patient should be withdrawn from the active treatment phase of the study (see Section 10.1 ). In case of asymptomatic LVEF decline, patients may resume **neratinib** within 1 week after LVEF
recovery is documented as above, even if the timeframe exceeds 3 weeks. If a site does not provide normal ranges for ECHO or MUGA, a lower limit of normal of 50% should be used. Hematologic Toxicity Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of <100 x 109/L should not be treated with **capecitabine**. If unscheduled laboratory assessments during a treatment cycle show Grade 3 or 4 hematologic toxicity, treatment with **capecitabine**
should be held. Guidelines for dose adjustments of capecitabine for hematologic toxicity due to combination of neratinib plus capecitabine are shown in **Table A2.6**.  
Table A2.6: Hematologic Abnormalities Requiring Dose Adjustment of Capecitabine
(When Administered in Combination with Neratinib)  
| (When Administered in Combination with Neratinib)  NCI CTCAE v 4.0 Action  Neratinib should be continued at the same dose  Hold capecitabine until event resolves or decreases  to Grade 1 or Grade 2  Reduce next capecitabine dose to 1100 mg/m2  (550 mg/m2 BID)  If the event recurs a 2nd time, hold capecitabine until event resolves or decreases to Grade 1 or  Grade 2  Reduce next capecitabine dose of 750 mg/m2 (375 mg/m2 BID)  If the event recurs/persists, discontinue  capecitabine permanently.   |                                                                                                                                                                                   |                                                 |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|
| Grade 4 Neutrophil: <500/mm3 ; <0.5 x 109 /L Platelet: <25,000/mm3 ; <25 x 109 /L Hemoglobin decreased: life-threatening consequences;  urgent intervention indicated Grade 3 Neutrophil: <1000-500/mm3 ; <1-0.5 x 109 /L Platelet: <50,000-25,000/mm3 ; <50-25 x 109 /L Hemoglobin decreased: <8 g/dL; <4.9 mmol/L; <80 g/L;  transfusion indicated                                                                                                                                                                      |                                                                                                                                                                                  | Neratinib should be continued at the same dose. |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Capecitabine should be discontinued permanently  OR if the Investigator deems it to be in the patient's  best interest to continue, hold capecitabine until  resolved to Grade ≤1 |                                                 |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | If the Investigator decides to resume capecitabine,  reduce the dose to 750 mg/m2 (375 mg/m2 BID)                                                                                 |                                                 |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | If the event recurs/persists, discontinue  capecitabine permanently                                                                                                               |                                                 |
| Abbreviations: BID: twice daily; L=liter; NCI CTCAE v 4.0: National Cancer Institute Common Terminology  Criteria for Adverse Events Version 4.0.                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                   |                                                 |
untitled h1
hand and foot syndrome

Guidelines for dose adjustments of neratinib and capecitabine for toxicity of Hand and Foot Syndrome (Palmar-Plantar Erythrodysesthesia syndrome) due to combination of neratinib plus capecitabine are show in Table A2.7. Table A2.7: Hand and Foot Syndrome (Palmar-Plantar Erythrodysesthesia Syndrome)
Requiring Dose Adjustment of Neratinib and Capecitabine  
| NCI CTCAE v4.0                                     | Action   |                                                 |
|----------------------------------------------------|----------|-------------------------------------------------|
| Grade 1: Minimal skin changes or dermatitis (e.g., |         | Continue neratinib and capecitabine at starting |
| erythema, edema, or hyperkeratosis) without pain   | dose     |                                                 |  
| NCI CTCAE v4.0                                                                                                                                                                                                 | Action                                                                                                                               |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                               | Continue neratinib at starting dose level and hold  capecitabine until recovery or to ≤grade 1, then  resume at starting dose.       |
|                                                                                                                                                                                                               | If the event recurs/persists, continue neratinib at  starting dose level and reduce capecitabine dose to  1100 mg/m2 (550 mg/m2 BID) |
| Grade 2: Skin changes, e.g., peeling, blisters, edema, or  hyperkeratosis, with pain, limiting instrumental ADL.  PI: painful erythema and swelling of the hands and/or  feet and/or discomfort affecting ADL. |                                                                                                                                      |
untitled h1
table a2.7 hand and foot

| NCI CTCAE v4.0                                                                                                                                                                                                                                                                                                                                                             | Action                                                                                                                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                                                                                                                                           | Continue neratinib at starting dose level and hold  capecitabine until recovery or to grade ≤1, then  reduce dose to 1100 mg/m2 (550 mg/m2 BID) |
|                                                                                                                                                                                                                                                                                                                                                                           | If the event recurs/persists, continue neratinib at  starting dose level and capecitabine dose of 750 mg/m2 (375 mg/m2 BID)                     |
| Grade 3: Severe skin changes, e.g., peeling, blisters,  edema, or hyperkeratosis, with pain, limiting self-case  ADL.  PI: moist desquamation, ulceration, blistering or severe  pain of the hands and/or feet and/or sever discomfort  limiting self-care ADL Abbreviations: ADL: activities of daily living; BID: twice daily; NCI CTCAE v 4.0 National Cancer Institute |                                                                                                                                                 |  
Abbreviations: ADL: activities of daily living; BID: twice daily; NCI CTCAE v 4.0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
untitled h1
pancreatitis

Guidelines for dose adjustments of neratinib and capecitabine for pancreatitis due to combination of neratinib plus capecitabine are show in Table A2.8.  
Table A2.8: Recommendations for Dose Adjustment of Neratinib and Capecitabine and  
Management of Patients with Pancreatitis  
| Management of Patients with Pancreatitis                                                                                                                                                             |                                                                                                             |                                                                                                                                                                                                                                               |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| NCI CTCAE v.4.0                                                                                                                                                                                      | Action                                                                                                      |                                                                                                                                                                                                                                               |
| Grade 2 Pancreatitis:                                                                                                                                                                                |                                                                                                            | Temporarily suspend (i.e., hold) neratinib and capecitabine                                                                                                                                                                                   |
| Enzyme elevation or radiologic  findings OR                                                                                                                                                          |                                                                                                            | Evaluate for any possible alternative causes                                                                                                                                                                                                  |
|                                                                                                                                                                                                     | If no alternative cause for pancreatitis is identified, discontinue neratinib and capecitabine permanently. |                                                                                                                                                                                                                                               |
| Grade 3 Pancreatitis:                                                                                                                                                                                |                                                                                                            | If an alternative cause is identified (e.g., gallstones) or enzyme levels return  to baseline within 3 weeks with clinical recovery, re-start treatment with  reduced doses of neratinib 160 mg and capecitabine 1100 mg/m2 (550  mg/m2 BID). |
| Severe pain; vomiting; medical  intervention indicated (e.g.,  analgesia, nutritional support)                                                                                                       |                                                                                                            | If the event occurs a second time, discontinue neratinib and capecitabine permanently.                                                                                                                                                        |
| Grade 4 Pancreatitis:                                                                                                                                                                                |                                                                                                            | Discontinue neratinib and capecitabine permanently.                                                                                                                                                                                           |
| Life-threatening consequences;  urgent intervention indicated Abbreviations: BID: twice daily; NCI CTCAE v 4.0 National Cancer Institute Common Terminology Criteria for  Adverse Events Version 4.0 |                                                                                                             |                                                                                                                                                                                                                                               |
untitled h1
appendix 3. eastern cooperative oncology

| 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  work of a light or sedentary nature, i.e., light house work, office work. | 1       |
| Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about more than 50% of waking hours.                            | 2       |
| Capable of only limited self-care, confined to bed or chair more than 50% of  waking hours.                                                                  | 3       |
| Completely disabled. Cannot carry on any self-care. Totally confined to bed or  chair.                                                                       | 4       |
| Dead                                                                                                                                                         | 5       |
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        |
| Diltiazem                          | Nelfinavir            | Sildenafil (weak) |
| Erythromycin                       | Nevirapine            | Troglitazone      |
| Fluconazole                        | Norfloxacin           | Troleandomycin    |
| Fluoxetine                         | Norfluoxetine         | Zafirlukast       |
| Fluvoxamine                        | CYP3A5-7 Inducers     |                   |
| Phenobarbital                      | Primidone             | Rifampin          |
| Phenytoin Source: Tatro,2012.      |                       |                   |
untitled h1
appendix 5. substrates and inhibitors

| (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, 2012.                                 |                               |                                |  
APPENDIX 6. **DRUGS ASSOCIATED WITH RISK OF QT/QTC**  
PROLONGATION LEADING TO TORSADE DE POINTES  
| 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)*b            |                      |
| Procainamide (eg, Procanbid)*                                         | Bretylium*                              |                      |
| Quinidine*                                                            | Dofetilide (Tikosyn)*b                  |                      |
| Class IC                                                              | Ibutilide (Corvert)*b                   |                      |
| Flecainide (eg, Tambocor)*a                                           | Sotalol (eg, Betapace)*b                |                      |
| Propafenone (eg, Rythmol)*b                                           |                                         |                      |
| Anticonvulsants Felbamate (Felbatol)*                                 | Fosphenytoin (Cerebyx)                  |                      |
| Antiemetics Dolasetron (Anzemet)b                                     | Droperidol (eg, Inapsine)*b             | 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)*b           |                      |
| Quinine*                                                              | Erythromycin (eg, Ery-Tab, EES)*b       |                      |
| Antivirals                                                            | Telithromycin (Ketek)b                  |                      |
| Efavirenz (Sustiva)*                                                  | Troleandomycin                          |                      |
| Azole antifungal agents                                               | Pentamidine (eg, Pentam 300, Nebupent)* |                      |
| Fluconazole (eg, Diflucan)*b                                          | Quinolones                              |                      |
| Itraconazole (eg, Sporanox)                                           | Gatifloxacin (eg, Tequin)*b             |                      | Protocol: PUMA-NER-6203 Original  
| Protocol: PUMA-NER-6203                                                                                | Original                                          |                           |
|--------------------------------------------------------------------------------------------------------|---------------------------------------------------|---------------------------|
| Drugs Reported to Prolong QT Interval Ketoconazole (eg, Nizoral)                                       | Levofloxacin (eg, Levaquin)*a, 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)b                                                             | Salmeterol (Serevent)b                            |                           |
| Formoterol (Foradil)b                                                                                  | Terbutaline (eg, Brethine)b                       |                           |
| 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 Cisapride (Propulsid)*b,                                                       | Famotidine (eg, Pepcid)*                          |                           |
| Immunosuppressants Tacrolimus (Protopic)*b (postmarketing) Miscellaneous Levomethadyl                  | Papaverine (eg, Pavaden three times daily [TID])* |                           |
| Moexipril/Hydrochlorothiazide (Uniretic)                                                               | Probucol (Lorelco)*                               |                           |
| Octreotide (Sandostatin)b                                                                              | Vasopressin (eg, Pitressin)*                      |                           |
| Oxytocin (eg, Pitocin; intravenous bolus) Psychotropics Droperidol (eg, Inapsine)* Primozide (Orap)*b, | Trazodone (eg, Desyrel)                           |                           |
| Haloperidol (eg, Haldol)*                                                                              | Quetiapine (Seroquel)b                            | Tricyclic antidepressants |
| Lithium (eg, Eskalith)*                                                                                | Risperidone (Risperdal)b                          | Amitriptyline*            |
| (overdose)                                                                                             |                                                   |                           |
| Puma Biotechnology                                                                                     | Page 91 of 92                                     | CONFIDENTIAL              | Protocol: PUMA-NER-6203 Original  
| Protocol: PUMA-NER-6203                                                                                                       | Original                                |                               |
|-------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|-------------------------------|
| Drugs Reported to Prolong QT Interval Maprotiline* Serotonin Reuptake Inhibitors                                              | Clomipramine (eg,                       |                               |
| (SRIs)                                                                                                                        | Anafranil)                              |                               |
| Phenothiazines                                                                                                                | Citalopram (eg, Celexa)*                | Desipramine (eg,  Norpramin)* |
| Chrlorpromazine (eg,                                                                                                          | Fluoxetine (eg, Prozac)*a               | Doxepin (eg, Sinequan)*       |
| Thorazine)* Fluphenazine (eg,                                                                                                 | Paroxetine                              | Imipramine (eg, Tofranil)*    |
| Prolixin)*                                                                                                                    | (eg, Paxil)*                            |                               |
| Perphenazine                                                                                                                  | Sertraline (Zoloft)*a, b                | Nortriptyline (eg, Pamelor)   |
| (postmarketing)                                                                                                               |                                         |                               |
| Thioridazine (Mellaril)*b                                                                                                     | Venlafaxine (Effexor)b  (postmarketing) |                               |
| Trifluopherazine                                                                                                              |                                         |                               |
| Serotonin 5-HT1 agonists Naratriptan (Amerge)                                                                                 | Sumatriptan (Imitrex)b                  | Zolmitriptan (Zomig)b         |
| Skeletal muscle relaxants Tizanidine (eg, Zanaflex)b (animals) *  Drugs for which Torsades de Pointes has also been reported. |                                         |                               |  
Tizanidine (eg, Zanaflex)b(animals)
* Drugs for which Torsades de Pointes has also been reported.  
a Association unclear b QT, QTc, and/or Torsades de Pointes association listed in FDA-approved product labeling Source: Tatro, 2012.  
Document Name: Protocol PUMA-NER-6203 Document Title: protocol-6203.docx Document Version: 2.0 Document State: Approved for Submission Page Number: 1 of 1
untitled h1
signed by

Functional Area: Clinical Operations Meaning Of Signature: I am approving this document Date/Time: 9/4/2019 11:42:40 AM  
Functional Area: Pharmacovigilance Meaning Of Signature: I am approving this document Date/Time: 9/4/2019 1:02:28 PM  
Functional Area: Regulatory Affairs Meaning Of Signature: I am approving this document Date/Time: 9/4/2019 3:34:47 PM  
Functional Area: Biostatistics Meaning Of Signature: I am approving this document Date/Time: 9/4/2019 5:59:59 PM  
Functional Area: Clinical Development Meaning Of Signature: I am approving this document Date/Time: 9/5/2019 8:44:21 AM