Clinical trial NCT01670877
Conditions: Breast Neoplasms
Keywords: Neratinib fulvestrant HER2 mutation metastatic breast cancer trastuzumab
Sponsor: Washington University School of Medicine
Start date: 2012-12-11; Completion date: 2021-03-11
Enrollment: 56 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how HER2 mutated cancer responds to treatment with neratinib.

Detailed description:
Overexpression of HER2 due to gene amplification is an established therapeutic target in breast cancer for which multiple HER2 targeted drugs are now available. However, the majority of breast cancers are without HER2 overexpression/non-amplified and not currently eligible to receive HER2 targeted drugs. Advances in tumor genome sequencing technology led to the identification of recurrent HER2 mutations (HER2mut) in approximately 2% of HER2 non-amplified primary breast cancers, and 3-5% of metastatic tumors. Importantly, tumor cells harboring HER2mut are sensitive to the anti-tumor effects of HER2-targeted agents in preclinical models, especially neratinib, a potent irreversible pan-HER inhibitor. However, neratinib monotherapy has demonstrated only modest single agent activity in HER2mut,, non-amplified metastatic breast cancer (MBC). Based on the hypothesis that the combination of neratinib and fulvestrant will be more effective than neratinib alone in ER+/HER2mut, non-amplified MBC the investigators conducted a single arm phase II study of neratinib plus fulvestrant with 2 cohorts, fulvestrant (FUL)-treated and FUL-naïve, for patients with ER+/HER2mut, non-amplified MBC to assess the anti-tumor effects of this combination. An exploratory ER-negative (ER-) HER2mut cohort was also included for the efficacy of neratinib monotherapy.

Arms: arm 1: -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 2: -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 3: -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 4: -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 5: -If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. arm 6: -If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
Interventions: intervention 1: Neratinib intervention 2: Fulvestrant intervention 3: Trastuzumab intervention 4: Tumor biopsy intervention 5: Research blood sample
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: -Optional at baseline and disease progression intervention 5: -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)

Protocol documents:
Prot_SAP_000.pdf: 
      
 
201209135 – Protocol Clarification Letter, 01 October 2020 
 
 
Protocol Administrative Letter 
 
October 1, 2020 
 
 
“A Phase II Study of Neratinib Alone and in Combination with Fulvestrant in Metastatic 
HER2 Non-amplified but HER2 Mutant Breast Cancer” 
 
The purpose of this letter is to clarify an error regarding the duration of follow-up after the last 
dose of protocol therapy.  In Protocol Amendment 13.0, 16MAR2020, Section 6.7 Duration of 
Follow-up currently reads,  
 
6.7 Duration of Follow-up 
Patients will be followed every 3 months for 2 years or until death, whichever occurs first. Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. Patients will be followed through either review of medical 
records, phone calls, or office visits. 
 
This section is incorrect, as it should read,  
 
6.7 Duration of Follow-up 
Patients will be followed until 30 days after last dose of study therapy. Patients removed from 
study for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. Patients will be followed through either review of medical records, phone calls, or 
office visits. 
 
If you have any questions, please contact me or the regulatory coordinator (Natalie Benford at 
natalienconner@wustl.edu, 314-747-8365) 
 
 
Regards, 
 
Dr. Cynthia Ma, MD, PhD. 
Professor of Medicine 
Washington University School of Medicine 
Internal Medicine – Medical Oncology 
Phone: 314-362-8903 
Email: cynthiaxma@wustl.edu 


 
 
Version 03/16/2020 – Amendment 13 
 
Page 1 of 87 
 
 
A Phase II Study of Neratinib Alone and in Combination with Fulvestrant 
in Metastatic HER2 Non-amplified but HER2 Mutant Breast Cancer   
 
Protocol#:  201209135 
Version date: 03/16/2020 
 
Coordinating Center:  
Washington University School of Medicine 
660 S. Euclid Ave, Campus Box 8056 
St. Louis, MO 63110 
 
Principal Investigator:  
Cynthia X. Ma, M.D., Ph.D. 
 
 
 
 
Washington University School of Medicine  
 
 
 
 
 
Telephone: 314-362-9383 
 
 
 
 
 
Email: cynthiaxma@wustl.edu 
 
 
Sub-Investigators: 
 
 
Institution: 
 
 
 
 
Division: 
Matthew J.C. Ellis, M.B., Ph.D.  
Baylor College of Medicine 
 
 
Medical Oncology 
Ron Bose, M.D., Ph.D.  
 
Washington University  
 
 
Medical Oncology 
Carey Anders, M.D. 
 
 
Lineberger Cancer Center 
 
 
Medical Oncology 
Rachel Freedman, M.D.  
 
Dana Farber Cancer Institute 
 
 
Medical Oncology 
Philippe Bedard, M.D.  
 
Princess Margaret Cancer Centre 
 
Medical Oncology 
Kimberly Blackwell, M.D. 
 
Duke Cancer Institute  
 
 
Medical Oncology 
Melody Cobleigh, M.D.  
 
Rush University Medical Center  
 
Medical Oncology 
Andres Forero, M.D. 
 
 
University of Alabama  
 
 
Medical Oncology 
Daniel Hayes, M.D. 
 
 
University of Michigan  
 
 
Medical Oncology 
Janice Lu, M.D. 
 
 
University of Southern California 
 
Medical Oncology 
Mark Pegram, M.D. 
 
 
Stanford Medicine Cancer Institute 
 
Medical Oncology 
Timothy J. Pluard, M.D. 
 
St. Luke’s Cancer Institute 
 
 
Medical Oncology 
Matthew Goetz, M.D.  
 
Mayo Clinic 
 
 
 
 
Medical Oncology 
Julie Nangia, M.D. 
 
 
Baylor College of Medicine 
 
 
Medical Oncology 
Jason Jones, M.D. 
 
 
Avera Cancer Institute  
 
 
Medical Oncology 
Marc E. Lippman, M.D.  
 
University of Miami 
 
 
 
Medical Oncology 
Massimo Cristofanilli, M.D. 
 
Northwestern University 
 
 
Medical Oncology 
Foluso Ademuyiwa, M.D. 
 
Washington University  
 
 
Medical Oncology 
Michael J. Naughton, M.D. 
 
Washington University  
 
 
Medical Oncology 
Rama Suresh, M.D. 
 
 
Washington University  
 
 
Medical Oncology 
Leonel Hernandez-Aya, M.D. 
 
Washington University  
 
 
Medical Oncology  
Katherine Weilbaecher, M.D. 
 
Washington University  
 
 
Medical Oncology 
Ashley Frith, M.D. 
 
 
Washington University  
 
 
Medical Oncology 
 
Haeseong Park, M.D. 
 
 
Washington University  
 
 
Medical Oncology 
Matthew Cherian, M.D.  
 
Washington University  
 
 
Medical Oncology 
Lindsay Peterson, M.D.  
 
Washington University  
 
 
Medical Oncology 
Feng Gao, M.D., Ph.D.  
 
Washington University  
 
 
Biostatistics 
 
Washington University Research Coordinator 
Caroline Bumb 
Telephone: 314-362-7249 
Email: cbumb@wustl.edu 
 


 
 
Version 03/16/2020 – Amendment 13 
 
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A Phase II Study of Neratinib Alone and in Combination with Fulvestrant 
in Metastatic HER2 Non-amplified but HER2 Mutant Breast Cancer   
 
Study Drug(s): Neratinib (PB-272) 
IND#: 116297 // Clinical Trials.gov#: NCT01670877 
 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
 
09/27/12 
Amendment #1 
 
 
 
 
 
 
 
 
01/02/13 
Amendment #2 
 
 
 
 
 
 
 
 
03/22/13 
Amendment #3 
 
 
 
 
 
 
 
 
04/22/13 
Amendment #4 
 
 
 
 
 
 
 
 
09/04/13 
Amendment #5 
 
 
 
 
 
 
 
 
11/08/13 
Amendment #6 
 
 
 
 
 
 
 
 
12/26/13 
Amendment #7 
 
 
 
 
 
 
 
 
02/05/15 
Amendment #8 
 
 
 
 
 
 
 
 
12/11/15 
Amendment #9                                                                                                
09/14/16 
Amendment #10 
 
 
 
 
 
 
 
 
02/07/17 
Amendment #11 
 
 
 
 
 
 
 
 
10/05/17 
Amendment #12 
 
 
 
 
 
 
 
 
06/15/18 
Amendment #13 
 
 
 
 
 
 
 
 
03/16/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Version 03/16/2020 – Amendment 13 
 
Page 3 of 87 
 
 
A Phase II Study of Neratinib Alone and in Combination with Fulvestrant 
in Metastatic HER2 Non-amplified but HER2 Mutant Breast Cancer 
 
 
Principal Investigator Signature Page 
 
 
Principal Investigator: 
 
Cynthia X. Ma, M.D., Ph.D. 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/HRPO procedures, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical 
studies. 
 
 
 
 
 


 
 
Version 03/16/2020 – Amendment 13 
 
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Contact Information 
 
 
Ron Bose, M.D., Ph.D. 
Washington University School of Medicine 
Telephone: 314-747-9308 
Email: rbose@wustl.edu  
 
  
Matthew J. Ellis, M.B., Ph.D. 
Baylor College of Medicine 
Email: matthew.ellis@bcm.edu  
 
 
Rachel Freedman, M.D. 
Dana-Farber Cancer Institute 
Harvard University 
Email: rachel_freedman@dcfi.harvard.edu  
 
Carey Anders, M.D. 
Lineberger Comprehensive Cancer Center 
University of North Carolina at Chapel Hill 
Email: canders@med.unc.edu 
 
Timothy Pluard, M.D. 
St. Luke’s Cancer Institute 
Email: tpluard@saint-lukes.org 
 
Kimberly Blackwell, M.D. 
Duke Cancer Institute 
Duke University Medical Center 
Email: kimberly.blackwell@duke.edu 
 
Melody Cobleigh, M.D. 
Rush University Medical Center 
Email: melody_cobleigh@rush.edu  
Janice Lu, M.D. 
Keck School of Medicine 
University of Southern California 
Email: Janice.Lu@med.usc.edu 
 
Andres Forero, M.D. 
University of Alabama Cancer Center 
Email: aforero@uabmc.edu  
Philippe Bedard, M.D. 
Princess Margaret Cancer Centre 
Email: philippe.bedard@uhn.ca 
 
Daniel Hayes, M.D. 
University of Michigan 
Email: hayesdf@umich.edu  
  
Mark Pegram, M.D. 
Stanford Medicine Cancer Institute 
Email: mpegram@stanford.edu  
 
Marc Lippman, M.D. 
University of Miami 
Email: mlippman@med.miami.edu 
Matthew Goetz, M.D. 
Mayo Clinic 
Email: goetz.matthew@mayo.edu 
 
Amy Krie, M.D. 
Avera Cancer Institute 
Email:  Amy.Krie@avera.org 
 
Julie Nangia, M.D. 
Baylor College of Medicine 
Email:  nangia@bcm.edu 
 
Massimo Cristofanilli, M.D. 
Northwestern University 
Email:  Massimo.Cristofanilli@nm.org 
 


 
 
Version 03/16/2020 – Amendment 13 
 
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SCHEMA – Part I (closed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 4-week Cycle 
† may escalate to 320 mg 
Metastatic Breast Cancer, HER2- 
Pre-registration 
Tumor DNA Sequencing for  
HER2 Mutation 
Mutation 
Present 
 
Mutation 
Absent 
 
Study Therapy 
Neratinib 240 mg† P.O. daily  
days 1-28 each cycle* 
Not Eligible for Study Therapy 
Restage every 2 cycles 
Continue therapy until disease progression, 
or unacceptable adverse events,  
or patient refusal  
Registration 


 
Version 03/16/2020 – Amendment 13 
 
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SCHEMA – Part II 
 
 
 
 
 
 
 
HER2 mutation identified in 
tumor tissue  
or circulating tumor DNA  
in a CLIA laboratory 
HER2 mutation status unknown 
Central Tumor DNA sequencing 
for HER2 mutation 
Mutation Present 
Mutation Absent 
Not Eligible for 
Study Therapy 
Registration 
Metastatic Breast Cancer, HER2- 
Pre-registration 
ER- 
ER+ 
ER- Cohort 
Fulvestrant naïve ER+ Cohort or 
Fulvestrant treated ER+ Cohort 
Neratinib 240mg† PO daily days 1-28 each 
cycle∆ 
Neratinib 240mg† PO daily days 1-28 each 
cycle∆ 
+  
Fulvestrant 500mg IM cycle 1 day 1 and 
day 15, then on day 1 of subsequent cycles 
† may escalate to 320 mg 
∆ 4-week Cycle 
Restage every 2 cycles 
Disease progression 
If trastuzumab (or FDA approved biosimilar) coverage obtained, add: 
Trastuzumb 6mg/kg IV cycle 1 day 1, followed by 4mg/kg IV cycle 1 day 15, then 4 
mg/kg IV on days 1-15 of subsequent cycles 
Continue therapy until disease progression, unacceptable adverse events, or patient refusal 


 
Version 03/16/2020 – Amendment 13 
 
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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
CR 
Complete remission 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLTs 
Dose Limiting Toxicities 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
EC 
Ethics Committee 
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
EGFR 
ER 
ethylenediaminetetraacetic acid 
Epidermal growth factor receptor 
Estrogen Receptor  
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
GCP 
HER2 
Good Clinical Practice 
Human epidermal growth factor receptor 2 
HHS 
Department of Health and Human Services’ 
HIV 
Human Immunodeficiency Virus 
HRPO 
IHC 
Human Research Protection Office (IRB) 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
IULN 
ILLN 
Intent-to-treat 
Institutional Upper Limit of Normal 
Institutional Lower Limit of Normal 
IV 
Intravenous (i.v.) 
LDH 
Lactate dehydrogenase 
LPS 
lipopolysaccharide 
MedDRA 
Medical Dictionary for Regulatory Activity 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 


 
Version 03/16/2020 – Amendment 13 
 
Page 8 of 87 
NCCN 
National Cancer Center Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
PB 
Peripheral blood 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PI 
Principal investigator 
PR 
Partial response (Partial remission) 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RFS 
Relapse free survival 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
TF 
Treatment failure 
TTP 
Time to progression 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
 
 


 
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Table of Contents 
SCHEMA – Part I (closed) .................................................................................................................................................. 5 
SCHEMA – Part II ................................................................................................................................................................. 6 
1.0 
BACKGROUND AND RATIONALE .................................................................................................................... 11 
1.1 
Metastatic HER2 Negative Breast Cancer .................................................................................................... 11 
1.2 
Neratinib ................................................................................................................................................................. 12 
1.3 
Fulvestrant ............................................................................................................................................................. 14 
1.4 
Trastuzumab (Herceptin)................................................................................................................................... 15 
1.5 
HER2 (ERBB2) ...................................................................................................................................................... 17 
1.6 
Mutation in HER2 (ERBB2) .............................................................................................................................. 17 
1.7 
Preliminary Results from Part I with Single Agent Neratinib ................................................................ 20 
1.8 
Correlative Studies Background ..................................................................................................................... 21 
2.0 
OBJECTIVES ........................................................................................................................................................... 21 
2.1 
Primary Objectives .............................................................................................................................................. 21 
2.2 
Secondary Objectives .......................................................................................................................................... 21 
2.3 
Exploratory Objectives ....................................................................................................................................... 22 
3.0 
PATIENT SELECTION .......................................................................................................................................... 22 
3.1 
Pre-registration (for patients with unknown HER2 mutation status to have tumor tissue 
screened centrally by Wash U GPS laboratory) ....................................................................................................... 22 
3.2 
Registration (for patients positive for HER2 mutation to receive study treatments) ..................... 23 
3.3 
Inclusion of Women and Minorities ............................................................................................................... 25 
4.0 
REGISTRATION PROCEDURES ....................................................................................................................... 26 
4.1 
Pre-Registration (for patients with unknown HER2 mutation status to have tumor tissue 
screened centrally by Wash U GPS laboratory) ....................................................................................................... 26 
4.2 
Registration for Study Therapy ....................................................................................................................... 27 
4.3 
Recruitment through Army of Women .......................................................................................................... 28 
4.4 
Recruitment from Outside Practice ................................................................................................................ 28 
5.0 
TUMOR HER2 SEQUENCING ............................................................................................................................ 28 
5.1 
Tumor HER2 sequencing at Washington University CLIA lab following pre-registration for 
eligibility ............................................................................................................................................................................... 28 
5.2 
Tumor or circulating tumor DNA HER2 Mutation/Variants Identified at Laboratories other 
than GPS@WU ................................................................................................................................................................... 29 
5.3 
Eligible HER2 mutations ................................................................................................................................... 29 
5.4 
Germline DNA Sequencing for HER2 to determine eligibility ................................................................ 30 
5.5 
HER2 Mutation Testing by ctDNA .................................................................................................................. 30 
6.0 
TREATMENT PLAN ............................................................................................................................................... 31 
6.1 
Neratinib Administration ................................................................................................................................... 31 
6.2 
Concurrent Prophylactic Administration of Loperamide ........................................................................ 31 
6.3 
Fulvestrant Administration .............................................................................................................................. 31 
6.4 
General Concomitant Medication and Supportive Care Guidelines .................................................... 31 
6.5 
Women of Childbearing Potential ................................................................................................................... 37 
6.6 
Duration of Therapy ............................................................................................................................................ 37 
6.7 
Duration of Follow-up ........................................................................................................................................ 38 
7.0 
DOSE DELAYS/DOSE MODIFICATIONS AND AE MANAGEMENT ..................................................... 38 
7.1 
Neratinib Dose Administration Table ............................................................................................................ 38 
7.2 
General Dose Adjustments for Neratinib-Related Toxicities .................................................................. 38 
7.3 
Guidelines for the Management of Diarrhea ............................................................................................... 39 
7.4 
Guidelines for the Management of Changes in Liver Function Tests ................................................. 42 
7.5 
Guidelines for the Management of LVEF Declines .................................................................................... 43 
7.6 
Subject Compliance ............................................................................................................................................ 44 
7.7 
Fulvestrant Dose Modifications ....................................................................................................................... 44 
7.8 
Trastuzumab (or FDA Approved Biosimilar) Dose Modifications ......................................................... 44 
8.0 
REGULATORY AND REPORTING REQUIREMENTS ................................................................................ 44 
8.1 
Reporting to the Human Research Protection Office (HRPO) at Washington University .............. 45 
8.2 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at Washington 
University ............................................................................................................................................................................ 45 
8.3 
Secondary Sites Reporting Requirements .................................................................................................... 45 


 
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8.4 
Reporting to Secondary Sites ........................................................................................................................... 45 
8.5 
Reporting to the FDA .......................................................................................................................................... 46 
8.6 
Reporting to Puma Biotechnology, Inc. ........................................................................................................ 47 
8.7 
Timeframe for Reporting Required Events ................................................................................................... 47 
9.0 
PHARMACEUTICAL INFORMATION............................................................................................................... 47 
9.1 
Neratinib ................................................................................................................................................................. 47 
9.2 
Fulvestrant ............................................................................................................................................................. 48 
10.0 CORRELATIVE STUDIES .................................................................................................................................... 50 
10.1 
Required archival tumor sample for research: ........................................................................................... 50 
10.2 
Required research blood collection ................................................................................................................ 50 
10.3 
Optional research tumor biopsy (kits will be provided):.......................................................................... 50 
10.4 
Reporting of a CLIA multi-gene NGS on tumor biopsy collected at disease progression on study 
drug: 50 
10.5 
Correlative Science Study Calendar .............................................................................................................. 51 
11.0 STUDY CALENDAR ................................................................................................................................................ 52 
12.0 DATA SUBMISSION SCHEDULE ...................................................................................................................... 55 
13.0 MEASUREMENT OF EFFECT ............................................................................................................................ 56 
13.1 
Antitumor Effect – Solid Tumors .................................................................................................................... 56 
13.2 
Disease Parameters ............................................................................................................................................. 56 
13.3 
Methods for Evaluation of Measurable Disease ......................................................................................... 57 
13.4 
Response Criteria ................................................................................................................................................. 59 
14.0 DATA AND SAFETY MONITORING ................................................................................................................. 61 
14.1 
Independent Research Monitor ....................................................................................................................... 62 
15.0 AUDITING ................................................................................................................................................................. 63 
16.0 STATISTICAL CONSIDERATIONS ................................................................................................................... 63 
16.1 
Study Objectives .................................................................................................................................................. 63 
16.2 
Study Design and Sample Size Justification .............................................................................................. 64 
16.3 
Data Analysis ........................................................................................................................................................ 65 
17.0 MULTICENTER REGULATORY REQUIREMENTS ..................................................................................... 66 
18.0 REFERENCES ......................................................................................................................................................... 68 
APPENDIX A: ECOG PERFORMANCE STATUS SCALE ....................................................................................... 74 
APPENDIX B PATIENT’S MEDICATION DIARY ...................................................................................................... 75 
APPENDIX C: PATIENT INSTRUCTIONS FOR THE MANAGEMENT OF DIARRHEA ............................... 76 
APPENDIX D: RECIST 1.1 Tumor Evaluation Form ............................................................................................ 80 
APPENDIX E: Definitions ................................................................................................................................................ 81 
APPENDIX F: Reporting Timelines ............................................................................................................................. 84 
APPENDIX G: Serious Adverse Event Reporting Cover Sheet ........................................................................ 87 
 
 


 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Metastatic HER2 Negative Breast Cancer 
 
Over 80% of breast cancers are HER2 negative (HER2-), defined by the lack of HER2 gene 
amplification, for which targeted therapies are lacking. The prognosis for the estrogen receptor 
negative (ER-)/HER2- subset is particularly poor[1]. Although patients with ER+/HER2- disease 
fair better, resistance to endocrine manipulation develops almost invariably[2]. The median 
survival is only 18-24 months when chemotherapy is necessary in the metastatic setting[3]. There 
is a significant unmet clinical need to uncover new drug targets to improve the outcome of these 
patients. 
 
HER2/neu (ERBB2) is a well established proto-oncogene that encodes a receptor tyrosine kinase 
of the Epidermal Growth Factor Receptor (EGFR) family[4]. Receptor activation via 
heterodimerization between HER2 and EGFR and other family members leads to strong mitogenic 
signals and cellular proliferation[5]. HER2-targeted agents are among the most successful cancer 
therapeutics in the clinic, revolutionizing the care for patients with HER2+ breast cancer [6-11]. 
HER2+ breast cancer is defined clinically by either HER2 protein overexpression on 
immunohistochemistry (IHC) or HER2 gene amplification by fluorescent in situ hybridization 
(FISH) testing and occurs in approximately 15-20% of all breast cancer cases. HER2- breast 
cancers as a whole have not been shown to derive benefit from these highly effective agents[12].  
 
Results from The Cancer Genome Atlas (TCGA) breast cancer project demonstrated that a small 
subpopulation of HER2- breast cancer carry mutations in HER2, with majority being in the kinase 
domain and compilation of data on 1,391 breast cancers documented 22 cases of somatic HER2 
mutation, a mutation rate of 1.6% [13-15].  In addition, laboratory investigations indicated that 
many of these mutations are activating mutations, with the capacity to induce cellular 
transformation and importantly an enhanced susceptibility to the inhibitory effects of anti-HER2 
agents (see Preliminary Investigation section). These discoveries raised the possibility that 
mutations in HER2 could be effectively targeted by the well established anti-HER2 agents in the 
clinic. The objective of this application is to establish HER2 mutation as a therapeutic target in 
HER2- breast cancer. We therefore propose a phase II study of neratinib, a pan HER inhibitor, in 
metastatic HER2-/HER2 mutated breast cancers for tumor response.   
 
As of January 17, 2015, the study enrolled 11 patients with HER2 mutations, among which 10 
patients had ER+ breast cancer.  Considering the well-established signaling crosstalk between ER 
and HER2 in ER+ HER2+ breast cancer16,17, we propose to add the ER down regulator fulvestrant 
to neratinib in the ER+ subpopulation in the second part of this trial. 
 
Although the prevalence of HER2 mutation is low, because breast cancer is so common this would 
account for approximately 4,000 new cases each year in the US alone, an annual incidence that is 
very similar to chronic myeloid leukemia (CML), a disease transformed by the introduction of 
tyrosine kinase inhibitors.  
 
 


 
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1.2 
Neratinib 
 
1.2.1 Mechanism of Action 
 
Neratinib (PB-272) is a potent irreversible pan HERB inhibitor.  Neratinib is an orally 
available small molecule that inhibits HER-1, HER-2, and HER-4 at the intracellular 
tyrosine kinase domains, a mechanism of action that is different from trastuzumab[16-18].  
Neratinib reduces HER-1 and HER-2 autophosphorylation, downstream signaling, and the 
growth of HER-1 and HER-2 dependent cell lines.  Preclinical data suggest that neratinib 
will have antitumor activity in HER-1 - and/or HER-2-expressing carcinoma cell lines, with 
cellular IC50 <100 nM. 
 
1.2.2 Preclinical Data 
 
Neratinib is highly active against cell lines overexpressing either HER-2 or HER-1.  
Neratinib blocks HER receptor autophosphorylation in cells at doses consistent with 
inhibition of cell proliferation.  Neratinib most likely inhibits kinase activity through 
irreversible binding at a targeted cysteine residue in the adenosine triphosphate binding 
pocket of the receptor.  In agreement with the predicted effects of HER-2 inactivation, 
neratinib treatment of cells results in inhibition of downstream signal transduction events 
and cell cycle regulatory pathways. 
 
In vivo, neratinib is active in HER-2- and HER-1-dependent tumor xenograft models, when 
administered orally on a once-a-day schedule.  Overall, neratinib is less potent against HER-
1 dependent tumors than HER-2-dependent tumors in vivo, even though it has equivalent 
activity against the 2 kinases in vitro. 
 
1.2.3 Neratinib Phase 1 and Pharmacokinetic Data 
 
Preliminary pharmacokinetic analyses demonstrated that neratinib absorption was 
relatively slow, and the maximum concentration (Cmax) was generally attained within 3 to 
6 hours.  After oral administration, the neratinib Cmax and area under the concentration 
versus time curve (AUC) increased in a dose-dependent manner in general.  Mean steady-
state Cmax and AUC values were 70.1 ng/mL and 975 ng·h/mL for the 180-mg dose group, 
respectively, 73.5 ng/mL and 939 ng·h/mL for the 240-mg dose group, respectively, 90.4 
ng/mL and 1333 ng·h/mL for the 320-mg dose group, respectively, and 105 ng/mL and 
1704 ng·h/mL for the highest dose of 400 mg, respectively.  The neratinib exposure (AUC) 
increased 1.2- to 2.7-fold (mean accumulation ratio) when comparing the steady-state 
exposure on day 21 after repeated daily administration with the exposure on day 1 after 
administration of 80 to 400 mg of neratinib.  The mean accumulation ratio was 1.2 after a 
240-mg dose, indicating no significant accumulation of neratinib after repeated daily dose 
administration at the dose to be used in this proposed trial. The data indicated a slow 
distribution of neratinib with a large apparent volume of distribution (Vz/F on day 1: about 
3188 to 6181 L) after oral absorption.  After oral administration on day 1, neratinib was 
eliminated with a mean apparent terminal half-life (t½) of approximately 13 to 17 hours.  
There was moderate to large variability in neratinib t½, Cmax, and AUC; coefficients of 
variation generally ranged from 8% to 90%. In the single agent, first in human, phase 1 
study 3144A1-102-US, neratinib single agent administered orally was given in increasing 


 
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doses from 40 mg to 400 mg.  Diarrhea was the main dose limiting toxicity (DLT) observed.  
At the 400-mg dose level, 4 of 6 subjects had DLT of grade 3 diarrhea.  Thus, the maximum 
tolerated dose (MTD) was determined to be 320 mg per day.  However, due to the frequency 
and severity of neratinib-related diarrhea observed in subsequent subjects treated at the 
MTD (34% of subjects reported grade 3 diarrhea), the MTD was reevaluated to 240 mg per 
day.  Neratinib monotherapy phase 2 data showed that oral daily doses of 240 mg of 
neratinib were generally well tolerated with significant antitumor activity in subjects with 
HER-2-positive advanced breast cancer [19].   In this trial, patients will receive 240 mg 
continuous daily oral doses of neratinib.  Since diarrhea has been tolerable with prophylactic 
use of loperamide during the first cycle therapy in the first 3 patients treated in this trial, we 
elected to allow dose escalation to 320mg in subsequent cycles, with initial prophylactic 
use of loperamide, in patients who tolerated the 240mg daily dosing.  
 
1.2.4 Single-Agent Activity of Neratinib in HER2+ Breast Cancer 
 
Neratinib as a single agent has been studied in a phase 2 trial in subjects with metastatic 
HER-2 positive breast cancer [19].  Sixty-six (66) subjects with prior trastuzumab based 
therapy were enrolled into arm A; 70 subjects without any prior trastuzumab exposure were 
enrolled into arm B.  Objective response rate and median progression free survival were 
used as estimates of antitumor activity. For patients with prior trastuzumab treatment, the 
objective response rate was 24% (95% CI, 14% to 36%); for patients with no prior 
trastuzumab treatment, the objective response rate was 56% (95% CI, 43% to 69%). Six 
and eight patients with and without prior trastuzumab treatment, respectively, had stable 
disease for at least 24 weeks that yielded clinical benefit rates of 33% and 69%. The median 
duration of objective tumor response was 39.3 weeks (95% CI, 32.3 weeks to 93.7 weeks) 
for patients with prior trastuzumab treatment and 52.4 weeks (95% CI, 33.1 weeks to not 
estimable) for patients with no prior trastuzumab treatment. The median onset of first 
complete response or partial response was rapid at 7.1 weeks for patients both with and 
without prior trastuzumab treatment (prior trastuzumab range, 3.0 to 24.0 weeks; no prior 
trastuzumab range, 3.1 to 15.6 weeks; 75th percentile, 7.1 weeks for both). Similar efficacy 
results were obtained by investigator assessment. 
 
1.2.5 Adverse Event Profile of Neratinib Monotherapy 
 
In the neratinib monotherapy phase II breast cancer study, diarrhea was the only grades 3 
to 4 adverse event that occurred in more than 10% of patients (28 patients with grade 3; one 
patient with grade 4) and was the predominant adverse event associated with dose 
reductions, which were required in 29% of patients with prior trastuzumab treatment and in 
4% of patients with no prior trastuzumab treatment. However, only one patient (with prior 
trastuzumab treatment) discontinued treatment because of grade 2 diarrhea. The onset of 
diarrhea occurred early in the course of therapy (median time to onset, 2 to 3 days) and 
lasted a median of 5 to 7 days per event. Diarrhea severity abated during multiple weeks of 
treatment. During study week 1, diarrhea occurred in 70% to 90% of patients and decreased 
to 10% to 15% of patients after month 2. Only one patient had grade 3 diarrhea after month 
2. With use of antidiarrheals and dose modification, neratinib treatment was continued in 
99% of patients, despite this common lower gastrointestinal adverse effect. Mild, often 
transient, skin rashes were observed in approximately one quarter of the patients.  
 
Other common AEs are nausea, vomiting, fatigue, anorexia, abdominal pain, asthenia, 
dehydration, rash, elevated alanine aminotransferase (ALT), and elevated aspartate 


 
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aminotransferase (AST).  The above AEs are considered to be adverse drug reactions for 
neratinib.  
 
As opposed to treatment with other HER-2 targeted agents, such as trastuzumab, 
cardiotoxicity has not been observed with neratinib, even in subjects previously treated with 
anthracyclines and/or trastuzumab. 
 
Interstitial lung disease, which can sometimes be fatal, has been reported with other oral 
tyrosine kinase inhibitors that target EGFR (HER-1) +/- HER2 (HER-2), including 
lapatinib, gefitinib, and erlotinib.  Pneumonitis which was considered to be drug related, 
according to the investigator’s assessment, has been reported in clinical studies of neratinib.  
Subjects receiving neratinib should be monitored for acute onset or worsening of pulmonary 
symptoms such as dyspnea, cough, and fever and treated appropriately. There has been one 
event of bone marrow suppression reported on December 9, 2009, in a subject who was 
taking neratinib monotherapy for 4 months without any other clear cause.  This resulted in 
neutropenia, and thrombocytopenia.  Refer to the most recent version of the investigator’s 
brochure for a summary of findings from nonclinical studies that potentially have clinical 
significance and from clinical studies that are relevant to the study.  Also, refer to the most 
recent version of the investigator’s brochure for a summary of the known and potential risks 
and benefits to human subjects. 
 
1.3 
Fulvestrant 
 
1.3.1 Fulvestrant in the Treatment of ER+ Breast Cancer 
 
Fulvestrant (Faslodex) is an estrogen receptor antagonist that binds to ER and leads to its 
degradation, a distinct mechanism of action from other endocrine therapy agents that target 
ER. Fulvestrant blocks ER action without agonist effect. It is FDA approved for patients 
who have disease progression on other antiestrogen agents in the advanced breast cancer 
setting.  In two phase III trials, fulvestrant 250 mg monthly was found to be at least as 
effective as anastrozole with respect to disease progression and overall survival [20, 21]. In 
the EFECT trial, fulvestrant 250 mg monthly was found to be at least as effective as 
exemestane in patients with metastatic ER+ breast cancer resistant to non-steroidal AIs [22]. 
In the CONFIRM trial, high-dose fulvestrant at 500 mg monthly was found to be more 
effective compared to the previous dosing of 250 mg monthly, which prompted FDA’s 
subsequent approval of fulvestrant 500 mg every 28 days, following a loading dose of 500 
mg on days 1 and 15 during the first month of therapy for refractory metastatic breast 
cancer[23].  
 
Overall, fulvestrant demonstrated an overall response rate of approximately 10% in 
aromatase inhibitor resistant, fulvestrant naive ER+ HER2- breast cancers [24, 25].  There 
is no data at this time regarding the activity of fulvestrant in ER+ HER2- breast cancer with 
HER2 mutations.  However its efficacy in ER+ HER2+ breast cancer has been described in 
a retrospective study [26].  In this study, fulvestrant resulted in an overall response rate of 
9% and clinical benefit rate of 42% (43/101 patients), with anti-tumor activity observed in 
up to the fourth line of endocrine therapy and seventh line of overall therapy [26].  Since 
the response rate approximated 10% in both HER2+ and HER2- population based on the 
studies described above, we assume a similar response rate of 10% in fulvestrant naïve 
HER2 mutant patient population in this trial.    
 


 
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1.3.2 Fulvestrant in Combination with Receptor Tyrosine Kinase Inhibitor the 
Treatment of ER+ Breast Cancer 
 
Although there is no data in the literature for the combination of fulvestrant and neratinib 
in ER+ breast cancer, fulvestrant was combined with the HER1/HER2 inhibitor lapatinib 
in a randomized phase III trial of fulvestrant with or without lapatinib in patients with AI 
resistant metastatic ER+ HER2 1+, 2+, 3+ [25].  The study demonstrated an overall 
response rate of 9% in the fulvestrant plus placebo arm and 20% in the fulvestrant plus 
lapatinib arm, with anticipated side effects observed with single agents alone [25].   
 
Since fulvestrant is well tolerated, there is no obvious theoretical pharmacokinetic 
interaction between neratinib and fulvestrant, and the mechanism of action of neratinib is 
similar to lapatinib, we do not anticipate the side effects profile be different from single 
agent therapy with neratinib and fulvestrant.    
 
1.3.3 Adverse Event Profile of Fulvestrant  
 
The most common adverse reactions reported in the fulvestrant study groups, regardless of 
causality, were GI symptoms including nausea and vomiting (26%/13%), constipation 
(12.5%), diarrhea (12.3%) and abdominal pain (11.8%); as well as headache (18.9%); back 
pain (15.4%); hot flashes (17.7%); and pharyngitis (16.1%). Vaginal bleeding was reported 
in < 1% of patients and occurred most commonly during the first 6 weeks after changing 
from existing hormonal treatment to fulvestrant. If vaginal bleeding persists, further 
evaluation is required. Injection site reaction with mild transient pain (9.1-11.6%) and 
inflammation were seen with fulvestrant. Seven percent of patients (1% of treatments) given 
a single 5 ml IM injection and 27% of patients (4.6% of treatments) given 2 x 2.5 ml IM 
injections experienced reactions. Additional adverse reactions occurring in > 5% of patients 
treated with fulvestrant during clinical trials include asthenia (weakness) (68.3%), bone 
pain (15.8%), dyspnea (14.9%), increased cough (10.4%), pelvic pain (10%), anorexia 
(9%), peripheral edema (9%), rash (unspecified) (7.3%), chest pain (unspecified) (7.1%), 
dizziness (6.9%), insomnia (6.9%), fever (6.4%), paresthesias (6.4%), urinary tract 
infection (6.1%), depression (5.7%), anxiety (5%), diaphoresis (5%), and anemia (4.5%). 
 
Other adverse events reported as fulvestrant-related and occurring infrequently (< 1%) 
include thromboembolism, myalgia, vertigo, and leukopenia. In addition, hypersensitivity 
reactions such as angioedema and urticaria have been infrequently reported. 
 
1.4 
Trastuzumab (Herceptin) 
 
1.4.1 Mechanisms of Action 
 
Trastuzumab is an IgG1 kappa that selectively binds to the extracellular domain of the 
HER2 receptor.  Trastuzumab inhibits HER2+ breast cancer cell proliferation in preclinical 
models[27, 28].  In addition, trastuzumab is a mediator of antibody-dependent cellular 
cytotoxicity (ADCC)[29, 30]. 
 
1.4.2 Clinical Studies  
 
Trastuzumab is effective either as a single agent or in combination with a variety of 
chemotherapy agents for HER2 positive breast cancer [31].  In a study of single agent 


 
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trastuzumab, administered 4mg/kg loading dose followed by 2mg/kg weekly, or 8mg/kg 
loading dose and 4mg/kg weekly, as first-line therapy for HER2-overexpressing breast 
cancer, the objective response rate was 35%  in HER2 3+ and 34% in HER2 amplified 
cases[32]. In another phase II trial of single agent trastuzumab in HER2+ breast cancer, 
trastuzumab was administered 8 mg/kg then 6 mg/kg Q3 weeks and the clinical benefit rate 
was 33%[33]. In patients who had received extensive prior therapies, the objective response 
rate was found to be around 15% [34].  Trastuzumab also demonstrated its ability to reduce 
cancer recurrence and death in the adjuvant setting as demonstrated by the large multi-
center randomized controlled trials [8, 35]. Trastuzumab is a recombinant DNA-derived 
humanized monoclonal antibody against HER2 and is approved by FDA for treatment of 
metastatic and early stage breast cancer that overexpresses HER2. 
 
1.4.3 Dual Targeting in HER2+ Breast Cancer 
 
Approximately 15% of HER2+ breast cancer patients relapse after initial therapy with 
trastuzumab. [36] Preclinical evidence has shown synergistic interaction between 
trastuzumab and other HER-2 targeted agents, and several clinical studies have shown that 
dual HER2 targeting may prolong time to resistance and improve survival outcomes.[37] A 
double-blind phase III study (CLEOPATRA) compared first-line trastuzumab plus 
pertuzumab plus docetaxel with trastuzumab plus placebo plus docetaxel in 808 patients 
with metastatic HER2+ breast cancer. The pertuzumab arm had longer median progression 
free survival (PFS) (19 months vs. 12 months; HR=0.62; 95% CI, 0.51-0.75; P <0.001) and 
overall survival (OS) (not yet reached in pertuzumab arm vs. 37.6 months; HR 0.66; 95% 
CI, 0.52-0.84). [38] A randomized phase III, study of single agent lapatinib vs. combination 
of trastuzumab plus lapatinib in patients with HER2+ metastatic breast cancer who had 
disease progression on prior trastuzumab-based therapy showed superior PFS (HR=0.73; 
95% CI, 0.57-0.93; P =0.008) and clinical benefit rate (CBR) (24.7% in the combination 
arm vs. 12.4% in the monotherapy arm; P =0.01) for the combination arm. There was also 
a median OS advantage seen in the combination arm (14 months vs 9.5 months; HR 0.74; 
95% CI 0.75-0.97; P=0.026). The side effect profile is favorable with the combination arm 
showing a higher incidence of diarrhea (P=0.03). [39] A meta-analysis examining the 
cardiac toxicity in breast cancer patients treated with dual HER2 blockade showed no 
significant increase in cardiotoxicity, although the trials generally only included patients 
with good baseline cardiac function and patients who have tolerated prior treatment with 
trastuzumab,[40] Long term outcomes on cardiac toxicity remain to be seen. 
 
1.4.4 Neratinib in Combination with Trastuzumab 
 
A phase I/II, nonrandomized, open label study of neratinib in combination with trastuzumab 
was performed in women with advanced HER2+ breast cancer.[41] The phase I, dose-
escalation phase enrolled 8 patients. No DLT was reported and the recommended dose of 
neratinib was 240mg daily in combination with trastuzumab 4mg/kg loading dose followed 
by 2mg/kg weekly thereafter. In phase II, 37 patients received neratinib and trastuzumab at 
the recommended dose and 28 patients were evaluable for efficacy. In the evaluable 
population, the 16-week PFS rate was 44.8% (95% CI, 25.9 – 62.1%), and the median PFS 
was 15.9 weeks (95% CI 15.1 – 31.3), with data censored for 5 patients. Two patients had 
the best overall response of complete response (CR), 6 patients had partial response (PR) 
and 14 patients had stable disease (SD). The overall response rate was 28.6% (95% CI, 13.2 
– 48.7%) and the clinical benefit rate (CBR) was 35.7% (95% CI, 18.6 – 55.9%).[41]   
 


 
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In this trial, trastuzumab (or FDA approved biosimilar) will be added to the study drug 
neratinib or neratinib and fulvestrant (ER+ cohort, Part II of the trial) at disease progression 
if insurance coverage is obtained to explore the activity of combined HER2 targeting in 
HER2 mutant breast cancer.  
 
1.5 
HER2 (ERBB2)  
 
HER2/neu (ERBB2), located on chromosomal 17q21.1, is a well established proto-oncogene that 
encodes HER2, a transmembrane tyrosine kinase receptor of the EGF receptor (EGFR) family 
composed of four members (EGFR/HER1, HER2, HER3 and HER4) that contain an extracellular 
ligand-binding domain, a lipophilic transmembrane domain, and an intracellular tyrosine kinase 
domain[4]. Receptor activation via heterodimerization between HER2 and EGFR and other 
members leads to strong mitogenic signals and cellular proliferation[5].  
 
The identification of HER2 gene amplification and the subsequent invent of HER2-targeted agents 
have revolutionized the care of patients with breast cancer [11].  Approximately 20% of invasive 
breast cancer cases carry HER2 gene amplification, leading to increased HER2 protein expression, 
an aggressive clinical behavior and a decreased disease free and overall survival [42-44].  
Trastuzumab, a monoclonal antibody against HER2, was the first anti-HER2 agent which was 
found to markedly improve the survival of patients with HER2 positive breast cancer in both 
metastatic and early stage setting [6-10], establishing one of the first molecular cancer therapies.  
Multiple agents are currently available in clinical practice either approved by FDA or through 
clinical trials for patients with HER2 positive breast cancer defined by either HER2 overexpression 
or gene amplification [11].  
 
1.6 
Mutation in HER2 (ERBB2)  
 
1.6.1 The Identification of HER2 Mutation in Whole Genome Sequencing Studies 
 
The vast majority of HER2 
mutations were identified in 
patients with HER2 negative 
disease who would not have 
been eligible to receive HER2 
targeted drugs under the current 
standard of care.  In addition to 
the TCGA-breast cancer project 
patients, we compiled data from 
6 
other 
breast 
cancer 
sequencing projects[15, 45-49] 
and identified 15 HER2 somatic 
mutations in 22 out of the 1391 
patients, an overall incidence of 1.6% (Fig. 1).  Mild enrichment for HER2 mutations may 
occur in lobular breast cancer as three HER2 somatic mutations were observed in 39 lobular 
breast cases in the TCGA study[50] and three were observed among 113 lobular cases in 
Shah et al., suggesting a prevalence of 4% in this histological subtype[46]. Mutations 
clustered in two locations, the extracellular domain (ECD) at aa 309-310 (5 of 25) and the 
kinase domain between aa 755-781 (17 of 25). 
 
 
 
Fig. 1.  HER2 somatic mutations from 22 patients 
 
Blue circles represent individual cases. 


 
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1.6.2 Preclinical Functional Characterization of HER2 Mutations[51] 
 
Effects on kinase activities: We successfully expressed HER2 kinase domain constructs 
for WT, and V777L, D769H, V842I mutants and purified them to >80% purity. In vitro 
kinase assays demonstrated that both the D769H-HER2 and the V777L-HER2 had greater 
tyrosine kinase activity than WT-HER2 (Figure 2, left) and were sensitive to lapatinib in 
vitro (Figure 2, right). In contrast, V842I-HER2 showed modestly increased kinase activity 
and a small shift in lapatinib in vitro IC50 (22 vs 10 nM).   
 
 
Effects on Signaling and Growth: HER2 mutations were introduced into non-
transformed, MCF10A breast epithelial cells using a 
retroviral vector.  The V777L, D769H, D769Y, 
P780ins, V842I, and R896C mutants are activating 
mutations that increased HER2 autophosphorylation 
and substrate protein (phospholipase γ C1, PLCγ) 
phosphorylation relative to WT HER2 (Fig. 3).  
Modest increases in HER2, PLCγ, and EGFR 
phosphorylation were seen with G309A, L755S, and 
R678Q.  HER2 del.755-759 showed a marked 
decrease in HER2 and PLCγ phosphorylation, but 
increased EGFR phosphorylation, which suggests 
that del.755-759 has an increased ability to activate 
other HER/ErbB family members.  The ability of 
various TKI drugs to block signaling from HER2 
mutations was tested (not shown) and we observed 
that L755S mutation is a lapatinib-resistant mutation 
that is sensitive to neratinib and canertinib.  While all 
three drugs are HER2/EGFR selective, lapatinib is a 
reversible inhibitor[52].  In contrast, neratinib and 
canertinib are irreversible inhibitors that form a 
covalent bond with a Cys residue in HER2’s active site[53]. 
WT
D769H
V777L
V842I
Specific Activity
(pmol product/µg Her2/min)
0
50
100
150
200
250
Monomer
Dimer
2.3-fold
5-fold
22-fold
33-fold
20-fold
3.3-fold
7.5-fold
A 
Lapatinib (nM)
0.01
0.1
1
10
100
Relative activity (%)
0
20
40
60
80
100
WT
D769H
V777L
V842I
     HER2     IC50(nM)
      WT           10
    V777L          8
    D769H       10
     V842I        22
B 
Fig. 2.  In vitro kinase activity of HER2 mutations  
(A) fold change values are relative to HER2 monomers.  
(B) In vitro inhibition by lapatinib. 
Fig. 3.  Activation of downstream 
signaling by HER2 mutations.  
KD indicates kinase domain 
mutations; JM:  juxtamembrane; 
ECD:  extra-cellular domain. 


 
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The effect on cell growth and 
morphology in three dimensional 
cultures 
was 
measured. 
As 
previously 
reported[54, 
55], 
MCF10A-HER2 
WT 
formed 
spherical structures (Fig. 4, upper 
left).  MCF10A cells bearing 
HER2 V777L, D769H, D769Y, 
P780ins, 
V842I, 
R896C, 
or 
G309A 
mutations 
formed 
irregular structures with spiculated, invading protrusions (Fig. 4, top row).   Addition of the 
HER2 antibody, trastuzumab, restored the spherical morphology to these mutations (Fig. 4, 
middle row).  HER2 L755S, del.755-759, and R678Q formed spherical structures, similar 
to WT HER2.  MCF10A cells are an EGF-dependent cell line and require supplementary 
EGF in their media.  Addition of lapatinib, a dual HER2/EGFR inhibitor, blocked the 
growth of MCF10A-HER2 WT cells and most of the HER2 mutant cells (Fig. 4, lower 
row).  Interestingly, L755S and del.755-759 were resistant to this dose of lapatinib and 
continued to form large spherical structures, but they were sensitive to the irreversible 
inhibitor, neratinib (Fig. 5).  The del.755-759 mutation was sensitive to gefitinib (Fig. 5), 
consistent with the increased activation of EGFR observed in HER2 del.755-759 mutant 
cells (Fig. 3).  
 
The ability of the HER2 mutations to 
increase tumor formation in xenografts was 
also tested (Fig. 6). NIH3T3-HER2 WT cells 
served as the control cell line.  NIH3T3-
HER2 V777L, D769H, and G309A mutant 
cell lines had more rapid tumor growth than 
the HER2 WT control (p-values all <0.01, as 
indicated in the figure by **).  The L755S, 
V842I, R678Q and mutations showed tumor 
growth indistinguishable from the HER2 WT 
control (Fig. 6).  These mutations did have 
more rapid tumor growth than empty vector 
cells, suggesting that these mutations do not 
impair HER2 functioning.  Xenograft 
experiments using MCF7 cell lines are in 
progress (not shown).  
 


 
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Summary of HER2 preclinical data:   To date, we have tested thirteen HER2 somatic 
mutations, of which seven are found to be activating mutations that are sensitive to HER2 
targeted drugs: G309A, D769H, D769Y, V777L, P780ins, V842I and R896C[51]. In 
addition, a recent HER2 functional study by Greulich et al. also identified G309E and 
S310F as activating mutations[56]. Notably, the L755S mutation showed a lapatinib-
resistant phenotype, but was sensitive to neratinib[51].    
 
We hypothesize that tumors with mutations in HER2 can be effectively treated with 
neratinib. As a pilot study, we will conduct a 2-stage phase II single arm trial of neratinib 
in patients with HER2-/HER2 mutation+ metastatic breast cancer.  Neratinib is chosen as 
it is an irreversible inhibitor of HER1, HER2 and HER4 rather than lapatinib which is a 
reversible inhibitor of HER1 and HER2.  Importantly, neratinib has shown activity in 
lapatinib resistant HER2 mutations in our preclinical studies (Figure 5).   
 
HER2 mutation is present in 1.6% of primary breast cancer overall, but certain 
subpopulation of breast cancer may have higher incidence.  We therefore plan to analyze 
the clinical and pathological features of tumors with or without HER2 mutation during this 
trial and preferentially screen those that are most likely to carry the HER2 mutations. 
 
1.7 
Preliminary Results from Part I with Single Agent Neratinib 
 
As of Jan 17, 2015, we have identified 16 patients with metastatic breast cancer carrying HER2 
mutations (Table 1).  Fifteen of these patients (94%) had ER+ disease.  Among the first 10 patients 
with somatic Her2 mutations (9 with activating mutations and 1 with unknown significance), 1 
patient with known activating mutation HER2 L755S had a partial response to neratinib.  The study 
passed the efficacy criteria to continue enrollment to the 2nd stage (refer to statistical section).  
Because of the high incidence of ER positivity in HER2 mutated breast cancer and the well 
established crosstalk between ER and HER2 pathways, we propose to examine the combination of 
neratinib and fulvestrant in patients with ER+, HER2-/HER2 mutated breast cancers in Part II of 
the trial. 
Figure 6. HER2 induces growth of tumors in nude mice.   
5 x 10
5 NIH3T3 cells expressing indicated construct were injected subcutaneously. 


 
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1.8 
Correlative Studies Background 
 
Metastatic HER2- breast cancer is a heterogeneous group of diseases.  Understanding the molecular 
and genomic structure of these tumors is the first step toward individualized therapy.  In this 
protocol, additional tumor specimens at metastatic sites will be collected at baseline if possible 
when the biopsy is performed for sequencing analysis of HER2. All patients are required to consent 
to research on archival primary tumor specimens. Patients will be consented for research related 
molecular studies including genomic studies, such as whole or targeted genomic sequencing 
analysis, gene expression studies, for novel therapeutic target discovery. In addition, blood samples 
will be collected at baseline and post therapy for studies of circulating markers that correlate with 
breast cancer prognosis and treatment response. 
 
  
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. Part I: To determine the clinical benefit (CR+PR+SD>6 months) of neratinib alone in patients 
with metastatic HER2- breast cancer that carry HER2 mutations. 
2. Part II fulvestrant-naïve ER+ cohort: To examine the clinical benefit (CR+PR+SD>6 months) 
of neratinib in combination with fulvestrant in patients with fulvestrant-naïve metastatic HER2-
, ER+ breast cancer carrying activating HER2 mutations. 
3. Part II fulvestrant-treated ER+ cohort: To examine the clinical benefit (CR+PR+SD≥6 months) 
of neratinib in combination with fulvestrant in patients with  metastatic HER2-, ER+ breast 
cancer carrying activating HER2 mutations previously treated with fulvestrant. 
4. Part II ER- cohort: To determine the clinical benefit rate of neratinib alone in patients with 
metastatic HER2-, ER- breast cancer carrying activating HER2 mutations. 
 
2.2 
Secondary Objectives 
 
1. To determine the PFS of patients treated with neratinib alone in patients with metastatic HER2- 
but HER2 mutated breast cancer by ER status and by HER2 mutations (activating vs. unknown 
significance). 
Table 1: Pathologic Characteristics of 
HER2 Mutant Breast Cancer Identified in 
Part I  (N=16) 
 
Histology 
N 
% 
Ductal 
9 
56% 
Lobular 
6 
38% 
Unknown 
1 
6% 
Biomarkers 
 
 
ER +, PR + 
7 
44% 
ER+, PR - 
8 
50% 
ER-, PR - 
1 
6% 
 


 
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2. To assess the PFS and response rate of neratinib in combination with fulvestrant in patients 
with fulvestrant-naïve metastatic ER+ HER2- breast cancer carrying activating HER2 
mutations. 
3. To assess the PFS and response rate of neratinib in combination with fulvestrant in patients 
with metastatic ER+ HER2- breast cancer carrying activating HER2 mutations previously 
treated with fulvestrant. 
4. To assess the safety profile and tolerability of neratinib in combination with fulvestrant in 
patients with metastatic ER+ HER2- breast cancer carrying activating HER2 mutations. 
5. To correlate the presence of HER2 mutation with histology subtype (invasive lobular vs. 
invasive ductal cancer), tumor grade (grade 1-2 vs 3), tumor staging at initial diagnosis (I vs. II 
or III vs. IV), disease free survival in HER2- breast cancer.  
 
2.3 
Exploratory Objectives 
 
1. To compare the occurrence of HER2 mutation in paired primary and metastatic sites 
2. To collect peripheral blood plasma samples for circulating HER2 mutation analysis 
3. To investigate other potential therapeutic targets in HER2- breast cancer 
4. To explore potential mechanisms of treatment resistance 
5. To explore anti-tumor response after adding trastuzumab (or FDA approved biosimilar) to 
neratinib or neratinib plus fulvestrant when tumor progresses on single agent neratinib or 
neratinib in combination with fulvestrant. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Pre-registration (for patients with unknown HER2 mutation status to have tumor 
tissue screened centrally by Wash U GPS laboratory) 
 
3.1.1 Inclusion Criteria for Pre-registration  
 
1. Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or non-
amplified by FISH) breast cancer that is stage IV.   
2. Agree to provide archival tumor material for research 
3. There is no limitation on the number of prior lines of systemic therapy.  
4. Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except 
to be eligible for the Part II fulvestrant-naïve ER+ cohort, at least one measurable 
disease by RECIST 1.1 is required. 
5. At least 18 years of age. 
6. ECOG performance status < 2 (see Appendix A). 
7. Adequate organ function as defined below within 8 weeks of pre-registration: 
• Serum creatinine: ≤1.5 x ULN 
• Child-Pugh class A if with liver disease 
8. Able to understand and willing to sign an IRB approved written informed consent 
document. 
 
Note: HER2 mutation testing may be performed while the patient is receiving active 
systemic therapy for metastatic breast cancer so that the result can be used to determine 
eligibility for study drug therapy in the future. 
 
3.1.2 Exclusion Criteria for Pre-registration 


 
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1. Testing for LVEF is not required for pre-registration, but patient must not have a recent 
LVEF < LLN or have symptoms of congestive heart failure. 
2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
3. Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the 
exception of Gilbert’s syndrome, asymptomatic gallstones, liver metastases, or stable 
chronic liver disease per investigator assessment). 
4. History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias. 
5. Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs 
resulting in dyspnea at rest. 
 
3.2 
Registration (for patients positive for HER2 mutation to receive study treatments)  
 
3.2.1 Inclusion Criteria for Registration (for patients initially pre-registered and 
with HER2 mutation identified by Wash U GPS laboratory) 
 
1. Tumor tissue tested positive for HER2 mutation.  See the list of mutations eligible for 
Part II enrollment in Table 2 (Section 5.1.6).  Mutations outside the list will be assessed 
on a case-by-case basis by the study team to determine eligibility. 
Note: HER2 mutations listed in Table 2 detected by Guardant360 are also eligible  
2. Agree to provide archival tumor material for research 
3. ECOG performance status < 2 (see Appendix A). 
4. Adequate organ function as defined below within 2 weeks of registration: 
• Absolute neutrophil count: ≥1.5 × 109/L (1500/mm3) 
• Platelet count: ≥100 × 109/L (100,000/mm3) 
• Serum creatinine: ≤1.5 x ULN 
• Child-Pugh class A if with liver disease 
5. The patient must have completed radiation therapy and be at least 1 week from the last 
systemic therapy administration, with adequate recovery of bone marrow and organ 
functions, before starting neratinib.  
6. Presence of disease progression on the most recent disease evaluation. 
7. Patients with known treated brain metastasis are eligible, but must have received 
radiation and be off steroids and stable (without evidence of disease progression by 
imaging or exam) for 3 months. 
8. QTc interval ≤ 450 msec for men or ≤ 470 msec for women within 2 weeks of 
registration. 
9. LVEF > institutional LLN within 4 weeks of registration.  
10. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she must inform her treating physician 
immediately.  Men must agree and commit to use a barrier method of contraception 
while on treatment and for 3 months after the last dose of the investigational product 
(see Section 6.3). 
11. Able to understand and willing to sign an IRB approved written informed consent 
document. 
12. There is no limitation on the number of prior lines of systemic therapy. 


 
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13. To be eligible for the Part II fulvestrant-naïve ER+ cohort, prior treatment with 
fulvestrant is not allowed. In addition, ER and/or PR positivity by institutional standard 
is required on pathology from the most recent tumor specimen if biopsy was done unless 
the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield 
false negative ER and/or PR result, in which case the pathology from an earlier time 
point could be used and a discussion with the study chair is required. 
14. To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression 
on fulvestrant is required.  In addition, ER and/or PR positivity by institutional 
standard is required on pathology from the most recent tumor specimen unless the 
tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false 
negative ER and/or PR result, in which case the pathology from an earlier time point 
could be used and a discussion with the study chair is required. 
 
3.2.2 Inclusion Criteria for Registration (for patients with HER2 mutation 
identified at an outside CLIA certified location) 
 
1. Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or non-
amplified by FISH) breast cancer that is stage IV.   
2. Tumor tissue or circulating tumor DNA tested positive for HER2 mutation.  See the list 
of mutations eligible for Part II enrollment in Table 2 (Section 5.1.6).  Mutations outside 
the list will be assessed on a case-by-case basis by the study team to determine 
eligibility. 
3. Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except 
to be eligible for the Part II fulvestrant-naïve ER+ cohort, at least one measurable 
disease by RECIST 1.1 is required. 
4. At least 18 years of age. 
5. ECOG performance status < 2 (see Appendix A). 
6. Adequate organ function as defined below within 2 weeks of registration: 
• Absolute neutrophil count: ≥1.5 × 109/L (1500/mm3) 
• Platelet count: ≥100 × 109/L (100,000/mm3) 
• Serum creatinine: ≤1.5 x ULN 
• Child-Pugh class A if with liver disease 
7. The patient must have completed radiation therapy and be at least 1 week from the last 
systemic therapy administration, with adequate recovery of bone marrow and organ 
functions, before starting neratinib.  
8. Presence of disease progression on the most recent disease evaluation. 
9. Patients with known treated brain metastasis are eligible, but must have received 
radiation and be off steroids and stable (without evidence of disease progression by 
imaging or exam) for 3 months. 
10. QTc interval ≤ 450 msec for men or ≤ 470 msec for women within 2 weeks of 
registration. 
11. LVEF > institutional LLN within 4 weeks of registration.  
12. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she must inform her treating physician 
immediately.  Men must agree and commit to use a barrier method of contraception 
while on treatment and for 3 months after the last dose of the investigational product 
(see Section 6.3). 


 
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13. Able to understand and willing to sign an IRB approved written informed consent 
document. 
14. There is no limitation on the number of prior lines of systemic therapy. 
15. To be eligible for the Part II fulvestrant-naïve ER+ cohort, prior treatment with 
fulvestrant is not allowed. In addition, ER and/or PR positivity by institutional standard 
is required on pathology from the most recent tumor specimen if biopsy was done unless 
the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield 
false negative ER and/or PR result, in which case the pathology from an earlier time 
point could be used and a discussion with the study chair is required. 
16. To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression 
on fulvestrant is required.  In addition, ER and/or PR positivity by institutional 
standard is required on pathology from the most recent tumor specimen unless the 
tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false 
negative ER and/or PR result, in which case the pathology from an earlier time point 
could be used and a discussion with the study chair is required. 
 
3.2.3 Exclusion Criteria for Registration 
 
1. Currently receiving any other investigational agents or systemic cancer therapy. 
2. Currently taking medications and herbal or dietary supplements that are strong 
cytochrome P450 (CYP) 3A4 inducers or inhibitors (refer to Section 6.4.4).  A washout 
period of at least 5 days is required and must have been completed prior to the start of 
neratinib if the patient was taking any of these agents. If unavoidable, patients taking 
CYP3A4 inhibitors should be monitored closely. 
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
4. Acute or currently active hepatic or biliary disease requiring antiviral therapy (with the 
exception of patients with Gilbert’s syndrome, asymptomatic gallstones, liver 
metastases, or stable chronic liver disease per investigator assessment). 
5. Pregnant and/or breastfeeding. 
6. History of significant cardiac disease, cardiac risk factors, or uncontrolled arrhythmias. 
7. Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs 
resulting in dyspnea at rest. 
8. Experiencing grade 2 or greater diarrhea. 
9. Prior treatment with neratinib. 
10. Child-Pugh class B or C liver dysfunction. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
 


 
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4.0 
REGISTRATION PROCEDURES 
 
4.1 
Pre-Registration (for patients with unknown HER2 mutation status to have tumor 
tissue screened centrally by Wash U GPS laboratory) 
 
Patients must not start any protocol intervention prior to pre-registration through the 
Siteman Cancer Center. All eligible and consenting patients will be pre-registered to this protocol 
for the purposes of HER2 sequencing; if HER2 mutation is identified, the patient will then be 
registered if eligible for study treatment.  
 
The following steps must be taken: 
1. Confirmation of patient pre-registration eligibility by Washington University 
2. Pre-Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN)  
 
Once the patient has been entered in the Siteman Cancer Center database, the WUSM coordinator 
will forward verification of enrollment and the UPN via email. 
 
4.1.1 Confirmation of Patient Eligibility for Pre-Registration 
 
Confirm patient eligibility by faxing the information listed below to the research 
coordinator listed in the Siteman Cancer Center Clinical Trials Core Protocol Procedures 
for Secondary Sites packet and email Caroline Bumb (cbumb@wustl.edu) at least one 
business day prior to registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of sample shipment 
8. Completed pre-registration eligibility checklist (Appendix B), signed and dated by 
a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.1.2 Patient Pre-Registration in the Siteman Cancer Center OnCore Database  
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email or fax within one business day. 
Verification of eligibility and pre-registration should be kept in the patient chart. 
 
Patients at all sites must be pre-registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
 


 
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4.1.3 Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
4.2 
Registration for Study Therapy 
 
Patient who initially pre-registered and found to have HER2 mutation in the tumor will be 
registered to receive study therapy if the patient remains eligible.  The same UPN will be used.    
 
Patients with HER2 mutation identified by another CLIA certified laboratory and meet all 
eligibility will be registered prior to study drug therapy.   An UPN will be assigned as described in 
Section 4.1.3.  
 
4.2.1 Confirmation of Patient Eligibility for Registration 
 
Confirm patient eligibility by faxing the information listed below to the research 
coordinator listed in the Siteman Cancer Center Clinical Trials Core Protocol Procedures 
for Secondary Sites packet and email Caroline Bumb (cbumb@wustl.edu) at least two 
business days prior to registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of treatment to start 
8. Completed registration eligibility checklist (Appendix C), signed and dated by a 
member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2.2 Patient Registration in the Siteman Cancer Center OnCore Database  
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email or fax within one business day if all 
required documentation to determine patient eligibility is provided. Verification of 
eligibility and registration should be kept in the patient chart. 
 
Patients at all sites must be registered through the Siteman Cancer Center OnCore database 
at Washington University. 
 
 


 
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4.3 
Recruitment through Army of Women 
 
The following procedures describe how women recruited via Army of Women (AOW) will be 
screened and registered for this trial: 
 
1. HRPO-approved Eblast will be sent by AOW coordinator to women signed up through 
AOW to receive recruitment messages. 
2. Women responding to the Eblast will be referred by AOW coordinator to WUSM study 
coordinator at HER2MutationTrial@dom.wustl.edu. 
3. WUSM study coordinator will send a HRPO-approved introductory email to each AOW 
recruit requesting a time to discuss the trial and attaching the version of the screening 
consent form drafted specifically for outside recruits. 
4. WUSM study coordinator will consent the AOW recruit over the phone.  If the recruit 
consents to be screened for this trial, the WUSM study coordinator will mail the patient info 
sheet and a SASE, requesting that the patient complete the info sheet and return it along 
with the screening consent form. 
5. Once the screening consent form and patient info sheet have been received by the WUSM 
study coordinator, the medical records for the AOW recruit will be requested by the WUSM 
study coordinator. 
6. Once the medical records have been received, the pre-registration process described in 
Section 4.1 will be followed and the pre-registration eligibility criteria described in Section 
3.1 will be checked.  The patient will be informed of eligibility for HER2 mutation testing 
via email. 
7. If the patient is shown to be eligible for screening, the WUSM study coordinator will request 
a tumor specimen for HER2 mutation testing.  The WUSM study coordinator will send the 
report to the patient after reviewing with the PI.  If negative, the patient is not eligible to 
continue in the study.  If positive, the PI will discuss with the patient and the patient’s 
oncologist if the patient desires it and will refer the patient to a participating institution for 
consent to the main study. 
 
4.4 
Recruitment from Outside Practice  
 
An informational card with the title of the study and contact information of the WUSM study 
coordinator will be made and distributed to medical oncologists from outside practices at scientific 
meetings and lectures.  These physicians will be encouraged to refer potentially eligible patients to 
the WUSM study coordinator, who will begin the pre-registration screening process as described 
in #3 in Section 4.3.  Screening and testing will continue as described in Section 4.3. 
 
 
5.0 
TUMOR HER2 SEQUENCING  
 
5.1 
Tumor HER2 sequencing at Washington University CLIA lab following pre-
registration for eligibility 
 
Patients meeting the pre-registration eligibility criteria with unknown tumor HER2 
mutation status could undergo tumor HER2 sequencing centrally at the CAP/CLIA certified 
Genomic and Pathology Services at Washington University (GPS@WU) after pre-
registration to the study. Sanger sequencing of Exons 18, 19, 20, 21, 22, 23 and 24 was 
initially used for the study.  Since October 2014, this was switched to a next generation 


 
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sequencing (NGS) HER2 assay that covers all coding exons of the HER2 gene.   
 
Archival tumor specimens from the primary breast cancer or from a metastatic site is 
required for the sequencing analysis.  Samples will be need to be shipped to the “Clinical 
Support Services Office at the Washington University Department of Pathology & 
Immunology”.  Please refer to the Correlative Science Procedures Manual Section 1.0 for 
tumor sample requirement and shipping instructions.  Note that sample shipment and 
sequencing analysis can be performed while the patient is receiving other systemic therapies 
so the results could be used to determine whether the patient is eligible to receive the study 
therapy when disease progresses on the current treatment.  
 
The study coordinator from the participating institution listed on the sample shipment form 
will be notified of the results per email within 3-4 weeks.  The study chair and the 
Washington University study coordinator have access (requiring password) to a secure 
folder on the WUSM pathology department network drive where the clinical reports are 
stored. For remotely screened participants, the reports will be faxed or emailed to the 
participant or the treating physician as applicable.  
 
5.2 
Tumor or circulating tumor DNA HER2 Mutation/Variants Identified at 
Laboratories other than GPS@WU  
 
Patients with tumor or circulating tumor DNA HER2 mutations meeting the criteria defined 
in Section 5.3 identified at other CAP/CLIA-certified laboratories are eligible for study 
entry if they meet all other eligibility criteria.  To determine the eligibility of the reported 
mutation from laboratories other than Wash U GPS, the full report will need to be sent to 
Caroline Bumb (cbumb@wustl.edu) and Cynthia Ma (cynthiaxma@wustl.edu). 
 
Pre-registration process is not required for patients with known mutations as above but the 
archival tumor sample must be submitted to Wash U Alliance/ACOSOG-CSB/TPC, not to 
the Clinical Support Service Office, for future confirmation of the HER2 mutation and 
correlative studies (also refer to the Section 10 for Correlative Study).  Please refer to the 
Correlative Science Procedure Manual regarding the sample requirement and shipping 
instructions for Correlative Studies.     
 
5.3 
Eligible HER2 mutations   
 
HER2 mutation is defined as a  single nucleotide variant (SNV) or an indel variation that changes 
the encoded amino acid in the coding region of HER2 or an intronic mutation known to affect the 
splicing of HER2. Identified SNVs will be compared to known single nucleotide polymorphisms 
(SNPs) identified in the SNP data base as well as to the variants identified in cancer mutation 
databases including the Catalogue Of Somatic Mutations In Cancer (COSMIC) database.  HER2 
SNPs would be not considered as an HER2 mutation.  Germ-line DNA will be sequenced to rule 
out single nucleotide polymorphisms if needed.  
 
All somatic HER2 mutations were eligible for Part I of the trial.  However, due to the lack of 
response in patients with HER2 mutations of unknown significance observed in Part I of the trial 
[68], only known activating mutations listed in Table 2 are considered eligible for patients 
enrolling to Part II of the trial unless approved by the study chair. Mutations outside the list will 
be assessed on a case-by-case basis by the study team to determine eligibility. 
 


 
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Table 2   Known Activating HER2 Mutations 
HER2 mutation 
Reference 
G309A/E 
[56, 57] 
S310F/Y 
[56] 
S653C 
[58] 
L755S 
[57, 59, 60] 
L755P 
[60] 
Del. 755-759 
[57] 
D769Y/H 
[57] 
V777L 
[57, 60] 
V842I 
[57] 
T862A 
[60] 
L869R 
[62] 
H878Y 
[60, 63, 64] 
G776V/C 
[65] 
All exon 20 insertions, including: 
A771_Y772insYVMA 
A775_G776insYVMA 
P780_Y781insGSP 
[66, 67]  
 
5.4 
Germline DNA Sequencing for HER2 to determine eligibility 
 
In cases where it is unclear whether the identified HER2 variant is somatic (tumor specific) versus 
germline in origin, the study team at WUSM will notify the site investigator to submit a blood 
sample of the patient for germline DNA sequencing at Wash U GPS laboratory. Please refer to 
Section 2.0 of the Correlative Science Procedure Manual for the submission and shipment.  
 
5.5 
HER2 Mutation Testing by ctDNA 
 
Plasma in cancer patients often carries small amounts of fragmented cell-free DNA of 160-180 
base pairs, which are originated from the necrosis or apoptotic process of cancer cells.  Advances 
in the next generation sequencing (NGS) technology and digital genomic techniques support the 
clinical validity of cell-free circulating DNA (ctDNA) sequencing analysis to non-invasively 
identify actionable genomic alterations, monitor treatment response, and investigate resistance 
mechanisms [69].  ctDNA sequencing is particularly helpful in cases that tumor DNA sequencing 
is not possible due to insufficient quality or quantity of the tumor tissue.   
 
In collaboration with Guardant Health, Inc., we analyzed the plasma ctDNA collected from patients 
enrolled in this trial using the CLIA certified digital sequencing panel (Guardant 360), which 
utilizes hybrid capture followed by NGS of all exons in 30 genes (including HER2) and critical 
exons (those reported as having a somatic mutation in COSMIC) of 40 additional genes to detect 
and report single nucleotide variants (SNVs) and small indels in 70 genes, copy number 
amplifications in 18 genes, and select fusions [70].  The plasma ctDNA sequencing successfully 
identified HER2 mutation in 11/14 (79%; 90% CI: 53-94%) patients tested positive for HER2 
mutation by tumor DNA NGS of HER2.  Importantly, none of the 32 patients who were negative 
for HER2 mutation by tumor DNA sequencing was positive by ctDNA sequencing.  Therefore, the 
specificity of the Guardant 360 ctDNA sequencing for HER2 mutation was 100% (90% CI: 91-
100%).  These data are being prepared for publication.  Based on these results and the fact that 
tumor DNA sequencing for HER2 was unsuccessful in over 25% of patients pre-registered to this 


 
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trial, we will allow patients with HER2 mutation detected in plasma by a CLIA lab to enroll on the 
study to receive neratinib.   
 
 
6.0 
TREATMENT PLAN 
 
To be eligible to receive neratinib, mutation in HER2 either in the primary or metastatic tumor or 
circulating tumor DNA is required.  However, data that have been collected during pre-registration from 
patients who have HER2 non-mutant tumors will also be used for studies to correlate HER2 mutation with 
histology subtype (invasive lobular vs. invasive ductal cancer), tumor grade (grade 1-2 vs. 3), tumor 
staging at initial diagnosis (I vs. II or III vs. IV), and disease-free survival in HER2-negative breast cancer.  
The left over tumor specimens from HER2 sequencing analysis from all patients will be assayed in future 
studies to understand the biology of HER2-negative breast cancer.  The future studies could include tumor 
DNA, RNA or protein analysis. 
  
6.1 
Neratinib Administration 
 
Neratinib is administered in the outpatient setting.  It will be taken by mouth with food, preferably 
in the morning daily, starting at 240mg per day.  Neratinib will be given on a 28-day cycle (+/- 3 
days).  The dose modification guidelines are provided in Section 7.0.  In Cycle 2 or subsequent 
cycles, patients may begin taking 320mg per day of neratinib with prophylactic loperamide 
provided the patients did not experience any intolerable grade 2 or higher treatment-related AEs 
during previous cycles (including diarrhea while receiving prophylactic loperamide).  
 
6.2 
Concurrent Prophylactic Administration of Loperamide 
 
Investigators must ensure that subjects have loperamide on hand when starting to take the 
investigational product.  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.  Loperamide 
will be dispensed directly by the site on day 1 (preferred option), or a prescription for loperamide 
will be provided for the subject with the instruction to have loperamide on hand prior to taking the 
first dose of investigational product.  If none of the above is feasible, the subject must obtain 
loperamide “over-the-counter” prior to taking the first dose of investigational product on Day 1. 
 
6.3 
Fulvestrant Administration 
 
Fulvestrant will be given on a 28-day cycle (+/- 3 days).  It is administered at a dose of 500 mg (2 
x 250 mg injections) IM on Days 1 and 15 of Cycle 1, and 500 mg IM on Day 1 of each subsequent 
cycle.  Administer intramuscularly slowly in the buttock.  (NOTE: 500 mg dose will require one 
250 mg injection in each buttock).  Immediately activate needle protection device upon withdrawal 
from patient by pushing lever arm completely forward until needle tip is fully covered.  Visually 
confirm that the lever arm has fully advanced and the needle tip is covered.  If unable to activate, 
discard immediately into an approved sharps container. 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antinausea/diarrhea, etc., when appropriate.  
 


 
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Subjects on digoxin, a P-glycoprotein substrate with a narrow therapeutic window, should be 
monitored closely and their digoxin dose adjusted as needed, since neratinib is an inhibitor of P-
glycoprotein.  Co-administration of neratinib and digoxin could result in increased digoxin levels 
and associated digoxin toxicity. 
 
Elective surgery should be avoided while receiving investigational product.  If surgery is required 
the recommendation is to hold investigational product for 3 to 4 days prior to surgery, and then 
resume product when the subject is tolerating a full diet post-operatively (no later than 3 weeks 
after holding it). 
 
The start date and stop date and indication for concomitant treatments and/or therapies and 
medications given because of an AE occurring from the signing of the consent form until the end 
of treatment will be recorded on the Concomitant Medications Form in REDCap. 
 
6.4.1 Prohibited Concomitant Treatment  
 
The following treatments are prohibited during neratinib therapy: 
• Any chemotherapy, radiation therapy, immunotherapy, biotherapy, or surgery for 
breast cancer.  
• Any other investigational agent. 
 
6.4.2 Permitted Concomitant Treatment during Neratinib Therapy 
 
The following treatments are permitted during the study: 
• Standard therapies for preexisting medical conditions, and for medical and/or 
surgical complications.  All medication should be recorded. 
• Bisphosphonates, regardless of the indication. 
 
6.4.3 Addition of Trastuzumab (or FDA Approved Biosimilar) at Disease 
Progression on Neratinib or Neratinib in combination with Fulvestrant 
 
If a patient experiences disease progression following neratinib or neratinib in combination 
with fulvestrant, trastuzumab may be added to the treatment regimen provided it is covered 
by the patient’s insurance company.  Trastuzumab has available biosimilar products FDA 
approved for use. Trastuzumab or any of the FDA approved commercially available 
biosimilar products for trastuzumab may be administered to patients based on their 
insurance requirements or institutional practice. If a biosimilar product is required, dosing, 
schedule of administration, and premedications are identical to the guidance described 
throughout the protocol for trastuzumab. Preparation of the drug product will be dependent 
on the biosimilar selected for use. 
 
Patients should start trastuzumab (or FDA approved biosimilar) with their next scheduled 
fulvestrant injection. Neratinib does not need to be held between progression and Day 1 of 
trastuzumab (or FDA approved biosimilar) treatment. Palliative radiation for pain is 
allowed prior to starting trastuzuamb with prior approval from the Washington University 
PI. Neratinib should be held during radiation.  AE monitoring, dose modifications for 
neratinib, and tumor response on combination therapy will be followed per protocol.  For 
these patients, treatment cycle will be restarted at cycle 1 at the start of trastuzumab.  
Research blood collection will follow the study calendar (beginning at C1D1).  
 


 
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Trastuzumab (or FDA approved biosimilar) is administered intravenously with a loading 
dose of 6 mg/kg then 4 mg/kg every 2 weeks +/- 3 days.  A cycle will be defined as 28 days.  
For the first (loading) dose of trastuzumab (or FDA approved biosimilar), premedication 
with diphenhydramine 50 mg PO or other antihistamine equivalent and acetaminophen 650 
mg PO will be given.  
 
 
 
 
 


 
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6.4.4 Effect of Other Drugs on Neratinib 
 
Gastric Acid Reducing Agents 
Clinical Impact 
• Concomitant use of neratinib with a proton pump 
inhibitor (PPI, lansoprazole) resulted in a decrease 
of neratinib Cmax by 71% and AUC by 65% 
• Concomitant use with other pH lowering agents was 
not studied but a decrease in neratinib AUC is also 
considered likely 
• Decreased neratinib AUC may reduce neratinib 
activity 
Prevention or 
Management 
 
• PPIs 
 
 
Avoid concomitant use 
 
• H2-receptor antagonists 
 
 
Avoid concomitant use 
 
• Antacids 
 
 
Separate neratinib dosing 
by 3 hours after antacids 
Strong and Moderate CYP3A4 Inhibitors 
Clinical Impact 
• Concomitant use of neratinib with a strong CYP3A4 
inhibitor (ketoconazole) increased neratinib Cmax by 
321% and AUC by 481% 
• Concomitant use of neratinib with other strong or 
moderate 
CYP3A4 
inhibitors 
may 
increase 
neratinib concentrations 
• Increased neratinib concentrations may increase the 
risk of toxicity 
Preventation or 
Management 
Avoid concomitant use of neratinib with strong or moderate 
CYP3A4 inhibitors. 
Examples1 
Strong CYP3A4 inhibitors:  boceprevir, clarithromycin, 
cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, 
elvitegravir and ritonavir, grapefruit juice, idelalisib, 
indinavir 
and 
ritonavir, 
itraconazole, 
ketoconazole, 
lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir 
and 
ritonavir 
and 
(ombitasvir 
and/or 
dasabuvir), 
posaconazole, ritonavir, saquinavir and ritonavir, tipranavir 
and ritonavir, troleandomycin, voriconazole 
Moderate CYP3A4 inhibitors:  aprepitant, cimetidine, 
ciprofloxacin, 
clotrimazole, 
crizotinib, 
cyclosporine, 
dronedarone, erythromycin, fluconazole, fluvoxamine, 
imatinib, tofisopam, verapamil 
Strong or Moderate CYP3A4 Inducers 
Clinical Impact 
• Concomitant use of neratinib with a strong CYP3A4 
inducer (rifampin) reduced neratinib Cmax by 76% 
and AUC by 87% 


 
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• Concomitant use of neratinib with other strong or 
moderate CYP3A4 inducers may decrease neratinib 
concentrations 
• Decreased neratinib AUC may reduce neratinib 
activity 
Prevention or 
Management 
Avoid concomitant use of neratinib with strong or moderate 
CYP3A4 inducers 
Examples1 
Strong CYP3A4 inducers:  carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. John’s wort 
Moderate CYP3A4 inducers:  bosentan, efavirenz, 
etravirine, modafinil 
1These examples are a guide and not considered a comprehensive list of all possible drugs that may fit this 
category.  Please contact study chair.  
  
If unavoidable, patients taking CYP3A4 inhibitors should be monitored closely. 
Subjects on coumarin-derivative anticoagulants (eg, warfarin) should be monitored closely 
and their anticoagulant dose adjusted as needed.  Subjects on chronic laxatives should be 
followed closely and consideration should be given to decreasing or stopping laxatives prior 
to starting investigational agent, given the potential for neratinib-related diarrhea to be 
worsened by concomitant laxative use.  Drugs known to cause QTc prolongation which are 
being given concomitantly require close monitoring of the subject with serial ECGs. 
 
MEDICATIONS THAT MAY CAUSE QTc PROLONGATION 
 
The following table presents a list of drugs that prolong, may prolong, or are unlikely to prolong the QTc. Please note that 
this list is frequently updated. For the most current list of medications, users should be directed to the following website: 
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm. 
 
Patients using drugs known to cause QT/QTc prolongation should be monitored closely with serial electrocardiograms (ECG) 
at the Investigator’s discretion.  
 
Compound 
Compound Half Life 
Possible 
Washout Period 
- Hours 
Possible 
Washout 
Period - Days 
Alfuzocin 
~10 hours 
 
7 
Amantadine 
17 +/- 4 hours (10-25) 
 
4 
Amiodarone (cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hr (26-64) 
 
10 
Chloral hydrate 
Readily converted to Trichloroethanol (active 
metabolite T1/2=7-10 hour) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 +/- 7 hours 
 
7 
Cisapride 
6 – 12 hour, up to 20 hour 
60 
 
Clarithromycin 
Non linear PK3-4 hr (250mg Q12) 
5-7 hr (500mg Q12) 
36 
 
Cloroquine 
6 to 60 days; mean 20 days 
 
 
Desipramine* 
> 24 hours, wide interpatient variability 
 
 
Disopyramide 
6.7 hr (4-10) 
36 
 
Dofetilide 
10 hr 
48 
 
Dolesetron 
8.1 hr 
 
 


 
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Domperidone 
7-8 hr 
48 
 
Doxepin* 
> 24 hours, wide interpatient variability 
 
 
Droperidol 
2.2 hours 
10 
 
Erythromycin 
* Each salt form has different Half life* 
 
 
Felbamate 
20-23 hr 
 
5 
Flecainide 
20 hr (12-27) 
 
5 
Foscarnet  
87.5+/-41.8 hours 
*distribution and release from bone* 
 
20 
Fosphenytoin 
12-29 hr 
 
6 
Gatifloxacin 
7-14 hr 
48 
 
Gemifloxacin 
7 hours 
48 
 
Grepafloxacin 
16 hr 
 
3 
Halofantrine 
6-10 days ( variable among individual) 
 
45 
Haloperidol 
18 +/-5 hr 
 
5 
Ibutilide 
6 hours (2-12) * variable among subject* 
36 
 
Imipramine* 
> 24 hours, wide interpatient variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
Isradipine 
8 hours ( multiple metabolites) 
48 
 
Levofloxacin 
6-8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with active metabolite 
2.6 day for LAAM, 2 day for nor-LAAM, 4 day for 
dinor-LAAM 
 
20 
Lithium 
24 hour (10-50) 
 
7 
Mesoridazine 
24-48 hours ( animal study) 
 
10 
Methadone 
15-30 hours 
 
7 
Moexipril/HCTZ 
2-9 hour (include active metabolite) for moexipril; 
5.6-14.8 hours for HCTZ  
48 
 
Moxifloxacin 
12 +/-1.3 hours 
72 
 
Naratriptan 
6 hours 
36 
 
Nicardipine 
~ 2 hour post IV infusion 
12 
 
Nortriptyline* 
> 24 hours, wide interpatient variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5 to 7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4+/-1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Procainamide 
3-4 hour for PA and NAPA (active metabolite) 
24 
 
Protiptyline* 
> 24 hours, wide interpatient variability 
 
 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult; 3-4 hours in children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor metabolizer) 
9-hydroxyrisperidone (active metabolite) T ½ =21-30 
hours (extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours ( only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
~34 hours in healthy; ~19 hours in Kidney transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hr 
24 
 
Thioridazine 
20-40 hours (Phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenifil 
4 to 5 hours 
 
 
Venlaflaxine 
5 +/-2 hours for parent comp. 
11+-2 hours for OVD (active metabolite) 
60 
 
Voriconizole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hr 
36 
 


 
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Zolmitriptan 
2.8-3.7 hours (higher in female) 
18 
 
*Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk for Torsades de Pointes when used in usual 
recommended dosages and in patients without other risk factors (e.g., concomitant QT prolonging drugs, bradycardia, electrolyte disturbances, congenital 
long QT syndrome, concomitant drugs that inhibit metabolism). 
 
References: 
1. Physician’s Desk Reference 2002 
2. Facts and Comparisons ( update to June 2005) 
3. The Pharmacological Basis of Therapeutics 9th Edition, 1996 
 
6.5 
Women of Childbearing Potential 
 
Women of childbearing potential (women with regular menses, women with amenorrhea, women 
with irregular cycles, women using a contraceptive method that precludes withdrawal bleeding, 
and women who have had a tubal ligation) are required to have a negative serum or urine pregnancy 
test within 7 days prior to the first dose of neratinib.   
 
Female and male patients (along with their female partners) are required to use two forms of 
acceptable contraception, including one barrier method, during participation in the study and for 
one month following the last dose of the neratinib. Men must agree and commit to use a barrier 
method of contraception while on treatment and for 3 months after the last dose of the 
investigational product. 
 
If a patient is suspected to be pregnant, neratinib should be immediately discontinued.  In addition 
a positive urine test must be confirmed by a serum pregnancy test.  If it is confirmed that the patient 
is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or within 
one month after the last dose of neratinib, the investigator must be notified in order to facilitate 
outcome follow-up. 
 
6.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the patient’s health 
and/or the patient no longer wishes to continue protocol therapy, the protocol therapy should be 
discontinued and the reason(s) for discontinuation documented in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or permanent 
harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 


 
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Patients who prematurely discontinue treatment for any reason will be followed as indicated in the 
study calendar. 
 
6.7 
Duration of Follow-up 
 
Patients will be followed every 3 months for 2 years or until death, whichever occurs first.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  Patients will be followed through either review of medical 
records, phone calls, or office visits. 
 
 
7.0 
DOSE DELAYS/DOSE MODIFICATIONS AND AE MANAGEMENT 
 
7.1 
Neratinib Dose Administration Table 
 
The allowed dose levels for dose reduction(s) due to toxicity which is deemed possibly, 
probably, or definitely related to neratinib are listed in the below dose administration 
table. 
 
Dose Level 
Neratinib (mg) 
 
Number of 40 mg 
tablets 
2 
320 
8 
Starting dose (1) 
240 
6 
-1 
200 
5 
-2 
160 
4 
-3 
120 
3 
 
7.2 
General Dose Adjustments for Neratinib-Related Toxicities 
 
Dose escalation of neratinib to 320 mg per day with prophylactic loperamide is allowed to start 
at Cycle 2 or subsequent cycles in patients who experienced no intolerable grade 2 or higher 
treatment-related AEs during the previous cycle(s) of therapy (including diarrhea while receiving 
prophylactic loperamide).  The guideline for diarrhea management outlined in Section 7.3 is to be 
followed, except that patients will be contacted over the phone within the first week of escalation 
to 320 mg, and then on a weekly basis thereafter during the first month at the higher dose of 
neratinib.   
 
Subjects should be withdrawn from the study if the 120-mg dose level of neratinib is not tolerable, 
or if the subject fails to recover to NCI grade 0 to 1 (or to within baseline of starting values for 
preexisting laboratory abnormalities) from treatment-related toxicity, leading to treatment delay of 
>3 weeks.  Missed dose(s) of the investigational product will not be made up. Dose adjustments 
are described below.  Additional clinical situations may result in dose adjustments as clinically 
indicated (e.g., intolerable, persistent grade 2 drug-related AE).  For general guidelines for the 
management of diarrhea, refer to Section 7.3.  The management of LFT changes is specifically 
addressed in Section 7.4.  For the management of LVEF declines, follow the guidelines in Section 
7.5. 
 
 


 
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Event 
(Based on NCI CTC 4.0) 
Action 
Pneumonitis/Interstitial Lung Disease: 
Symptomatic Grade 2 or Grade ≥3 
• Symptomatic 
Grade 
2: 
Hold 
the 
investigational product until resolution to ≤ 
grade 1 or baseline within 3 weeks of 
stopping the investigational product. Then 
resume the investigational product at the 
next lower dose level. 
• Grade ≥3: Discontinue the investigational 
product permanently. 
Grade 4 (Hematologic or 
Nonhematologic) 
 
(Including nausea and/or vomiting despite 
optimal medical therapy) 
• Hold the investigational product until 
recovery to ≤grade 1 or baseline within 3 
weeks of stopping the investigational 
product, then resume the investigational 
product with 2 dose levels reduction. 
Other Grade 3 Nonhematologic 
(Including nausea and/or vomiting 
despite optimal medical therapy, and 
asthenia lasting 
>3 days) 
• Hold the investigational product until 
recovery to ≤grade 1 or baseline within 3 
weeks of stopping the investigational 
product.  Then resume the investigational 
product at the next lower dose level. 
 
7.3 
Guidelines for the Management of Diarrhea 
 
Diarrhea is the major DLT of neratinib with onset typically occurring early in the course of 
treatment (during the first few weeks of treatment).  Primary prophylactic use of antidiarrheal 
medication is mandatory for all enrolled subjects receiving neratinib at either 240mg or 320mg 
daily.  Loperamide is the recommended standard therapy to treat diarrhea in this study.  If 
alternative antidiarrheal medication is proposed, this should be discussed with the Principal 
Investigator and the reason documented in the source documents. Second-line antidiarrheal 
treatments and adjunctive therapies (i.e., octreotide [SANDOSTATIN®]) are also recommended 
for use when appropriate. 
 
The investigator must review with the subject the patient instructions for the management of 
diarrhea and the Medication Diary (Appendix B) for the subject’s daily recording of investigational 
product dose, any adverse reactions, number of stools and use of loperamide and/or other 
antidiarrheals.  Both the subject and the investigator must sign the IRB-approved patient 
instructions (template is Appendix C) for the management of diarrhea.  Copies of both documents 
are handed to the subject before leaving the site with investigational product on Day 1 with clear 
instructions to contact the investigator in the event of de novo onset or persistent ≥ grade 2 diarrhea 
to discuss the appropriate course of treatment. In addition, the Investigator or designee will contact 
the subject within 24, 48, and 72 hours after the first dose of study drug is administered to inquire 
about any diarrhea. 
 
Documentation of any occurrences of stools or diarrhea must be as precise as possible and captured 
in the Medication Diary (Appendix B).  For adverse event recording, documentation of 
“Intermittent” events of diarrhea is limited to grade 1.  If events of grade 1 diarrhea are separated 


 
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by 3 days without any diarrhea, then each event must be documented as separate adverse events 
with corresponding start and stop dates. 
 
The entries on the Medication Diary should be reviewed together with the subject at every visit and 
the data provided on the diary serves as source data for adverse event documentation on the CRF.  
If the subject has experienced diarrhea since the last visit, details of the daily number of unformed 
stools provided on the diary help to grade the diarrhea as precisely as possible (per NCI CTC 4.0).  
Also, daily dose of loperamide (or other antidiarrheals, if applicable) noted on the diary will be 
reviewed and recorded on the CRF. 
 
Loperamide will be dispensed directly by the site (either as a script or from over the counter) on 
day 1 with neratinib. It is very important to initiate treatment with loperamide concomitantly with 
the first dose of neratinib to minimize occurrence and severity of diarrhea. 
 
Prophylactic dosing instructions (Cycles 1 and 2) 
• Inform patients that they will experience diarrhea while taking neratinib 
• Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first dose of 
neratinib 
• For days 1 through 14, administer 4 mg (2 tablets/capsules) three times daily 
• For days 15 through 56, administer 4 mg (2 tablets/capsules) twice daily 
• If diarrhea occurs despite prophylaxis, treat with additional antidiarrheals, fluids and 
electrolytes as clinically indicated. NERLYNX dose interruptions and dose reductions 
may also be required to manage diarrhea 
• For patients with persistent grade 1 diarrhea (<4 stools per day above baseline) on 
loperamide, Lomotil (diphenoxylate hydrochloride and atropine sulfate) 1 tablet (2.5 mg) 
every 6-8 hours may be added. 
• Prophylactic loperamide administration may continue for subsequent cycles at the 
physician’s discretion. 
• For grade 2 diarrhea during cycle 1 (4 to 6 stools per day above baseline, despite intensive 
anti-diarrheal therapy as described above), consider adding octreotide (short-acting) 150 
micrograms SC TID; or after initial dose of short-acting octreotide, if well tolerated, a single 
dose of octreotide LAR 20 mg IM. 
 
For new onset uncomplicated grade 1 or grade 2 diarrhea (in Cycle 2 and beyond) 
Dietetic measures 
• Stop all lactose-containing products 
• Drink 8 to 10 large glasses of clear liquids per day 
• Eat frequent small meals 
• Recommend low fat regimen enriched with bananas, rice, applesauce and toast (BRAT diet) 
until resolution of diarrhea. 
 
Pharmacological Treatment 
• For days 57 through 365, administer 4mg (2 tablets/capsules) as needed (not to exceed 8 
tablets capsules or 16 mg per day) 
• For patients with persistent grade 1 diarrhea on loperamide, Lomotil (diphenoxylate 
hydrochloride and atropine sulfate) 1 tablet (2.5 mg) every 6 hours to 8 hours may be added. 
• For grade 2 diarrhea  (4 to 6 stools per day above baseline, despite intensive anti-diarrheal 
therapy), consider adding octreotide (short-acting) 150 micrograms SC TID; or after initial 
dose of short-acting octreotide, if well tolerated, a single dose of octreotide LAR 20 mg IM. 


 
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For grade 3 or grade 4 diarrhea with complicating features (dehydration, fever, and/or grade 
3-4 neutropenia 
Dietetic measures (same as above) 
Pharmacologic treatment 
• Administer loperamide: initial dose of 4 mg (2 tablets) with the first bout of diarrhea 
followed by 2 mg (1 tablet) every 4 hours or after every unformed stool (maximum 16 mg 
a day) and continue loperamide at this frequency until diarrhea free for 12 hours. Then 
titrate the amount of loperamide used to keep diarrhea controlled (< 4 stools/day). 
• Administer octreotide (SANDOSTAINE®) [100-150 µg SC BID or IV (25-50 µg/h) if 
dehydration is severe, with dose escalation up to 500 µg SC TID] 
• Use intravenous fluids as appropriate 
• Consider prophylactic antibiotics as needed (e.g., fluoroquinolones) especially if diarrhea 
is persistent beyond 24 hours or there is fever or grade 3-4 neutropenia. 
 
Stool cultures should be done to exclude infectious causes of grade 3 or 4 diarrhea or diarrhea of 
any grade with complicating features (dehydration, fever, and/or grade 3 or 4 neutropenia) per the 
investigator’s discretion.  Results from occult blood, fecal leukocyte stain, Clostridium difficile, 
Campylobacter, Salmonella, and Shigella testing, when performed, should be reported.   
 
Subjects with significant diarrhea who are unresponsive to medical treatment may require treatment 
interruption or dose reduction.   
 
Gastrointestinal Toxicities Requiring Dose Adjustment of Neratinib 
NCI CTCAE V4.0 
Action 
Grade 1 Diarrhea [Increase of < 4 stools per 
day over baseline; mild increase in ostomy 
output compared to baseline.] 
OR 
Grade 2 Diarrhea [Increase of 4-6 stools per 
day over baseline; moderate increase in ostomy 
output compared to baseline;] lasting ≤ 5 days 
OR 
Grade 3 Diarrhea [Increase of ≥7 stools per day 
over baseline; incontinence; hospitalization 
indicated; severe increase in ostomy output 
compared to baseline limiting self-care activities 
of daily living {ADL};] lasting ≤ 2 days 
• 
Adjust anti-diarrheal treatment, as per the 
guidelines for management of diarrhea at the 
first onset of diarrhea.  
• 
Continue neratinib at full dose.  
• 
Instruct patient to follow dietetic 
recommendations in the guidelines for 
management of diarrhea.  
• 
Fluid intake of ~2L should be maintained to 
avoid dehydration. 
• 
Once the event resolved to ≤ grade 1 or 
baseline, start loperamide 4 mg with each 
subsequent neratinib administration. 
Persisting and intolerable Grade 2 Diarrhea 
lasting >5 days despite being treated with 
optimal medical therapy,  or associated with 
fever, dehydration, or grade 3-4 neutropenia 
OR 
Grade 3 Diarrhea lasting > 2 days despite being 
treated with optimal medical therapy, or 
• 
Adjust anti-diarrheal treatment, as per the 
guidelines for management of diarrhea at the 
first onset of diarrhea. 
• 
Hold neratinib until recovery to ≤ grade 1 or 
baseline. 
• 
Instruct patient to follow dietetic 
recommendations of the guidelines for 
management of diarrhea.  


 
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NCI CTCAE V4.0 
Action 
associated with fever, dehydration, or grade 3-4 
neutropenia 
OR 
Any Grade 4 diarrhea [Life-threatening 
consequences; urgent intervention indicated] 
• 
Fluid intake of ~2L should be maintained, 
intravenously if needed. 
• 
If recovery occurs:  
o ≤1 week after withholding treatment, 
resume same dose of neratinib.  
o Within 1-3 weeks after withholding 
treatment, reduce neratinib dose to the 
next lower dose level.  
• 
If event recurs and the neratinib dose has 
not already been decreased, reduce neratinib 
dose to the next lower dose level. 
• 
If subsequent events occur, reduce neratinib 
dose to the next lower dose level.  
• 
Once the event resolved to ≤ grade 1 or 
baseline, start loperamide 4 mg with each 
subsequent neratinib administration. 
• 
If event recurs and the neratinib dose has 
already been reduced at the lowest level, 
discontinue neratinib. 
 
7.4 
Guidelines for the Management of Changes in Liver Function Tests 
 
Changes in LFTs have been reported in subjects taking neratinib.  Subjects experiencing grade 3 
or 4 diarrhea requiring IV hydration and associated with 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 LFT changes. 
 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) concurrent 
with abnormal elevations in total bilirubin that meet the criteria in the table 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. 
 
The possibility of hepatic neoplasia (primary or secondary) should also be considered. 
 
During evaluation of potential hepatotoxicity, bilirubin should be fractionated and prothrombin 
time should be measured. 
 
Also, liver imaging should be obtained for subjects with any signs or symptoms of hepatotoxicity 
and/or grade 3 or greater LFT elevations, or as clinically indicated. 
 
 
 
 
 
 
 
 
 


 
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Event 
(Based on NCI CTC4.0) 
Action 
Grade 3 ALT (>5-20x ULN), or 
Grade 4 ALT (>20x ULN), or 
Grade 3 Bili (>3-10x ULN) and direct bili ≥ 
35% of total bili, or 
Grade 4 Bili (>10x ULN) and direct bili ≥ 
35% of total bili. 
• 
Permanently discontinue 
investigational product (IP) 
• 
Evaluate alternative causes. 
ALT > 3x ULN and 
Total bilirubin > 2x ULN  and 
Alkphos < 2x ULN. 
• 
Hold IP and immediately contact the 
PI to discuss next steps, including 
evaluation of alternative causes, and 
management of IP. 
• 
Report as SAE. 
Signs or symptoms related to liver injury (abdominal 
pain, fever, jaundice, rash, eosinophilia, or drop in 
performance status) with either: 
Grade 2 ALT (>3-5x ULN), or 
Grade 2 ALT (>3-5x ULN) and 
Grade 2 Bili (>1.5-3x ULN) and direct bili 
≥ 35% of total bili. 
• 
Permanently discontinue IP. 
• 
Evaluate alternative causes. 
 
7.5 
Guidelines for the Management of LVEF Declines 
 
LVEF assessments will be performed at the completion of every four cycles during the treatment 
period.  It is strongly recommended to use the same method of cardiac evaluation (ECHO or 
MUGA) at each time point for each subject. 
 
In case of symptomatic heart failure, the investigational product must be discontinued permanently. 
 
Asymptomatic decline in LVEF that warrants intervention is defined as: 
• LVEF < LLN AND absolute decrease in LVEF of ≥ 10% compared with pre-treatment 
LVEF, OR 
• Absolute decrease in LVEF of ≥ 15% compared with pre-treatment LVEF 
 
If asymptomatic decline in LVEF that warrants intervention is experienced, then: 
• Temporarily HOLD neratinib and 
• Repeat LVEF in 3-4 weeks 
 
If asymptomatic decline in LVEF as defined above persists, permanently discontinue neratinib, 
repeat LVEF in 3-4 weeks and consider cardiology consult.  If LVEF recovers to ≥ LLN and 
absolute decrease in LVEF of resolves to < 15%, resume neratinib at the same dose, and resume 
LVEF monitoring per this protocol. 
 
If a subject 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. 
 


 
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Note that, for adverse events other than asymptomatic LVEF decline, if neratinib is held for > 3 
weeks, subject should be withdrawn from the treatment phase of the study.  In case of asymptomatic 
LVEF decline, subjects may resume neratinib within one 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, the LLN should be defaulted to 50%. 
 
7.6 
Subject Compliance 
 
Compliance is monitored by study personnel at the site by using subject-completed diaries and 
verbal information from the subject that is recorded on source documents, the drug inventory 
record, and CRFs.  A subject must have taken the prescribed investigational product dosage 75% 
of the days in the treatment period to be compliant.  Dose adjustments must follow the 
recommendations in this section. 
 
Site personnel will review subject-completed diaries at every visit and will document on drug 
accountability forms provided to the sites.  Dose administration will be recorded on sponsor drug 
accountability forms. 
 
7.7 
Fulvestrant Dose Modifications 
 
There are no planned dose modifications for fulvestrant.  Dosing may be modified or discontinued 
at the discretion of the treating physician. 
 
7.8 
Trastuzumab (or FDA Approved Biosimilar) Dose Modifications 
 
There are no planned dose modifications for trastuzumab (or FDA approved biosimilar).  Dosing 
may be modified or discontinued at the discretion of the treating physician. 
 
 
8.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as outline 
below.  Please refer to Appendix E for definitions and Appendix F for a grid of reporting timelines. 
 
Adverse events will be tracked from start of treatment up to 28 days following the last day of study 
treatment.  All adverse events must be recorded on the toxicity tracking case report form (CRF) with the 
exception of: 
• 
Baseline adverse events, which shall be recorded on the medical history CRF 
 
Refer to the data submission schedule in Section 12 for instructions on the collection of AEs in the 
EDC.The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined in 
Section 8.1.5 and 8.1.6. 
 
The FDA requires that all serious and unexpected adverse events considered related to the study drug be 
reported as outlined in Section 8.6.  In addition, any fatal or life-threatening adverse experiences where 
there is a reasonable possibility of relationship to study intervention must be reported. 
 
Puma Biotechnology requires that all adverse events be reported as outlined in Section 8.7. 
 


 
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8.1 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
Reporting will be conducted in accordance with Washington University IRB Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the change.   
8.2 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University 
 
The Sponsor-Investigator (or designee) is required to notify the QASMC of any unanticipated 
problem involving risks to participants or others occurring at WU or any BJH or SLCH institution 
that has been reported to and acknowledged by HRPO.  Unanticipated problems reported to HRPO 
and withdrawn during the review process need not be reported to QASMC. 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
qasmc@wustl.edu.  Submission to QASMC must include the MyIRB form and any supporting 
documentation sent with the form.   
 
For events that occur at secondary sites, the Washington University Sponsor Investigator (or 
designee) is required to notify the QASMC within 10 days of Washington University notification 
via email to qasmc@wustl.edu.  Submission to QASMC must include either the myIRB form and 
supporting documentation or (if not submitted to myIRB) the date of occurrence, description of the 
event, whether the event is described in the currently IRB approved materials, the event outcome, 
determination of relatedness, whether currently enrolled participants will be notified, and whether 
the informed consent document and/or any study procedures will be modified as a result of this 
event. 
 
8.3 
Secondary Sites Reporting Requirements 
 
The research team at each secondary site is required to promptly notify the Washington University 
Sponsor-Investigator and designee of all serious adverse events (refer to Appendix E) within 1 
working day of the occurrence of the event or notification of the secondary site’s PI of the event.  
This notification may take place via email if there is not yet enough information for a formal written 
report (using FDA Form 3500a (MedWatch) and Washington University’s cover sheet (Appendix 
G).  A formal written report must be sent to the Washington University Sponsor-Investigator and 
designee within 4 calendar days (for fatal or life-threatening suspected adverse reactions) or 11 
calendar days (for serious unexpected suspected adverse reactions) of the occurrence of the event 
or notification of the secondary site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for reporting 
applicable events to its site’s IRB according to its own institutional guidelines.  The research team 
at Washington University is responsible for reporting all applicable events to the FDA, IBC, and 
Puma Biotechnology, Inc. as needed. 
 
Washington University pre-approval of all protocol exceptions must be obtained prior to 
implementing the change.  Local IRB approval must be obtained as per local guidelines.  
Washington University IRB approval is not required for protocol exceptions occurring at secondary 
sites. 
8.4 
Reporting to Secondary Sites 
 


 
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The Washington University Sponsor-Investigator (or designee) will notify the research team at 
each secondary site of all reportable events that have occurred at other sites within 10 working 
days of the occurrence of the event or notification of the Sponsor-Investigator of the event.  This 
includes events that take place both at Washington University and at other secondary sites, if 
applicable. Refer to Section 16.0 (Multicenter Management) for more information. 
 
8.5 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  PLEASE NOTE 
THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM REPORTING 
REQUIREMENTS FOR HRPO/QASMC.  It is the responsibility of the Washington University 
principal investigator to report to the FDA as follows: 
 
• Report any unexpected fatal or life-threatening suspected adverse experiences (Refer to Appendix 
E for definitions) no later than 7 calendar days after initial receipt of the information.   
 
 
• Report a suspected adverse reaction that is both serious and unexpected (SUSAR, 
refer to Appendix E) no later than 15 calendar days after it is determined that the 
information qualifies for reporting.  Report an adverse event (refer to Appendix E) 
as a suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event, such as: 
o A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure 
o One or more occurrences of an event that is not commonly associated with 
drug exposure but is otherwise uncommon in the population exposed to the 
drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment group than 
in a concurrent or historical control group 
• Report any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies that suggest a significant risk in humans exposed to the 
drug no later than 15 calendar days after it is determined that the information 
qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant risk in 
humans exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting.  
• Report any clinically important increase in the rate of a serious suspected adverse 
reaction of that listed in the protocol or IB within 15 calendar days after it is 
determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 3500A 
or in an electronic format that FDA can process, review, and archive.  Study teams must 
notify the Siteman Cancer Center Protocol Development team of each potentially reportable 
event within 1 business day after initial receipt of the information, and must bring the signed 
1571 and FDA Form 3500A to the Siteman Cancer Center Protocol Development team no 
later than 1 business day prior to the due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND Safety 
Report”) and must be transmitted to the review division in the Center for Drug Evaluation 


 
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and Research (CDER) or in the Center for Biologics Evaluation and Research (CBER) that 
has responsibility for review of the IND.  Relevant follow-up information to an IND safety 
report must be submitted as soon as the information is available and must be identified as 
such (“Follow-up IND Safety Report”). 
 
 
8.6 
 Reporting to Puma Biotechnology, Inc. 
 
Any serious adverse events which occur during the clinical study or within 28 days of receiving 
the last dose of study medication, whether or not related to the study drug, must be reported by the 
investigator.  In addition, any SAEs which occur as a result of protocol specific diagnostic 
procedures or interventions must also be reported.   
 
All serious adverse events, in addition to being reported to the FDA by the investigator, must be 
reported by email to Puma Biotechnology, Inc. as follows: 
 
For expedited reports, (Site) will send the MEDWATCH report to the Company no later than seven 
(7) days for initial life-threatening and death reports, and fifteen (15) days for all other initial or 
follow-up serious and unexpected suspected adverse reaction (SUSAR) as assessed by the 
investigator for causality and by the Investigator-Sponsor for causality and expectedness based on 
the adverse reaction table in the most current Investigator Brochure, from the time of receipt of the 
SAE by (Site).  For non-expedited reports (i.e., unrelated to study drugs or listed/expected event), 
(Site) will send the MEDWATCH report to the Company no later than thirty (30) days from the 
time of receipt of the SAE by (Site). 
 
By e-mail to PumaSAE@parexel.com 
 
SAEs brought to the attention of the investigator at any time after cessation of neratinib and 
considered by the investigator to be related or possibly related to neratinib must be reported to 
Puma Biotechnology, Inc. if and when they occur. Additionally, in order to fulfill international 
reporting obligations, SAEs that are related to study participation (e.g., procedures, invasive tests, 
changes from existing therapy) or are related to a concurrent medication will be collected and 
recorded from the time the subject consents to participate in the study until he/she is discharged 
from the study. 
 
8.7 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 28 days following the last day of study treatment. 
 
 
9.0 
PHARMACEUTICAL INFORMATION 
 
9.1 
Neratinib 
 
9.1.1 Description  
 
Neratinib (PB-272) is a potent irreversible pan erbB inhibitor.  Neratinib is an orally 
available small molecule that inhibits erbB-1, erbB-2, and erbB-4 at the intracellular 
tyrosine kinase domains, a mechanism of action that is different from trastuzumab. 
 


 
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9.1.2 Clinical Pharmacology 
 
Please refer to section 1.2.3. 
 
9.1.3 Supplier(s) 
 
Neratinib will be provided free of charge by Puma Biotechnology, Inc.   
 
9.1.4 Dosage Form and Preparation 
 
Neratinib 40-mg tablets will be supplied by the sponsor.  There are 210 pills per bottle.  
Repackaging of product is not allowed.  
 
9.1.5 Storage and Stability 
 
Investigational products will be stored by sites in a secure location at the storage conditions 
listed on the label; store at 25°C (77°F) or below with desiccant (bottle contains the 
dessicant); do not freeze.  Correspondingly, subjects must be instructed to store 
investigational products in a safe place at these same storage conditions.  Storage in a 
refrigerator or cold room is acceptable as long as the temperature remains above 0 °C. 
 
The investigational product must be stored as indicated.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor. 
Once a deviation is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product. 
 
The investigational product is only to be administered to subjects who have provided 
informed consent.  Once the investigational product has been assigned to a subject it must 
not be reassigned to another subject. 
 
9.1.6 Administration 
 
The number of tablets of neratinib taken will depend on the prescribed dose per the dose 
administration table.  The investigational product will be taken by mouth with food, 
preferably in the morning. 
 
9.1.7 Special Handling Instructions 
 
None. 
 
9.2 
Fulvestrant 
 
9.2.1 Description 
 
Fulvestrant (Faslodex) is an estrogen receptor antagonist which down-regulates the ER 
protein in breast cancer cells. 
 
9.2.2 Availability 
 


 
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Fulvestrant injection is commercially available as a sterile single-patient pre-filled syringe 
containing 250 mg at a concentration of 50 mg/ml. The solution is a clear, colorless to 
yellow, viscous liquid. In addition to the fulvestrant, each injection contains as inactive 
ingredients alcohol, USP, benzyl alcohol, NF, and benzyl benzoate, USP as co-solvents and 
castor oil, USP as a co-solvent and release rate modifier. 
 
For patients who cannot obtain fulvestrant commercially, such as those who are without 
medical insurance or with a limited income, AstraZeneca Foundation Patient Assistance 
Program can be reached at 1-800-424-3727 or by downloading a PDF application from the 
AstraZeneca US web site at www.astrazeneca-us.com. Completed applications should be 
mailed to: 
AstraZeneca Foundation Patient Assistance Program 
PO Box 66551 
St. Louis, MO 63166-66551 
 
9.2.3 Storage and Stability 
 
The syringes of fulvestrant for all cycles of treatment should be stored in the original 
container and refrigerated at 2°- 8°C (36°- 46°F). 
 
9.2.4 Preparation 
 
Remove glass syringe barrel from tray and check that it is not damaged. Peel open the safety 
needle (SafetyGlide™) outer packaging. Break the seal of the white plastic cover on the 
syringe luer connector to remove the cover with the attached rubber tip cap. Twist to lock 
the needle to the luer connector. Remove needle sheath. Remove excess air from the syringe 
(a small gas bubble may remain). 
 
9.2.5 Administration 
 
Fulvestrant will be administered at a dose of 500 mg (2 x 250 mg injections) IM on Cycle 
1 Day 1 and Day 15, then on Day 1 of each subsequent cycle. Administer intramuscularly 
slowly in the buttock. (NOTE: 500 mg dose will require one 250 mg injection in each 
buttock.) Immediately activate needle protection device upon withdrawal from patient by 
pushing lever arm completely forward until needle tip is fully covered. Visually confirm 
that the lever arm has fully advanced and the needle tip is covered. If unable to activate, 
discard immediately into an approved sharps container. 
 
9.2.6 Drug Interactions 
 
In vitro studies using human hepatocytes, fulvestrant was metabolized predominantly by 
conjugation. The metabolites thus formed are thought to possess no estrogenic activity and 
minimal anti-estrogenic activity. In studies using human liver microsomes, fulvestrant 
inhibited the activity of CYP1A2, 2C9 and 3A4 minimally. CYP3A4 did metabolize 
fulvestrant in these studies, but the human hepatocyte studies noted above indicate 
conjugation is a more important metabolic pathway. In addition, studies in healthy 
volunteers indicate that fulvestrant metabolism is not significantly affected by inducers or 
inhibitors of CYP3A4, nor does fulvestrant affect the metabolism of 3A4 substrates. Thus, 
fulvestrant is not expected to be involved in significant drug interactions mediated by 
CYP3A4. 


 
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10.0 
CORRELATIVE STUDIES 
 
10.1 
Required archival tumor sample for research:  
 
• Archival tumor specimens that are left over from the HER2 mutation analysis at 
Washington University are not returned and will be used for investigations of potential 
therapeutic targets in HER2-negative breast cancer.   
• Additional archival tumor specimens may be requested for studies that compare mutations 
in primary versus metastatic disease sites, and predictors of treatment response to neratinib.  
• For patients who had HER2 mutation identified in another laboratory and registered to the 
study, please submit archival tumor specimens to Wash U Alliance/ACOSOG-CSB/TPC.   
• Please refer to the Correlative Science Procedure Manual Section 3.1 for sample 
requirement and shipping instructions.  
 
10.2 
Required research blood collection 
 
Peripheral blood samples will be collected in patients who have HER2 mutation and are registered 
to receive study drug therapy.  Blood will be collected at baseline, during therapy as well as at 
disease progression (Also refer to the Correlative Science Calendar Section 10.5), for ctDNA 
sequencing and other circulating markers that may affect disease outcome. Please ship samples 
to Wash U Alliance/ACOSOG-CSB/TPC.   
 
Please refer to the Correlative Science Procedure Manual Section 3.2 for sample requirement and 
shipping instructions. 
 
10.3 
Optional research tumor biopsy (kits will be provided):  
 
If a patient is registered to this trial to receive neratinib and has tumors that are safe for biopsy, 
we encourage consenting for tumor collection prior to study drug administration and/or at the 
time of disease progression on neratinib for investigations that assess predictors of response to 
therapy and mechanisms of resistance.  
 
Note that the tumor biopsy collected at disease progression on study treatment will be subjected to 
the CLIA NGS panel of 122 genes (the Comprehensive Cancer Gene Set, verion 3.2 (CCGSv3.2)), 
at the Wash U GPS and a clinical report will be issued to the site investigator to provide to the 
treating physician and the patient within 3-4 weeks of receiving the specimen.  The sequencing 
report will provide interpretations of genomic findings, but it is at the discretion of the treating 
physician and the patient in regards to any need for referral to clinical genetic counseling service.  
The report may be helpful in assessing patient eligibility for clinical trials that require mutation 
screening.  
 
Please refer to the Correlative Science Procedure Manual Section 3.3 in regards to sample 
requirements and shipping instructions. 
 
10.4 
Reporting of a CLIA multi-gene NGS on tumor biopsy collected at disease 
progression on study drug:  
 


 
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This will follow a full clinical workflow including evaluation of the FFPE biopsy specimen by a 
qualified surgical pathologist (WU Anatomic and Molecular Pathology Core lab), extraction of 
DNA, NGS library preparation and sequencing, NGS data analysis and variant interpretation for 
the CCGSv3.2 Solid Tumor gene set (122 genes). Cases with negative results (no level 1 or 2 
variants identified) will proceed to additional reflex testing for the hematopoietic disorders gene 
set (54 genes).  
 
10.5 
Correlative Science Study Calendar 
 
Specimen Type 
Collection/Submission Time Point 
Shipping 
Condition 
Ship 
To 
Pre-
registration 
Pre-
treatment / 
C1D1 (prior 
to starting 
treatment) 
C1D15, C2D1, 
C3D1 and day 
1 of each odd 
cycle 
EOT / 
Prog 
Archival Tissue for HER2 
mutation testing (see CSPM 
1.0) 
X 
 
 
 
Ambient 
GPS 
10 ml Whole Blood in EDTA 
for germline DNA sequencing 
(see CSPM 2.0) 
X1 
 
 
 
Ambient 
GPS 
Archival Tissue for correlative 
studies (See CSPM 3.0) 
 
X2 
 
 
Ambient 
TPC 
10 ml Whole Blood in EDTA 
tube 
 
X 
 
 
Ambient 
TPC 
3 ml plasma (from 10 ml 
EDTA tube)  
 
X 
X 
X 
Frozen3 
TPC 
3 ml serum (from 10 ml SST 
tube) 
 
X 
X 
X 
Frozen3 
TPC 
(2) 8 ml Streck tubes 
 
X 
X 
X 
Ambient 
TPC 
Optional Fresh Biopsies (see 
CSPM 3.3) 
 
X 
 
X 
Frozen and 
Ambient 
TPC 
1 Only required if notified by WUSM study team 
2 FFPE tumor rich block/slides are required – due within 60 days of registration for patients who receive treatment on trial. 
3Store frozen samples at -70oC to -80oC.  Ship frozen samples quarterly on dry ice. 
CSPM:  Correlative Science Procedure Manual 
 
 
 


 
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11.0 
STUDY CALENDAR 
 
Evaluations for pre-registration should be conducted within 8 weeks prior to pre-registration and specimen submission.  Evaluations for 
registration should be conducted within 2 weeks prior to registration, with the following exceptions: echocardiogram, scans, and x-rays, which 
should be performed within 4 weeks of registration. Study drug therapy should start within 7 days of registration.   
Screening Through Cycle 1 
 
Pre-ScreeningW  
-56 to 0 days 
Pre-Registration 
Screening 
-14 to 0 days 
unless otherwise 
noted 
Registration 
C1D1 
(- 7) 
C1D2 
C1D3 
C1D4 
C1D8 
(+/- 1) 
C1D15 
(+/- 1) 
C1D22 
(+/- 1) 
Informed Consent 
X 
XV 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
Physical Exam w/ECOG 
XI 
X 
X 
 
 
 
X 
X 
X 
Vital SignsA 
 
X 
X 
 
 
 
XL 
XL 
XL 
Safety Phone CallK 
 
 
 
X 
X 
X 
 
 
 
Adverse Events 
 
 
X-----------------------------------------------------------------X 
CBC w/Differential 
X 
X 
XM 
 
 
 
 
 
 
Blood Chemistry 
X 
X 
XM 
 
 
 
 
 
 
Pregnancy TestH 
 
X 
 
 
 
 
 
 
 
Blood for ResearchS 
 
 
X 
 
 
 
 
X 
 
ECG 
 
X 
 
 
 
 
 
 
 
Echocardiogram or MUGAC 
 
XE 
 
 
 
 
 
 
 
Tumor Assessment (CT or MRI)D 
 
XE 
 
 
 
 
 
 
 
Tumor Biopsy (optional) 
 
XO 
 
 
 
 
 
 
 
Archival Tumor 
XU 
XT 
 
 
 
 
 
 
 
HER2 Mutation Report 
 
XB 
 
 
 
 
 
 
 
Patient Instructions for Diarrhea 
Management (Appendix C) 
 
 
X 
 
 
 
 
 
 
NeratinibN 
 
 
X-----------------------------------------------------------------X 
FulvestrantN, R 
 
 
X 
 
 
 
 
X 
 
Medication Diary (Appendix B) 
 
 
X-----------------------------------------------------------------X 
Concomitant Medications 
 
X 
X-----------------------------------------------------------------X 
Serious Adverse Events 
XJ 
XJ 
X-----------------------------------------------------------------X 
 
 


 
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Cycle 2 Through End of Study 
 
C2D1 
(+/- 3) 
C3D1 
(+/- 3) 
Day 1 of 
Subsequent 
Even Cycles 
(+/- 3) 
Day 1 of 
Subsequent 
Odd Cycles 
(+/- 3) 
End of 
Treatment 
(+ 7) 
30 Day Follow 
Up 
(+/- 3) 
Physical Exam w/ECOG 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
 
Adverse Events 
X------------------------------------------------------------------------------------------------X 
Follow Up Phone Call 
 
 
 
 
 
X 
CBC w/Differential 
X 
X 
X 
X 
X 
 
Blood Chemistry 
X 
X 
X 
X 
X 
 
Blood for ResearchS 
X 
X 
 
X 
 
 
Tumor Assessment (CT or MRI)D 
 
XF 
 
XF 
 
 
Tumor Biopsy (optional) 
 
 
 
 
XP 
 
Medication Diary (Appendix B) 
 
 
 
 
 
 
NeratinibG 
X------------------------------------------------------------------------------X 
 
FulvestrantR 
X 
X 
X 
X 
 
 
Trastuzumab (or FDA approved biosimilar)Q 
 
X----------------------------------------X 
 
 
Concomitant Medications 
X------------------------------------------------------------------------------------------------X 
Serious Adverse Events 
X------------------------------------------------------------------------------------------------X 
A:  
Height to be recorded only at baseline 
B:  
The sequencing report identifying the eligible HER2 mutation is required. 
C:   
Pre-registration and HER2 mutation testing, ECHO or MUGA is not required, but a patient with a known recent LVEF < LLN or with symptoms of congestive heart 
failure is not eligible for Pre-registration and HER2 mutation testing. ECHO or MUGA is required for all patients continuing to the treatment portion of the trial. 
D:   
CT of the chest, abdomen and pelvis with contrast is required for the study. If contrast could not be administered, CT of the chest without contrast, and MRI of abdomen 
and pelvis would be acceptable. The same method should be used at each evaluation. Patients with skin lesions should have photographs taken at baseline and each 
evaluation. Please have a CD copy of each radiology assessment at the completion of the exam or upload the image in the “drop box” specified in the secondary site 
instructions. Please use either the tumor measurement form in Appendix D for RECIST 1.1 response evaluation or an institutional RECIST 1.1 report for upload to the 
EDC.  
E:   
Within 28 days prior to Registration. 
F: 
Radiology test for tumor response assessment is to be performed at baseline and every 2 cycles (+/- 7 days). 
G: 
Neratinib is to be self-administered daily on each day of every 28-day cycle (+/- 3 days).  Please see Section 6.1 for dosing instructions. 
H: 
Premenopausal women of childbearing potential only 
I: 
Only performance status is required 
J:  
Determined to be related to screening procedures. 
K: 
Safety calls to the patient are to be conducted 24, 48, and 72 hours after first dose administration and can be performed by study coordinator. 
L: 
Physical exam on C1D8, C1D15, and C1D22 may be performed by MD or research NP or RN. 
M:   Cycle 1 Day 1 labs do not need to be repeated if done within 7 days of treatment. 


 
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N: 
To accommodate calls to patients at 24, 48, and 72 hours post-drug initiation, the first dose of neratinib +/- fulvestrant could be started any time within one week following 
the C1D1 visit. 
O: 
Optional baseline biopsy must be performed within 4 weeks before C1D1 or on C1D1 prior to starting neratinib +/- fulvestrant.  Please refer to Correlative Science 
Procedure Manual 
P: 
The biopsy at progression must occur prior to starting the next line of cancer therapy.  Note that a clinical sequencing report will be provided to the treating physician in 
3-4 weeks from Wash U.  Please refer to the Correlative Science Procedure Manual. 
Q: 
May be administered if patient progresses on neratinib +/- fulvestrant; refer to Section 6.4.3 for dosing and schedule. The +/- 3 day window applies to all treatment days. 
Trastuzumab or any of the FDA approved commercially available biosimilar products for trastuzumab may be administered to patients based on their insurance 
requirements or institutional practice. 
R:  
In Part II ER+ cohorts, fulvestrant will be administered at a dose of 500 mg (2 x 250 mg injections) IM on Days 1 and 15 of Cycle 1, then on Day 1 of each subsequent 
cycle.  Please see Section 6.3 for dosing instructions.  Patients already on fulvestrant 500mg every 28 days prior to registration to the fulvestrant-treated cohort do not 
need to receive the loading dose on C1D15.  In these patients, it is acceptable that C1D1 neratinib does not coincide with fulvestrant administration schedule per discretion 
of treating physician. 
S: 
Research blood is collected at baseline, on Cycle 1 day 15, Cycle 2 day 1, on Cycle 3 Day 1, followed by Day 1 of every other cycles (including Cycles 5, 7, etc), and 
EOT.  Please refer to Correlative Science Procedure Manual. 
T: 
Due within 60 days of Registration. If sample was submitted for HER2 sequencing after pre-registration a new block may not be required. See Correlative Science 
Procedure Manual. 
U:   
See Correlative Science Procedure Manual for instructions for submitting archival tissue for HER2 sequencing 
V:   
Consent can be obtained earlier than the 14 day screening window 
W: 
Patients with known HER2 mutations (see Section 5.2) are not required to complete pre-screening and pre-registration. 
 


 
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12.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed within 60 days of the schedule 
listed in this section. 
 
Electronic data management systems will be used in this trial in collaboration with the Institute for 
Informatics (I2) at Washington University.  REDCap is a web-based clinical studies data management 
system that will be used for capture of clinical data from this trial.  The case report forms developed for 
this trial will be transformed to electronic format. An electronic study calendar will drive the study’s data 
collection workflow.  Each center has access only to data from its own participants.  Washington 
University, as the data coordinating center, has access to data from all sites.  Contact the WUSTL study 
coordinator for instructions on how to request access. 
 
Case Report Form 
Submission Schedule 
Only for patients being screened for HER2 mutation 
at Washington University 
Pre-registration Consent Form 
Pathology Source Documents 
 
Prior to HER2 mutation testing 
(send to main site registrar to confirm 
eligibility) 
Biospecimen Submission Form (CSPM Appendix 2) 
GPS Submission Form (CSPM Appendix 1) 
Sent with tumor sample  
Biospecimen Submission Form (CPSM Appendix 2) Sent with peripheral blood  
Consent Form 
Pathology Source Documents (only for patients who 
were previously screened for HER2 mutation at 
outside location) 
Eligibility Checklist 
Prior to starting treatment 
Within REDCap 
Pre-Study Form 
Prior Therapy Form 
Vital Signs Form 
CBC Form 
Chemistries Form 
Tissue Collection Form 
Enter prior to treatment start 
Vital Signs Form 
CBC Form 
Chemistries Form 
Treatment Form 
Enter within 2 week of the end of each 
cycle 
Peripheral Blood Collection Form 
Due within 2 weeks of collection 
Toxicity Form 
Concomitant Medications Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
30 Day follow up 
Tumor Measurement Form 
Baseline 
End of every other cycle 
End of treatment 
MedWatch Form 
See Section 8.0 for reporting requirements 
 


 
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Any queries generated by Washington University must be responded to within 14 days of receipt by the 
participating site.  The Washington University research team will conduct a regular review of data status 
at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 
13.0 
MEASUREMENT OF EFFECT 
 
13.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks (2 
cycles).   
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).  Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
13.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Tumor lesions from a previously irradiated area may only be used as index lesions if they have 
demonstrated clear progression since completion of the radiation. 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 


 
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longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be recorded 
at baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up.  
 
13.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 


 
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PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality 
to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 


 
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follow-up CT  scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring.  
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication.  However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
13.4 
Response Criteria 
 
13.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or more 
new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
13.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase.     


 
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Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
 
13.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
 
 


 
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                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
13.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
 
14.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this trial to 
review toxicity data.  A DSMB will consist of no fewer than 3 members including 2 clinical investigators 
and a biostatistician.  DSMB members must be employed by Washington University, Barnes-Jewish 
Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members are subject to the 
Washington University School of Medicine policies regarding standards of conduct. Individuals invited 
to serve on the DSMB will disclose any potential conflicts of interest to the trial principal investigator 
and/or appropriate university officials, in accordance with institution policies.  Potential conflicts that 
develop during a trial or a member’s tenure on a DSMB must also be disclosed.  
 
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to be 
prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring Committee 
(QASMC) semi-annually beginning six months after study activation at Washington University (if at least 
one patient has been enrolled) or one year after study activation (if no patients have been enrolled at the 
six-month mark). 
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician, will be reviewed by the DSMB, and will be submitted to the QASM Committee.  The DSMB 
must meet at least every six months beginning six months after study activation at Washington University 
or six months after enrollment of the first patient at a secondary site, no more than one month prior to the 
due date of the DSM report to QASMC.  This report will include: 


 
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• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of 
HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual suspensions 
including start/stop dates and reason; and summary of protocol exceptions, error, or breach of 
confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each participating site 
• Expected accrual end date, accrual by site 
• Objectives of protocol with supporting data and list the number of participants who have met each 
objective 
• Measures of efficacy  
• Early stopping rules with supporting data and list the number of participants who have met the 
early stopping rules 
• Summary of toxicities at all participating sites  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
Further DSMB responsibilities are described in the DSMB charter. 
 
The study principal investigator and Research Patient Coordinator will monitor for serious toxicities on 
an ongoing basis. Once the principal investigator or Research Patient Coordinator becomes aware of an 
adverse event, the AE will be reported to the HRPO and QASMC according to institutional guidelines. 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee Policies 
and Procedures for full details on the responsibilities of the DSMC.  This is located on the QASMC 
website at https://siteman.wustl.edu/research/clinical-research-resources/protocol-office-prmcqasmc/ 
 
14.1 
Independent Research Monitor 
 
Dr. Brian Van Tine, Associate Professor of Medicine and Sarcoma Program Director at 
Washington University School of Medicine, will serve as the independent research monitor for the 
trial. 
 
The independent research monitor may discuss the research protocol with the investigators, 
interview human subjects, and consult with others outside of the study about the research.  The 
research monitor shall have authority to stop the research protocol in progress, remove individual 
human subjects from the research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor’s report.  The 
research monitor has the responsibility to promptly report his/her findings to the IRB or other 
designated official and to the US Army Medical Research and Materiel Command, Office of 
Research Protections, Human Research Protection Office. 
 
In addition, the independent research monitor is required to review all unanticipated problems 
involving risk to subjects or others, serious adverse events, and all subject deaths associated with 


 
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the protocol and provide an unbiased written report of the event.  At a minimum, the independent 
research monitor must comment on the outcomes of the event or problem and in case of a serious 
adverse event or death, comment on the relationship to participation in the study.  The independent 
research monitor must also indicate whether he/she concurs with the details of the report provided 
by the principal investigator. 
 
 
15.0 
AUDITING 
 
Since Washington University is the coordinating center, each site will be audited annually by Siteman 
Cancer Center personnel (QASMC) unless the outside institution has an auditing mechanism in place and 
can provide a report. The outside sites will be asked to send copies of all audit materials, including source 
documentation.  The audit notification will be sent to the Washington University Research Patient 
Coordinator, who will obtain the audit materials from the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. Once 
accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the cases selected 
for review (up to 10 for each site) will be sent to the research team. However, if during the audit the need 
arises to review cases not initially selected, the research team will be asked to provide the additional charts 
within two working days. 
 
Additional 
details 
regarding 
the 
Auditing 
Policies 
and 
procedures 
can 
be 
found 
at 
https://siteman.wustl.edu/wp-content/uploads/2015/QASMC-Policies-and-Procedures-03.31.2015.pdf 
 
 
16.0 
STATISTICAL CONSIDERATIONS 
 
16.1 
Study Objectives 
 
16.1.1 Primary Objectives 
 
1. To determine the clinical benefit (CR+PR+SD>6 months) of neratinib alone in 
patients with metastatic HER2- breast cancer that carry HER2 mutations (Part I) 
2. To examine the clinical benefit (CR+PR+SD>6 months) of neratinib in combination 
with fulvestrant in patients with fulvestrant naïve metastatic HER2-, ER+ breast 
cancer carrying activating HER2 mutations (Part II fulvestrant naïve ER+ cohort) 
3. To examine the clinical benefit (CR+PR+SD>6 months) of neratinib in combination 
with fulvestrant in patients with metastatic HER2-, ER+ breast cancer carrying 
activating HER2 mutations previously treated with fulvestrant (Part II fulvestrant 
treated ER+ cohort) 
4. To determine the clinical benefit rate of neratinib alone in patients with metastatic 
HER2-, ER- breast cancer carrying activating HER2 mutations (Part II ER- cohort) 
 
16.1.2 Secondary Objectives 
 
1. To determine the PFS of patients treated with neratinib alone in patients with 
metastatic HER2-, but HER2 mutated breast cancers by ER status and by HER2 
mutations (activating vs unknown significance) 


 
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2. To assess the PFS and RR of neratinib in combination with fulvestrant in patients with 
fulvestrant naïve metastatic ER+ HER2- breast cancer carrying activating HER2 
mutations 
3. To assess the PFS and response rate for neratinib in combination with fulvestrant in 
patients with metastatic HER2-, ER+ breast cancer carrying activating HER2 
mutations previously treated with fulvestrant 
4. To correlate the presence of HER2 mutation with histology subtype (invasive lobular 
vs. invasive ductal cancer), tumor grade (grade 1-2 vs 3), tumor staging at initial 
diagnosis (I vs. II or III vs. IV), disease free survival in HER2- breast cancer  
5. To assess the safety profile and tolerability of neratinib in combination with 
fulvestrant in patients with metastatic ER+, HER2- breast cancer carrying activating 
HER2 mutations 
 
16.1.3 Exploratory Objectives 
 
1. To compare the occurrence of HER2 mutation in paired primary and metastatic sites. 
2. To collect peripheral blood plasma samples for circulating HER2 mutation analysis. 
3. To investigate other potential therapeutic targets in HER2- breast cancer.  
4. To explore potential mechanisms of treatment resistance. 
5. To explore anti-tumor response of trastuzumab in combination with neratinib alone or 
neratinib and fulvestrant combination when tumor progresses on single agent neratinib 
or neratinib and fulvestrant combination, respectively. 
 
16.2 
Study Design and Sample Size Justification 
 
Sample size justification for Part I of the study with neratinib alone in metastatic HER2- breast 
cancer carrying HER2 mutations:  
 
Patients with any somatic HER2 mutations identified are eligible for the study. Based on Simon’s 
Optimal 2-stage design, our ultimate goal is to enroll a total of 29 patients with HER2 mutations. 
This will allow us 80% power at a 1-sided 0.05 significance level to detect an anticipated 20% 
clinical benefit rate against the null hypothesis of 5%.  Ten patients will be enrolled in the first 
stage. Accrual will continue until 10 patients are considered evaluable for clinical benefit, at which 
time a decision will be made whether to continue enrollment to the 2nd stage.  If none of the 10 
patients in the first stage had clinical benefit, we will continue the trial until we enroll 10 patients 
with known activating mutations by preclinical studies.  If 1 or more of the 10 patients in the first 
stage have shown clinical benefit, a total of 19 patients (with or without known activating 
mutations, depending on the enrollment criterion in stage 1) will be enrolled in the 2nd stage.  In a 
multicenter study such as this, however, it is difficult for a trial to reach the planned sample exactly.  
The investigators would not turn away patients who have already been approached for participation 
just because the number of patients needed has been met.  Therefore, we adopted a flexible Phase 
II design (Chen and Ng 1998) to allow the actual number at final stage to deviate slightly from 
what is planned.  That is, if 4 or more cases with clinical benefit are observed out of 29-34 patients, 
or 5 or more cases with clinical benefit are observed out of 35 or more patients, we would conclude 
that preliminary evidence for efficacy exists and that further investigation of the treatment is 
warranted.   
 
As of Jan 17th 2015, 10 evaluable patients with HER2 mutations, including 9 with activating 
mutations, were enrolled in the study.  Among these patients, 1 patient with activating mutation 


 
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derived clinical benefit with a partial response.  However, since majority of patients (15 of 16) 
found to have HER2 mutations in the study had ER+ breast cancer, we propose to add fulvestrant 
to neratinib in the ER+ population in the second part of the study to evaluate the overall response 
rate for this combination.  The first part of the trial will close once the amendment (amendment 7) 
for the second part of the trial is approved.  As of August 25th, 2015, amendment 7 has been 
approved by all participating institutions; therefore enrollment is only open to the second part trial 
since that date.  
 
Sample size justification for the second part of the trial with neratinib alone in patients with 
metastatic ER- HER2- breast cancer carrying HER2 mutations: We will enroll 10 patients. This 
will provide us a reasonable precision to estimate the clinical benefit (CR+PR+SD>6 months) of 
neratinib alone in patients with metastatic ER-/HER2- breast cancer that carry HER2 mutations. If 
2 clinical benefits are observed out of 10 patients, for example, we will have 80% confidence that 
the true rate will be above 5%. Conversely, if the "true" response rate is above 20%, there will 
only 10% chance to observe none clinical benefit out of 10 patients. 
 
Sample size justification for the Part II fulvestrant naïve ER+ Cohort: Based on the phase III trials 
PALOMA 3 (fulvestrant alone vs fulvestrant + palbo), the CBR for fulvestrant naïve endocrine 
resistant population is 40% and adding palbo increase CBR to 67%. We propose a sample size of 
26 evaluable patients. Based on Simon’s Minimax  design, this will allow us 80% power at a 1-
sided 0.05 significance level to detect an anticipated 65% response rate for fulvestrant plus 
neratinib combination therapy against the null hypothesis of 40%.  Specifically, 12 patients will 
be enrolled in the first stage. If 6 or more clinical benefits are observed out of these 12 patients, 
additional 14 patients will be enrolled to the 2nd-stage. If 15 or more cases with clinical benefits 
are observed out of 26 patients, we would conclude that preliminary evidence for efficacy exists 
and that further investigation of the treatment is warranted.  If the “true” response rate is 40% or 
less, this design allows us 67% chance to stop the trial earlier.  
 
Sample size justification for the Part II fulvestrant treated ER+ Cohort: Patients enrolled in this 
cohort has had disease progression on prior fulvestrant, therefore we anticipate fulvestrant alone 
would be ineffective. Since neratinib alone resulted in clinical benefit rate of 38.5% (5 of 13 
evaluable  patients with metastatic ER+ breast cancer that carry activating HER2 mutations) based 
on the preliminary efficacy data observed in the part I of this trial, we propose a sample size of 41 
evaluable patients. Based on Simon’s Minimax design, this will allow us 80% power at a 1-sided 
0.05 significance level to detect an anticipated 55% clinical benefit rate for fulvestrant plus 
neratinib combination therapy against the null hypothesis of 35%. Specifically, 21 patients will be 
enrolled in the first stage. If 9 or more clinical benefits are observed out of 21 patients, additional 
20 patients will be enrolled to the 2nd-stage.  If 20 or more cases with clinical benefit are observed 
out of 41 patients, we would conclude that preliminary evidence for efficacy exists and that further 
investigation of the treatment is warranted. If the “true” benefit rate is 35% or less, this design 
allows us 70% chance to stop the trial earlier.     
 
In total, 77 patients (10 ER-, 26 ER+ fulvestrant naïve, 41 ER+ fulvestrant treated) will be 
enrolled in Part II of this study. 
 
16.3 
Data Analysis 
 
Data analysis will be performed for Parts I and II separately.  Only patients with tumors tested 
positive for HER2 mutations are eligible for study therapy but the clinical and pathology data will 


 
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be collected for all screened patients.  Subset analysis will also be performed on patients with 
known activating mutations if needed. 
 
For patients with HER2 mutation, the number and percentage of responses to neratinib alone (Part 
I, and Part II ER- cohort) or neratinib in combination with fulvestrant (Part II, fulvestrant naïve 
and fulvestrant treated cohorts) will be tabulated. The rate of overall clinical benefit (CR, PR, or 
SD > 6 months) and its 90% confidence interval (CI) will be calculated in each cohort separately. 
The time to progression or death will be listed, and the progression-free survival (PFS) will be 
estimated using Kaplan-Meier product limit method in each cohort.  For all the enrolled patients, 
the number and percentage of patients with HER2 mutation will be presented, and its 95% CI will 
also be calculated. The agreement for the occurrence of HER2 mutation in paired primary and 
metastatic sites will be described using contingency tables and assess by McNemar test. The 
association of the presence of HER2 mutation with histology subtype (invasive lobular vs invasive 
ductal cancer), tumor grade, tumor staging at initial diagnosis (I vs II or III vs IV), and disease-
free survival (DFS) will be assessed using Fisher’s exact test, Mann-Whitney rank sum test, or 
log-rank test as appropriate. 
 
 
17.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document to be 
reviewed and approved by the Washington University Principal Investigator (or designee) prior to 
IRB/IEC submission.    
 
Each participating institution must have the following documents on file at Washington University prior 
to first subject enrollment: 
• Documentation of IRB approval of the study in the form of a letter or other official document from 
the participating institution’s IRB.  This documentation must show which version of the protocol 
was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality Assurance 
and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and the Washington 
University study team. 
• Documentation of FWA, signed FDA Form 1572, and signed and dated CVs of all participating 
investigators. 
• Documentation of training in protection of human subjects by all participating investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The Principal Investigator is responsible for disseminating to the participating sites all study updates, 
amendments, reportable adverse events, etc.  There will be one current version of the protocol document 
at any given time and each participating institution will utilize that document.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 2 weeks of 
obtaining Washington University IRB approval with acknowledgement of receipt requested.  Secondary 
sites are to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt, and 
confirmation of submission must be forwarded to the appropriate contact person on the Washington 
University study team at the time of submission.  Upon the secondary sites obtaining local IRB approval, 
documentation of such shall be sent to the Washington University study team within 2 weeks of receipt 
of approval. 
 


 
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Documentation of participating sites’ IRB approval of annual continuing reviews, protocol amendments 
or revisions, all SAE reports, and all protocol violations/deviations/exceptions must be kept on file at 
Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call to update 
and inform regarding the progress of the trial. 
 
 


 
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18.0 
REFERENCES 
 
1. 
Ma CX, Luo J, Ellis MJ: Molecular profiling of triple negative breast cancer. Breast disease 
2010, 32(1):73-84. 
2. 
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, 
Smith R, Sleeboom HP, Jaenicke F et al: Phase III study of letrozole versus tamoxifen as 
first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival 
and update of efficacy from the International Letrozole Breast Cancer Group. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2003, 
21(11):2101-2109. 
3. 
Kiely BE, Soon YY, Tattersall MH, Stockler MR: How long have I got? Estimating typical, 
best-case, and worst-case scenarios for patients starting first-line chemotherapy for 
metastatic breast cancer: a systematic review of recent randomized trials. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2011, 29(4):456-463. 
4. 
Yarden Y: The EGFR family and its ligands in human cancer. signalling mechanisms and 
therapeutic opportunities. Eur J Cancer 2001, 37 Suppl 4:S3-8. 
5. 
Harari PM, Allen GW, Bonner JA: Biology of interactions: antiepidermal growth factor 
receptor agents. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2007, 25(26):4057-4065. 
6. 
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann 
W, Wolter J, Pegram M et al: Use of chemotherapy plus a monoclonal antibody against 
HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001, 
344(11):783-792. 
7. 
Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE, Jr., Martino S, 
Mamounas EP, Kaufman PA, Wolmark N: Four-year follow-up of trastuzumab plus adjuvant 
chemotherapy for operable human epidermal growth factor receptor 2-positive breast 
cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2011, 29(25):3366-
3373. 
8. 
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Jr., Davidson NE, Tan-Chiu E, Martino 
S, Paik S, Kaufman PA et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-
positive breast cancer. N Engl J Med 2005, 353(16):1673-1684. 
9. 
Smith I, Procter M, Gelber RD, Guillaume Sb, Feyereislova A, Dowsett M, Goldhirsch A, Untch 
M, Mariani G, Baselga J et al: 2-year follow-up of trastuzumab after adjuvant chemotherapy 
in HER2-positive breast cancer: a randomised controlled trial. The Lancet, 369(9555):29-36. 
10. 
Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre 
R, Cobleigh M et al: Randomized Phase III Study of Trastuzumab, Paclitaxel, and 
Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2Â–
Overexpressing Metastatic Breast Cancer. Journal of Clinical Oncology 2006, 24(18):2786-
2792. 
11. 
Abramson V, Arteaga CL: New Strategies in HER2-Overexpressing Breast Cancer: Many 
Combinations of Targeted Drugs Available. Clinical Cancer Research, 17(5):952-958. 
12. 
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, 
Murphy M, Novotny WF, Burchmore M et al: Efficacy and safety of trastuzumab as a single 
agent in first-line treatment of HER2-overexpressing metastatic breast cancer. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2002, 
20(3):719-726. 


 
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13. 
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Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory Metastatic Breast 
Cancer. Journal of Clinical Oncology 2010, 28(7):1124-1130. 
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et al: Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast 
carcinomas. Clin Cancer Res 2006, 12(1):57-61. 
46. 
Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany 
R, Senz J et al: Mutational evolution in a lobular breast tumour profiled at single nucleotide 
resolution. Nature 2009, 461(7265):809-813. 
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55. 
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57. 
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AB, Li S et al: Activating HER2 Mutations in HER2 Gene Amplification Negative Breast 
Cancer. Cancer discovery 2013, 3(2):224-237. 
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CL: Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 
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Truesdale AT, Shewchuk L et al: Impact of common epidermal growth factor receptor and 
HER2 variants on receptor activity and inhibition by lapatinib. Cancer research 2008, 
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HER2 H878Y mutant is highly sensitive to HER2 inhibitor. Oncotarget 2015, 6(31):31628-
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ErbB2 reveals a new protein kinase autoinhibition mechanism. J Biol Chem 2008, 
283(3):1588-1596. 
66. 
Minami Y, Shimamura T, Shah K, LaFramboise T, Glatt KA, Liniker E, Borgman CL, 
Haringsma HJ, Feng W, Weir BA et al: The major lung cancer-derived mutants of ERBB2 
are oncogenic and are associated with sensitivity to the irreversible EGFR//ERBB2 
inhibitor HKI-272. Oncogene 2007, 26(34):5023-5027. 
67. 
Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S, Carpenter G, Gazdar AF, 
Muthuswamy SK, Arteaga CL: HER2 kinase domain mutation results in constitutive 
phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine 
kinase inhibitors. Cancer Cell 2006, 10(1):25-38. 
68. 
Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, Winer EP, Naughton MJ, Goetz 
MP, Russell C et al: Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 


 
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Mutations in HER2 Non-amplified Metastatic Breast Cancer. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2017. 
69. 
De Mattos-Arruda L, Caldas C: Cell-free circulating tumour DNA as a liquid biopsy in 
breast cancer. Mol Oncol 2016, 10(3):464-474. 
70. 
Lanman RB, Mortimer SA, Zill OA, Sebisanovic D, Lopez R, Blau S, Collisson EA, Divers SG, 
Hoon DS, Kopetz ES et al: Analytical and Clinical Validation of a Digital Sequencing Panel 
for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. PloS 
one 2015, 10(10):e0140712. 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development, study coordination, and regulatory coordination services. The 
Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842.


 
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APPENDIX A: ECOG PERFORMANCE STATUS SCALE 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 


 
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APPENDIX B: PATIENT’S MEDICATION DIARY 
Today’s Date:    
 
 
 
Agent:  Neratinib 
Study ID#:   
 
 
 
 
Cycle:    
 
 
 
 
 
Patient Name:    
 
 
 
 
1. Complete one form for each month.  Take _____mg ( ___tablets) of neratinib daily with food every 
morning. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forget to take your neratinib dose within 12 hours of the usual time, do not take a dose that day.  
Restart taking the neratinib the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  
Record the time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next 
appointment.  Please bring your unused study medications and/or empty bottles with you to each clinic 
visit so that a pill count can be done. 
6. Avoid St. John’s wort, grapefruit, grapefruit juice, grapefruit hybrids, and star fruit from 7 days before you 
start taking neratinib and throughout the entire study.   
Day 
Date 
What time was 
dose taken? 
# of tablets 
taken 
# of loose 
stools 
Antidiarrheals 
taken? y/n 
Comments 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX C: PATIENT INSTRUCTIONS FOR THE MANAGEMENT OF DIARRHEA 
 
Please review these instructions with your study doctor/team.  Once all of your questions are 
answered, sign at the bottom and make sure you are given a copy of these instructions to take 
home.  
 
Diarrhea is the most common side effect you may have while participating in this study.  Diarrhea usually 
starts within a few hours to a few days of the first dose of study drug.  In order to reduce or even prevent 
diarrhea as far as possible, you will be supplied with an anti-diarrheal medicine called loperamide to take 
at the start of the study. Primary prophylactic use of antidiarrheal medication is mandatory for all 
enrolled subjects. Loperamide will be dispensed directly by your study doctor/team on day 1 with the 
instruction to initiate treatment with loperamide at the same time as you take your first dose of neratinib.  
 
Start taking the anti-diarrheal medication immediately with the first dose of neratinib as directed 
by your study doctor/team.   
 
Your study doctor/team will call you 1 day, 2 days and 3 days after your first dose of study drug to find 
out if you are experiencing diarrhea and to provide further treatment instructions and advice if necessary. 
You will also have an easy to follow flow-chart to help you each day in the management of diarrhea if it 
is present. 
 
If you are having new-onset diarrhea, persistent diarrhea or diarrhea with increase of 7 or more stools per 
day over usual, call your study doctor/team at 314-362-8903 to let them know so they can work with you 
to control the diarrhea.  If you are dizzy or weak because of diarrhea, go to the study doctor’s office or go 
to the hospital immediately. 
 
Please record the number of stools and any anti-diarrheal treatment during the first two cycles along with 
the daily dose of study medication in your diary and return the completed diary at the next scheduled visit. 
 
 
Information to provide when talking to your doctor 
When talking to the study doctor/team I will provide as much of the information below as possible, in 
order to help my study doctor/team to assess my diarrhea and decide on the best treatment: 
• Number of stools per day as compared to my normal bowel habits 
• Presence of diarrhea during the night 
• Presence of fever, dizziness, abdominal pain/cramping, or weakness 
• What the stool looks like, that is, watery stools, blood, or mucus   
• When I took my last study drug 
• Any other information that could explain my diarrhea (food, recent travel, contact with other 
people with diarrhea). 
 
 


 
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Medications to treat diarrhea 
My study doctor/team will provide me with loperamide on day 1 with the instruction to start treatment 
with loperamide along with the first dose of neratinib.  I need to take the medications as directed by my 
study doctor/team.  
 Loperamide: 
• I will take 2 tablets/capsules (4 mg) with the first dose of neratinib  
• After the first dose, I will take 4 mg (2 tablets/ capsules) three times daily for the first 14 
days(not to exceed a total of 8 tablets/day; if I get constipated, I should contact my study 
doctor/team who will instruct me on how often and how much loperamide to take but I should 
not stop taking loperamide).  
• After the first 14 days, I will take 2 tablets (4 mg) two times per day until the end of the second 
cycle of therapy regardless of whether I have diarrhea or not.  If I get constipated, I should 
contact my study doctor/team who will instruct me on how often and how much loperamide to 
take but I should not stop taking loperamide). 
• If I continue to have diarrhea while taking loperamide, I should contact my study doctor/team 
for additional anti-diarrheal medication.  
• If I have diarrhea with increase of up to 6 stools per day over usual any time after completing 
the second cycle of therapy and I am not taking any anti-diarrheal medication, I will take 4mg (2 
tablets/capsules) as needed (not to exceed 8 tablets capsules or 16 mg per day) 
• □ Other medication (Study doctor/team to write in name of medication and instructions):  
________________________________________________________ 
 
______________________________________________________________________ 
 
 
 
______________________________________________________________________  
  
In case of more severe diarrhea and any diarrhea associated with fever, pain, infection, or dehydration, I 
may receive IV fluids, antibiotics and/or other medications. 
 
Changes to my diet to treat diarrhea  
If I have diarrhea, I will: 
• Stop all lactose-containing products (milk, yogurt, cheese, etc) 
• Drink 8 to 10 large glasses of clear liquids per day 
• Eat frequent small meals 
• Eat low fat foods such as the BRAT diet that includes bananas, rice, applesauce, and/or toast: 
- 
The BRAT diet is a bland diet that is low in fat and fiber and will not irritate the stomach;  
- 
Bananas are high in potassium and can cause constipation which can help alleviate the 
diarrhea 
- 
Other similar foods are crackers, cooked cereals and pasta 
- 
This diet is not complete in nutrients and should only be taken for a short period of time 
and only upon the doctor’s advice 
 
My study doctor/team may have other suggestions for me. (Study doctor/team to write in any 
suggestions). ________________________________________________________ 
 
 


 
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Study Medication adjustments  
If I am experiencing loose stools or diarrhea and cannot reach my study doctor/team immediately, I will 
start taking anti-diarrheal medication per the instructions above until further advice is given by my study 
doctor/team. If I have more than 4-6 stools per day compared to normal despite taking anti-diarrheal 
medication for 24 hours, I will stop taking the study medication and wait for further instructions from 
my study doctor/team. 
 
My signature below indicates I have reviewed this information and have received the following 
medications: 
□ 
Neratinib Tablets  
□ 
Loperamide  
 
 
 
________________________________________________________________ 
Study participant name 
 
        Study participant Signature and Date 
 
 
 
 
________________________________________________________________ 
Investigator delegate name          Investigator delegate Signature and Date 
 
 
 
OR 
 
 
 
 
________________________________________________________________ 
Investigator name                                  Investigator Signature and Date 
 


 
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YES 
YES 
 
 
NO 
YES 
NO 
YES 
Have you already been taking loperamide over the previous 24 hours? 
Do you have diarrhea? 
Take 2 tabs of loperamide immediately, then 
1 tab every 4 hours until you have been 12 
hours without a loose stool (maximum of 8 
tabs/24 hours) 
Call your doctor right away for further 
advice and keep taking loperamide.  Your 
doctor may recommend additional anti-
diarrhea medicine. 
Nothing more needs to be 
done at this time. Make 
sure you keep drinking 
plenty of fluids each day. 
Do you continue to have diarrhea despite 
taking loperamide? 
While waiting for your doctor’s advice:                                 
-Drink 8 to 10 large glasses of clear liquids per day               
-Eat frequent small meals with low fat regimen enriched 
with bananas, rice, applesauce and toast (BRAT diet)           
-Stop all lactose-containing products 
NO 
Do you continue to have diarrhea despite taking 
loperamide? 


 
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Site #/Description 
Modality 
Image 
# 
Dimen- 
sion cm Modality 
Image 
# 
Dimen- 
sion cm Modality 
Image 
# 
Dimen- 
sion cm Modality 
Image 
# 
Dimen- 
sion cm 
#1 
CT 
CT 
CT 
CT 
#2 
CT 
CT 
CT 
CT 
#3 
CT 
CT 
CT 
CT 
#4 
CT 
CT 
CT 
CT 
#5 
CT 
CT 
CT 
CT 
0.0
0.0
0.0
0.0
Site #/Description 
Modality 
Image 
# 
F/U 
Status 
Modality 
Image 
# 
F/U 
Status 
Modality 
Image 
# 
F/U 
Status 
Modality 
Image 
# 
F/U 
Status 
#1 
CT 
CT 
CT 
CT 
#2 
CT 
CT 
CT 
CT 
#3 
CT 
CT 
CT 
CT 
#4 
CT 
CT 
CT 
CT 
#5 
CT 
CT 
CT 
CT 
#6 
CT 
CT 
CT 
CT 
#7 
CT 
CT 
CT 
CT 
#8 
CT 
CT 
CT 
CT 
Site #/Description 
Modality 
Image 
# 
Dimen- 
sion cm Modality 
Image 
# 
Dimen- 
sion cm Modality 
Image 
# 
Dimen- 
sion cm Modality 
Image 
# 
Dimen- 
sion cm 
#1 
CT 
CT 
CT 
CT 
#2 
CT 
CT 
CT 
CT 
#3 
CT 
CT 
CT 
CT 
#4 
CT 
CT 
CT 
CT 
#5 
CT 
CT 
CT 
CT 
APPENDIX D: RECIST 1.1 Tumor Evaluation Form       
Patient Name                       DOB 
                       Study                        PI 
 
                                                  Page 1 
Please record the following: 
* Description of Target, Non-Target, or New Lesions * Maximum of 5 Target lesions 
Version Date 10/30/2012 
 
* Dimensional measurements of Lymph Nodes (LNs) are shortest axis and >1.5 cm * All other lesions are longest axis. 
* Follow Up Status of Non-Target Lesions: Increase/Decrease/Stable/Resolved 
Date of Evaluation 
Target Lesions 
Baseline 
 
 
 
 
 
 
 
 
 
 
Sum of Longest Dimensions 
Non-Target Lesions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
New Lesions 
 
 
 
 
 
 
 
 
 
 
Comments 
 
Initials/Date of Form Prep/Data Entry 
SignatureDate 
Official IRAC Document - Do Not Modify - IRAC Staff Use Only 


 
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APPENDIX E: Definitions 
 
Adverse Events (AEs) 
 
Definition: any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized 
for all toxicity reporting.  A copy of the CTCAE version 4.03 can be downloaded 
from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this 
guidance 
can 
be 
found 
on 
OHRP’s 
website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
Suspected Adverse Reaction (SAR) 
 
Definition: any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event.  “Reasonable possibility” means there is evidence 
to suggest a causal relationship between the drug and the adverse event.  “Suspected 
adverse reaction” implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug 
 
Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” 
if, in the view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, 
based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes 
listed above 
 
Unexpected Adverse Experience 
 


 
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Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
Events that are both serious AND unexpected where there is a reasonable 
possibility of relationship to study drug must be reported to the FDA.  
 
Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
Definition: any adverse drug event or suspected adverse reaction is considered 
“life-threatening” if, in the view of the investigator, its occurrence places the 
patient at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
 
Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency based on the adverse 
reaction table (Table 63) in the most current Investigator Brochure) given (a) 
the research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent document; 
and (b) the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
Protocol Exceptions 


 
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Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the 
event.  For secondary sites, the Washington University PI will issue approval of the 
exception, but it must also be submitted to the local IRB with documentation of 
approval forwarded to Washington University.  Washington University IRB 
approval is not required for protocol exceptions occurring at secondary sites. 
 
 
 


 
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APPENDIX F: Reporting Timelines 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
IBC 
(Not Applicable) 
Puma Biotechnology, 
Inc. 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
 
Report within fifteen (15) 
days 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
Report no later than 7 
calendar days after initial 
receipt of the information 
 
Report within seven (7) 
days  
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day. 
Report via email after 
IRB acknowledgment 
 
 
 
Major deviation 
Report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day. 
 
 
 
 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working days.    
 
 
 
Protocol exception 
Approval must be obtained 
prior to implementing the 
change 
 
 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
that list in the protocol 
or IB 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
 
 
Complaints 
If the complaint reveals an 
unanticipated problem 
involving risks to participants 
or others OR noncompliance, 
 
 
 
 


 
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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
IBC 
(Not Applicable) 
Puma Biotechnology, 
Inc. 
report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day.  Otherwise, 
report at the time of continuing 
review. 
Breach of 
confidentiality 
Within 10 working days. 
 
 
 
 
Incarceration 
If withdrawing the participant 
poses a safety issue, report 
within 10 working days.   
 
If withdrawing the participant 
does not represent a safety issue 
and the patient will be 
withdrawn, report at continuing 
review. 
 
 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Puma Biotechnology, Inc. 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
Report within thirty (30) days 
 (i.e., unrelated to study 
drugs or listed/expected 
event) 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
 
 
 


 
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Routine Reporting Timelines 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
FDA 
Puma Biotechnology, Inc. 
Serious AND unexpected 
suspected adverse reaction 
Report no later than 11 calendar days 
after it is determined that the information 
qualifies for reporting. 
Report all applicable 
events to local IRB 
according to local 
institutional guidelines. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to the 
FDA as needed. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to 
[MANUFACTURER] as 
needed. 
Unexpected fatal or life-
threatening suspected 
adverse reaction 
Report no later than 4 calendar days after 
initial receipt of the information. 
Unanticipated problem 
involving risk to participants 
or others 
Report no later than 4 calendar days after 
initial receipt of the information. 
Adverse event or SAE that 
does not require expedited 
reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to 
implementing the change. 
 
 
 


 
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APPENDIX G: Washington University Serious Adverse Event Reporting Cover Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Sponsor-Investigator:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Event Start Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
 yes  
 
 no 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date 
 
 

ICF_001.pdf: 
FOR IRB USE ONLY 
 
IRB ID #: 201209135 
APPROVAL DATE: 01/14/21 
EXPIRATION DATE: 01/13/22 
 
Version 16 MARCH 2020 
 
Page 1 of 19 
Treatment Consent  
 
INFORMED CONSENT DOCUMENT – TREATMENT CONSENT  
 
Project Title: 
A Phase II Study of Neratinib Alone and in Combination with Fulvestrant in 
Metastatic HER2 Non-amplified but HER2 Mutant Breast Cancer 
 
Principal Investigator: 
Cynthia X. Ma, M.D., Ph.D. 
 
Research Team Contact: 
Cynthia X. Ma, M.D., Ph.D. – (314) 362-8903 
 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights and responsibilities as a research participant. By signing this 
form you are agreeing to participate in this study. 
• You should read and understand the information in this document including the procedures, 
risks, and potential benefits. 
• If you have any questions about anything in this form, you should ask the research team for 
more information before you agree to participate.   
• You may also wish to talk to your family or friends about your participation in this study. 
• Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study.  We invite you to participate in this research study because you have been 
diagnosed with metastatic breast cancer that is negative for HER2 overexpression, but the cancer has 
been found to have a mutation in HER2. 
 
HER2 is a protein involved in normal cell growth.  Some types of breast cancer test positive for 
overexpression HER2 and some test negative, and there are different treatments depending on whether 
the breast cancer is positive or negative.  However, doctors are discovering that there is a third group of 
people—people who have HER2-negative breast cancer with mutations in HER2.  Doctors are looking 
at whether people with a HER2 mutation might respond to the same treatment as people with HER2-
positive breast cancer. 
 
Neratinib is a drug which has been shown to be effective for treating HER2-positive breast cancer in 
clinical trials.  The purpose of this research study is to test the cancer of people who have HER2-
negative to see if it has a HER2 mutation and, if so, see how the cancer responds to neratinib.  
 
Neratinib is considered investigational, which means that it has not been approved by the U.S. Food and 
Drug Administration (FDA).  
 
Fulvestrant is a routine treatment for ER-positive breast cancer. ER-positive breast cancer means that the 
cancer cells may receive signals from estrogen that could promote their growth.  If you are in a group of 
people that have ER-positive breast cancer, you will also receive fulvestrant while you are enrolled in 
this study.  People enrolling in this study without ER-positive breast cancer will receive neratinib alone.   


FOR IRB USE ONLY 
 
IRB ID #: 201209135 
APPROVAL DATE: 01/14/21 
EXPIRATION DATE: 01/13/22 
 
Version 16 MARCH 2020 
 
Page 2 of 19 
Treatment Consent  
Fulvestrant has been approved by the FDA for the treatment of ER-positive breast cancer, but is 
considered investigational in the context of this study because the combination of fulvestrant and 
neratinib is not approved by the FDA. 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
All treatment will be given in either the outpatient or inpatient setting at Siteman Cancer Center.  We 
feel it is important to remind you that any procedures, whether you choose to take part in this study or 
not, will require you to remain at the Siteman Cancer Center up to several hours.  There may also be a 
wide variability in the length of clinic visits due to the unique characteristics of your medical history and 
health condition, and clinic factors such as physician availability, staffing shortages, and weather delays.  
This will also vary depending upon your needs at the visit as determined by your physician.  It is 
important that you are able to be available to complete the procedures at each visit to ensure that your 
safety and treatment needs are met. 
 
Before you begin study treatment: 
You will need to have the following screening exams, tests, or procedures to find out if you can continue 
to be in the study.  Most of these procedures are part of regular cancer care and may be done even if you 
do not join the study.  If you have had some of them recently, they may not need to be repeated.  This 
will be up to your study doctor. 
 
• Physical exam, including taking of vital signs, measuring your height and weight, reviewing your 
medical history, evaluation of your performance status, and talking about any symptoms or 
health problems you’re having 
• If your HER2 mutation testing was performed at a facility outside of Washington University and 
the results are unclear, approximately 2 teaspoons of blood will be drawn from you for this study 
to see whether the mutation is tumor-specific; if it is not, you will not be able to continue in the 
study 
• Blood tests to check your blood counts and organ function (approximately 2 teaspoons of blood 
will be drawn from a vein in your arm) 
• A pregnancy test (blood or urine) if you are a woman of childbearing potential (approximately 1 
teaspoon of blood will be drawn from a vein in your arm, if necessary) 
• EKG and either an echocardiogram or MUGA (a scan which involves the injection of a 
radioactive marker into a vein which allows your doctor to see how the tracer moves through 
your bloodstream) to see how well your heart functions 
• CT scan (computerized tomography, which uses x-rays to create a picture of the bones and soft 
tissues in your body) or MRI (magnetic resonance imaging, which uses a magnetic field and 
radio waves to create a picture of the organs and tissues in your body) to evaluate your disease 
• OPTIONAL tumor biopsy within 2 weeks prior to the start of neratinib.  Research on the tumor 
biopsy will help to explain why patients may respond differently in this trial. 
 
I agree to have a biopsy prior to the start of neratinib for research purposes: 
 
___ yes 
___ no  
____________ initials 
 
 


FOR IRB USE ONLY 
 
IRB ID #: 201209135 
APPROVAL DATE: 01/14/21 
EXPIRATION DATE: 01/13/22 
 
Version 16 MARCH 2020 
 
Page 3 of 19 
Treatment Consent  
It is possible that after your medical history, tests, and procedures are reviewed, you will not be able to 
continue in this study.  If this is the case, your study doctor will go over this with you.  
 
Procedures throughout the study: 
If you continue in the study, you will then begin taking neratinib.  Neratinib is a medication taken by 
mouth which you should take once a day, every day of each 28-day cycle, at the same time (preferably 
in the morning).  You should take neratinib with food.  Do not take neratinib with grapefruit or 
grapefruit juice, as this could affect how your body processes the drug. You will be contacted by the study 
staff at 24, 48, and 72 hours after you take your first dose of neratinib. If you tolerate neratinib well, it is 
possible that the dose you are taking may increase at any point after you complete the first cycle of 
treatment. 
 
One of the main side effects of neratinib is diarrhea.  When you begin your treatment with neratinib, we 
will also prescribe loperamide (also known as Imodium) for you to begin takingat the same time as you 
take your first dose of neratinib.  Diarrhea and vomiting can quickly lead to a loss of too much water 
from your body (dehydration).  Make sure you drink enough liquids each day (8 to 10 large glasses or 
cups).  If you have severe diarrhea and/or vomiting, even for a short period of time, call the study doctor 
immediately.  Please review the supplemental document titled “Patient Instructions for the Management 
of Diarrhea” with your physician. 
 
You will return to the clinic on Day 1 of each cycle to receive a refill. With each refill, you will receive 
a drug diary which you should use to record the number of pills taken each day and whether you 
experience any side effects.  Please bring this drug diary and any unused pills with you to the clinic at 
the beginning of each cycle. 
 
If you have ER-positive breast cancer, you will also begin receiving fulvestrant.  Fulvestrant is given as 
two intramuscular injections on Day 1 of each cycle, and also on Day 15 of Cycle 1 only. 
 
Each time you return to clinic at the beginning of a new cycle, you will have the following tests and 
procedures: 
• Physical exam  (exam will also take place on Days 8, 15 & 22 of Cycle 1) 
• Blood tests to check your blood counts and organ function (approximately 2 teaspoons of blood 
will be drawn from a vein in your arm) 
• CT scan or MRI (every other cycle) 
• 
Talking about any additional medication you are taking or symptoms/health problems you are having 
 
Additionally, 2 tablespoons of blood will be drawn for research purposes on Cycle 1 Day 1, Cycle 1 Day 
15, Cycle 2 Day 1, Cycle 3 Day 1, Day 1 of each odd numbered cycle, and at the end of treatment. 
 
You may continue in the study as long as you wish or until you experience unacceptable side effects, 
your disease gets worse, or your doctor believes it is in your best interests to withdraw.  It is possible 
that if your disease progresses while you are taking neratinib, you may be able to continue to receive 
neratinib in combination with a drug called trastuzumab if it is covered by your health insurance.  The 
dosing and scheduling of trastuzumab will be done as dictated by your study doctor; trastuzumab is 
usually given as an IV infusion once every 2 weeks. Trastuzumab in combination with Neratinib is 


FOR IRB USE ONLY 
 
IRB ID #: 201209135 
APPROVAL DATE: 01/14/21 
EXPIRATION DATE: 01/13/22 
 
Version 16 MARCH 2020 
 
Page 4 of 19 
Treatment Consent  
considered investigational, which means that it has not been approved by the U.S. Food and Drug 
Administration (FDA).  If you are taking neratinib and fulvestrant and your disease progresses, you may 
be able to continue to receive both drugs in combination with trastuzumab if it would otherwise be part 
of your routine care.  Trastuzumab is approved by the FDA for the treatment of HER2-positive breast 
cancer, but has not been approved by the FDA for the treatment of HER2-negative breast cancer and is 
considered investigational.   
 
At the End of Treatment visit, you will have the following tests and procedures: 
• Physical exam 
• Blood testing 
• CT or MRI 
 
You may be asked to have an OPTIONAL tumor biopsy if your disease progressed on neratinib.  The 
tumor tissue collected from this biopsy will be sent to a CLIA-certified laboratory at Washington 
University School of Medicine and a genetic mutation analysis will be performed on the tissue.  CLIA-
certified means that the Food and Drug Administration (FDA), Center for Medicaid Services (CMS), 
and the Center for Disease Control (CDC) work together to make sure the laboratory does quality 
laboratory testing. The analysis will check up to 122 genes to see if your tumor tissue has any mutations 
associated with those genes.  The analysis will be reviewed by a doctor who is board-certified in 
Genetics.  Only findings on the 122 genes will be returned to you and your doctor, these are called 
primary findings.  The report that will be provided to you and your doctor will be a written report and it 
will highlight any mutations that may be associated with any FDA approved treatment options or any 
other courses of action that may be taken.  The report will be provided to you and your doctor in 3-4 
weeks after the biopsy is obtained if you agree to receive this report.  There is not a test or another 
analysis to confirm these results as this analysis is a validated clinical test.  The results will only be 
returned to you once as the research team will not be continuously checking samples as time passes to 
see if more relevant results are found.   You may ask your doctor any questions about the results of the 
genetic mutation analysis.  You may also ask your doctor for a listing of additional resources, such as a 
genetic counselor, if you feel that you would like to learn more about the report; however, you will be 
responsible for any costs associated with these additional services.   Incidental findings are not being 
analyzed or reported.  Incidental findings are findings from a genetic analysis that are outside from what 
is being studied. 
 
The leftover tumor tissue will be used for research purposes to understand why the tumor progressed on 
neratinib.   
 
 
I agree to have a biopsy for research purposes if my tumor progresses on neratinib: 
 
___ yes 
___ no  
____________ initials 
 
 
 
 
 


FOR IRB USE ONLY 
 
IRB ID #: 201209135 
APPROVAL DATE: 01/14/21 
EXPIRATION DATE: 01/13/22 
 
Version 16 MARCH 2020 
 
Page 5 of 19 
Treatment Consent  
I agree to receive the mutation analysis report from the tumor biopsy obtained when my 
tumor progressed on neratinib: 
 
___ yes 
___ no  
____________ initials 
 
 
After you stop receiving treatment as part of this study, you will be contacted 30 days after your last 
treatment. This follow-up will involve either a telephone call from a research coordinator or having the 
research coordinator check through your medical records, or office visits (if needed). 
 
Genomic Research 
By participating in this trial, you agree that tumor samples from your previous breast cancer diagnostic 
or therapeutic procedures and the optional biopsies will be used for genetic and genomic research, 
including whole genome sequencing.  In addition, all participants in this trial will have 2 teaspoons of 
blood drawn for genetic and genomic research, including whole genome sequencing.  
 
Genes are a unique combination of molecules (called DNA) that we inherit from our parents.  There are 
millions of tiny differences in our genes that determine things like our height or the color of our eyes.  
Some of these differences may make some people more or less likely to develop certain diseases or 
make people respond to medicine in different ways.  Genomic research will look at the differences in 
specific genes or may involve sequencing a large amount of your DNA.  This sequencing will provide a 
detailed description of your DNA and is also called whole genome sequencing.  We may also perform a 
full genetic analysis of your tumor and blood samples to look for gene variations.  This analysis may 
reveal information about your hereditary risk of developing other diseases or serious illness and, if this 
information were revealed, might affect your privacy.  The samples will be stored for an indefinite 
period of time. The results of these research sequencing analyses of the blood will not be available to 
you or your treating physician.   
 
This genetic information may be shared with other scientists over the internet.  This is so scientists 
across the country can better work together to cure disease.  Information will be shared two ways: 
1. your genetic data will be shared through a publicly available database in a summary format 
grouped together with other individuals’ data 
2. individual-level data will be shared through a controlled-access database (which means that only 
people who have been authorized may view the information kept in the database) 
 
Traditional information that can identify you, such as your name and address, will not be included in 
either database.  However, it is possible that people could develop ways in the future to link the 
information in a genetic database back to you.  For example, everybody’s DNA (except identical twins) 
is unique, but some genetic information is shared with one’s biological relatives, which might provide a 
method for comparison between databases if the information was available.  Although the real risk is 
small, some people are concerned that this genetic information will be gathered by people other than 
scientists and used to identify or discriminate against you. 
 
 
 


FOR IRB USE ONLY 
 
IRB ID #: 201209135 
APPROVAL DATE: 01/14/21 
EXPIRATION DATE: 01/13/22 
 
Version 16 MARCH 2020 
 
Page 6 of 19 
Treatment Consent  
I agree to have whole genome sequencing performed on my samples for research 
purposes: 
 
___ yes 
___ no  
____________ initials 
 
 
 
Will you save my samples or research data to use in future research studies?  
As part of this study, we are obtaining blood, tissue, and data from you. We would like to use this blood, 
tissue, and data for studies going on right now as well as studies that are conducted in the future, 
including possible genetic research.  These studies may provide additional information that will be 
helpful in understanding breast cancer, or other diseases or conditions, including research to develop 
investigational tests, treatments, drugs or devices that are not yet approved by the U.S. Food and Drug 
Administration.  It is unlikely that what we learn from these studies will have a direct benefit to you.  
There are no plans to provide financial compensation to you should this occur.  By allowing us to use 
your blood, tissue, and data you give up any property rights you may have in it.   
 
Your tumor tissue may also be used to develop cell or animal models for research. These models may be 
used for future research to test how the tumor responds to new treatments before they are tested in 
humans. 
 
We will share your blood, tissue, and data with other researchers.  They may be doing research in areas 
similar to this research or in other unrelated areas.  These researchers may be at Washington University, 
at other research centers and institutions, or industry sponsors of research.  We may also share your 
research data with large data repositories (a repository is a database of information) for broad sharing 
with the research community.  If your individual research data is placed in one of these repositories only 
qualified researchers, who have received prior approval from individuals that monitor the use of the 
data, will be able to look at your information. 
 
Researchers may use your tissue specimens obtained from the OPTIONAL tumor biopsies to grow in 
mice and establish mice xenografts (which means that cells from your tumor will be transplanted into 
mice).  These xenograft tumors along with de-identified genetic data will be shared with researchers so 
that they can use them in a variety of projects to develop laboratory tests to study the effects of various 
drugs on human tissues and cells, or may be grown as “preclinical models” in animals such as mice to 
learn how tumors respond to new drugs for cancer, including the development of tests, studies in 
genetics, and the evaluation of new treatments for cancer.  The samples will be stored for an indefinite 
period of time.   
 
If you change your mind and do not want us to store and use your blood, tissue, and data for future 
research, you should contact the research team member identified at the top of this document.  The 
blood, tissue, and data will no longer be used for research purposes. However, if some research with 
your blood, tissue, or data has already been completed, the information from that research may still be 
used. Also, if it has been shared with other researchers it might not be possible to withdraw it to the 
extent it has been shared.  
 


FOR IRB USE ONLY 
 
IRB ID #: 201209135 
APPROVAL DATE: 01/14/21 
EXPIRATION DATE: 01/13/22 
 
Version 16 MARCH 2020 
 
Page 7 of 19 
Treatment Consent  
If you signed the screening consent form, you either agreed or did not agree to this.  If you did not sign 
the screening consent form, please complete the boxes below indicating whether researchers can use 
your specimens and data for future research: 
 
My tissue and blood may be stored and used for future research as described above. 
 
___ yes 
___ no  
____________ initials 
 
My tissue and blood may be shared with other investigators and used by these 
investigators for the future research as described above. 
 
___ yes 
___ no  
____________ initials 
 
 
My data may be stored and used for future research as described above. 
 
___ yes 
___ no  
____________ initials 
 
My data may be shared with other investigators and used by these investigators for the 
future research as described above. 
 
___ yes 
___ no  
____________ initials 
 
 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 77 people will receive treatment with neratinib in the phase II portion of the study. A 
maximum of 67 people who enroll will receive fulvestrant in addition to neratinib.  This study is taking 
part at Washington University and also at other research institutions in the country. 
 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last until one or more of the following 
occur:  
• Your cancer gets worse 
• You develop another condition that prevents you from receiving study treatment 
• You develop unacceptable side effects 
• You decide to withdraw from the study 
• Your study doctor decides to withdraw you from the study 
 
After you come off study, you will be followed for 30 days after your last treatment to check your health 
status (as described above). 
 
 
 


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WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study. 
 
Some risks described in this consent document, if severe, may cause death.  
 
Risks of Neratinib 
Very Common (≥ 10%) 
• Diarrhea 
• Nausea 
• Abdominal pain  
• Vomiting 
• Pain, redness, swelling or sores in the mouth, and/or throat 
• Fatigue 
• Decreased appetite 
• Muscle spasms 
• Skin reaction (includes rash, dry skin, itching, skin eruption, skin redness, skin reaction on the 
palms of the hands or soles of the feet (such as tingling, numbness, pain, swelling, or reddening) 
 
 
Common (between 1 and 10%) 
• Increased liver enzymes, which could indicate liver damage 
• Indigestion  
• Urinary tract infection 
• Weight loss 
• Dehydration 
• Nose bleed 
• Abdominal distension 
• Nail disorder (inflammation/infection, breaking or discoloration) 
• Dry skin including deep skin cracking and/or dry mouth  
• Blood creatinine increased (an increase in an enzyme that measures the function of the kidney)                       
 
Uncommon (less than 1%) 
• Blood bilirubin increased (an increase in an enzyme that measures the function of the liver)  
• Renal failure (damage to the kidney which may decrease its functioning) 
 
Diarrhea and vomiting can quickly lead to dehydration.  If you get very dehydrated, this could make 
your blood pressure low and could make it hard for your kidneys to clean your blood.  If the dehydration 
is not treated, this could lead to a subtype of kidney failure called pre-renal failure.  This kidney failure 
gets better when fluids are given.  Patients who suffered from pre-renal failure while taking neratinib on 
other studies have all recovered their kidney function. 
 
Symptoms of mild dehydration include thirst, decreased urine volume, abnormally dark urine, 
unexplained tiredness or fatigue, irritability and negative mood, headache, dry mouth and dry skin, 


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dizziness when standing, and in some cases insomnia.  Other possible symptoms include cloudy urine 
and stinging during urination. 
 
Make sure you drink enough liquids each day (8 to 10 large glasses or cups).  If you have severe 
diarrhea and/or vomiting, even for a short period of time, and you are experiencing any of the above 
described signs of dehydration, call the study doctor immediately 
 
Other potential side effects of neratinib 
The side effects listed below have been reported with neratinib; however, the relationship of these events 
to treatment with neratinib is unknown at this time.  They occurred in uncommon to rare (≥0.1% - < 1%) 
between 1 and 9 subjects in 1000, but can be ultimately life-threatening if not treated rapidly.  Call your 
study doctor immediately if you experience any of the symptoms described in the section below. 
 
• Severe liver damage. There have been reports of patients taking neratinib who have had severe 
changes in liver function tests which may indicate liver damage.  Based on the reports observed 
so far, these changes appear to be reversible when neratinib is stopped.  If you experience 
diarrhea or any worsening of fatigue, nausea, vomiting, abdominal pain or tenderness, fever, or 
rash, notify your doctor immediately as these may be associated with changes in liver function 
tests. 
• Interstitial lung disease.  One patient with non-small cell lung cancer who was treated with 
neratinib experienced interstitial lung disease, which is an inflammation of the lungs that is 
similar to pneumonia.  This could have been caused by neratinib.  The patient’s health improved 
when she stopped taking neratinib and began to take steroids and anti-infection medication to 
treat this side effect.  If you feel shortness of breath along with fever or cough, please let your 
study doctor know immediately. 
 
Risks of Taking Neratinib with Acid-Reducing Medication 
The absorption of neratinib in the stomach is dependent on stomach acidity. Medications that reduce the 
secretion of gastric acid in the stomach such as antacids, proton pump inhibitors (such as Lansoprazole), 
and H2-receptor antagonists (such as ranitidine) may affect how neratinib dissolves in the stomach. It 
has been observed that a single 240-mg dose of neratinib combined with a proton pump inhibitor 
lowered the absorption of neratinib up to seven-fold. It is not known whether separating the time of 
taking a proton pump inhibitor and neratinib reduces the interaction. If you are required to take a H2-
receptor antagonist (such as ranitidine) to reduce stomach acid, take neratinib 10 hours after taking the 
medication and at least 2 hours before the next dose of that medication. If antacids are necessary, the 
antacid dose and the neratinib dose should be separated by 2 to 4 hours. If you have any questions, you 
should consult with your doctor about what type of acid-reducing medication you are taking. 
 
Risks of Fulvestrant 
Common, Some May Be Serious (in 100 people receiving Fulvestrant, more than 20 and up to 100 may 
have): 
• Pain 
• Tiredness 
• Increased sweating 
• Hot flashes, flushing 


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• Swelling and redness at the site of the medication injection 
 
Occasional, Some May Be Serious (in 100 people receiving Fulvestrant, from 4 to 20 may have): 
• Constipation 
• Diarrhea 
• Nausea 
• Vomiting 
• Loss of appetite 
• Heartburn 
• Swelling of the body 
• Loss of bone tissue, broken bone, or decreased height 
• Dizziness 
• Headache 
• Difficulty sleeping 
• Fluid around lungs 
• Swelling of the liver which may cause belly pain 
• Worry, depression, mood swings 
• Hair thinning 
• Cough 
 
Rare, and Serious (in 100 people receiving Fulvestrant, 3 or fewer may have): 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• Liver damage which may cause yellow eyes and skin 
• Vaginal bleeding 
• Blood clot which may cause swelling, pain, shortness of breath 
• Heart attack or heart failure which may result in chest pain, shortness of breath, swelling of 
ankles, and tiredness 
• Stroke which may cause weakness, paralysis 
 
Risks of Trastuzumab  
• Fever 
• Nausea 
• Vomiting 
• Infusion reactions, which could include flushing, shortness of breath, swelling, headache, or low 
blood pressure 
• Diarrhea 
• Infection 
• Increased cough 
• Headache 
• Fatigue 
• Shortness of breath 
• Rash 


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• Low white blood cell count, which could increase your risk of infection 
• Low red blood cell count, which could cause fatigue 
• Muscle aches 
• Congestive heart failure or other heart problems 
• Weight loss 
• Upper respiratory tract infections 
 
• Low platelet count, which could increase your risk of bleeding 
• Heartburn 
 
Risks of Blood Draws 
Possible side effects from a blood draw include fainting, dizziness, pain, swelling, bruising, or bleeding 
where the needle is inserted.  There is also a slight possibility of infection where the needle is inserted. 
 
Risks of Tumor Biopsies 
Your doctor will inform you in detail about the risks associated with the biopsy. The level of risk will 
depend on where the tumor is located.  In general, having a biopsy can cause pain, swelling, bleeding 
and/or infection at the site where the biopsy penetrates through your skin. There is also the possibility 
that having this procedure may shift some cells from the tumor into the surrounding tissues that come in 
contact with the biopsy needle.  This means that the tumor may spread to that particular area.  
Depending on the area of the biopsy, a local anesthetic (to numb the area) may be injected into the skin, 
or a sedative medication may be given orally or intravenously. You will remain conscious during this 
procedure.  The risks of this anesthetic are minimal and include bleeding, bruising, infection, and 
allergic reaction. The risks associated with use of a sedative are similar, but also included drowsiness, 
slurred speech, staggering gait, poor judgment, and slowed reflexes. 
 
Risks of MUGAs 
The MUGA (Multiple Gated Acquisition) scan is used to assess the function of the heart. The MUGA 
scan produces a moving image of the beating heart, and from this image several important features can 
be learned about the health of your heart.  A small amount of low-level radioactive substance (tracer) is 
injected into your vein and temporarily “labels” your red blood cells. Then the heart is scanned by a 
camera which can “see” the marked blood and produce the moving image.  The final product is a movie 
of the heart beating.  Allergic reactions to the tracer are rare.  Most of the tracer will be eliminated from 
your body within a day.  You may have some pain or swelling where the tracer is injected into your 
vein. 
 
Risks of Echocardiograms 
An echocardiogram is a test that uses sound waves to create a moving picture of the heart.  An 
instrument that transmits high-frequency sound waves called a transducer is placed on your ribs near the 
breast bone and directed toward the heart.  You should feel no pain with this test.  You may experience 
discomfort from lying quietly for a long period of time. 
 
Risks of CT Scans 
CT scans involve exposure to radiation.  Although the amount of radiation exposure is higher than a 
typical x-ray, the risk of harmful effects from a single exam is very small.  If you are scheduled for a CT 


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with contrast, the dye that is injected into a vein for the scan is usually well tolerated.  Some people feel 
dizzy, queasy, or get a headache when given the dye or notice a cold feeling near the injection site.  
There is a rare chance of having an allergic reaction to the dye that very rarely can be serious or life 
threatening. You must tell your doctor if you have had bad reactions to dyes before.  There is also a rare 
chance that a CT scan may cause a malfunction of worn or implanted electronic medical devices.* 
 
* If you wear or have electronic medical devices implanted such as a pacemaker or a drug pump, please 
make sure you tell your study doctors and research staff.  It was recently reported by the FDA that the 
CT scan may cause a malfunction of electronic medical devices. 
 
Risks of MRIs 
You may be uncomfortable inside the MRI scanner if you do not like to be in closed spaces 
(“claustrophobia”).  During the procedure, you will be able to talk with the MRI staff through a speaker 
system.  You can tell them to stop the scan at any time.   
 
The MRI scanner produces a loud hammering noise, which has caused hearing loss in a very small 
number of patients.  You will be given earplugs to reduce this risk. 
 
If you have a device such as a pacemaker, bone hardware, or device placed in your uterus there may be 
additional risks.  We will review what device you have and inform you of these risks.  In general, these 
risks could be: 
• heating or movement of the device 
• device malfunction 
• damage to the tissue that surrounds the device. 
 
If you have a skin tattoo, including cosmetic tattoos (eye-liner, lip-liner) you could experience the 
following: 
• irritation, swelling or heating in the area of the tattoos 
• in rare instances a primary or secondary burn. 
If you have a tattoo we will offer you a cold, wet washcloth to put over the tattoo to reduce this risk. 
 
A contrast agent, such as gadolinium, may be used during the MRI scan to make the pictures clearer. 
Recent information shows that when you receive gadolinium repeatedly it may collect in the brain.  This 
would apply whether you receive the gadolinium as part of a research study or as part of your 
healthcare.  The importance of this information and how it impacts your health are not known. 
 
Gadolinium given during pregnancy could cause a still birth or the baby could have skin diseases later in 
their childhood. If you are a woman of child-bearing age, you must have a negative urine pregnancy test 
within 24 hours prior to getting the gadolinium.   
 
Risks of Pregnancy and Nursing 
Some parts of this study might cause physical or mental problems in an unborn baby.  You must tell the 
doctor immediately if there is any chance you are pregnant.  You must also tell the doctor if your birth 
control method fails while you are on the study.  If you are a woman of childbearing potential, you 
should avoid becoming pregnant for at least 3 months after finishing treatment.  Additionally, you 


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should use a highly effective method of birth control during the time you are receiving treatment and for 
at least 3 months after finishing treatment.  Highly effective methods of birth control include use of 
established oral, injected, or implanted hormonal methods of birth control, IUD, or IUS.   
 
It is not known whether neratinib is excreted in human milk; mothers should discontinue nursing prior to 
taking neratinib. 
 
Risks Associated with Genomic Research 
It may be possible that genetic information from family members could be used to try to identify your 
sample. Similarly, it may be possible that genetic information from the sample could be used to help 
identify family members. Even though the online databases developed for this project will NOT contain 
information that is traditionally used to identify you, people may develop ways in the future that would 
allow someone to link the genetic or medical information in these databases back to you. 
 
There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this 
law makes it illegal for health insurance companies, group health plans and employers with greater than 
15 employees to discriminate against you based on your genetic information. However, it does not 
protect you against discrimination by companies that sell life insurance, disability insurance or long 
term-care insurance.  
 
Risks of Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure, and we think the risk 
of accidental disclosure is very small.  Please see the section in this consent form titled “How will you 
keep my information confidential?” for more information. 
 
Even though the online databases developed for storing some information about your data, tissue, and 
blood will NOT contain information that is traditionally used to identify you, such as date of birth, social 
security number, medical record number, etc., people may develop ways in the future that would allow 
someone to link the genetic or medical information in these databases back to you.  For example, 
someone could compare information in one of these databases with information from you (or a relative) 
in another database and be able to identify you (or your relative).  It is also possible that there could be 
violations in the security of the computer system used to store the codes linking your genetic and 
medical information to you.   
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
You may or may not benefit from being in this study.   
 
However, we hope that, in the future, other people might benefit from this study because it might help in 
the development of more effective treatments for HER2-negative breast cancer. 
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you.  Instead of being in this study, you could: 
• get treatment or care for your cancer without being in a study 


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• take part in another study 
• get no treatment 
• get comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, 
appetite problems, and other problems caused by the cancer.  It does not treat the cancer directly, 
but instead tries to improve how you feel.  Comfort care tries to keep you as active and 
comfortable as possible. 
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
As part of this study you will receive tests and procedures that are similar to what you would receive 
during routine clinical care of your condition.  Your health plan/insurance company will be billed for 
some or all of these costs, and you will be responsible for any co-pays and deductibles that are normally 
required by your health plan/insurance.  Not all insurance plans cover the costs associated with being in 
a study. Even if they do, you may be responsible for more out-of-pocket expenses, such as co-pays and 
deductibles, when there are more tests and procedures or more expensive tests and procedures involved 
in the study than if you were to receive routine clinical care outside the study. 
 
If you wish to know whether there are more tests and procedures or more expensive tests and procedures 
in the study, you should ask your study doctor. 
 
If you wish to know whether your insurance will pay, you should contact them directly, or speak with 
the study team about obtaining a financial pre-certification prior to enrolling in this study. 
 
WILL I BE PAID FOR PARTICIPATING? 
You will not be paid for being in this research study. 
   
WHO IS FUNDING THIS STUDY? 
Puma Biotechnology, Fashion Footwear Association of New York, Barnard Trust, and the Department 
of Defense are funding this research study.  This means that Washington University is receiving 
payments from these sources to support the activities that are required to conduct the study.  No one on 
the research team will receive a direct payment or increase in salary from these sources for conducting 
this study.   
 
DOES THE INVESTIGATOR OR OTHER RESEARCH TEAM MEMBER HAVE A 
PERSONAL FINANCIAL INTEREST IN THIS STUDY? 
 
Dr. Michael Naughton, a member of the study team, is a paid speaker for AstraZeneca, the manufacturer 
of fulvestrant.  Dr. Naughton is also a paid speaker and consultant for Genentech, the manufacturer of 
trastuzumab. 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the investigator, Dr. 
Cynthia Ma, at (314) 362-8903 and/or the Human Research Protection Office at 1-(800)-438-0445.  
 
 
 


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Decisions about payment for medical treatment for injuries relating to your participation in research will 
be made by Washington University.  If you need to seek medical care for a research-related injury, 
please notify the investigator as soon as possible.  
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
We will keep your participation in this research study confidential to the extent permitted by law.  
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
• Government representatives, (including the Office for Human Research Protections) to complete 
federal or state responsibilities 
• The U.S. Food and Drug Administration 
• Puma Biotechnology, manufacturer of neratinib 
• Your primary care physician if a medical condition that needs urgent attention is discovered 
• Public health agencies to complete public health reporting requirements 
• Hospital or University representatives, to complete Hospital or University responsibilities 
• Information about your participation in this study may be documented in your health care records 
and be available to your health care providers who are not part of the research team. 
• The last four digits of your social security number may be used in hospital or University systems 
to track billing information for research procedures  
• Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The 
Institutional Review Board has reviewed and approved this study.  
• The Siteman Cancer Center Clinical Trials Office 
• The Quality Assurance and Safety Monitoring Committee at the Siteman Cancer Center for 
auditing purposes 
• The independent research monitor, who is responsible for monitoring the conduct of this study 
 
The research team will send study results to Puma Biotechnology.  Information sent to Puma 
Biotechnology will be de-identified and will be used for the evaluation of this research study, the drug, 
and/or cancer. In the future, Puma Biotechnology may continue to use your health information that is 
collected as part of this study. For example, Puma Biotechnology may combine information from this 
study with the results of other studies to re-analyze the safety and effectiveness of the study drug, to 
evaluate other products or therapies, to develop a better understanding of a disease, or to improve the 
design of future research studies.  Puma Biotechnology may also share information from the study with 
regulatory agencies in foreign countries. 
 
The Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital 
is supported by funding from the National Cancer Institute (NCI). To meet NCI requirements, your PHI 
relating to your participation in this study (including your social security number) will be stored in a 
secure database at the Siteman Cancer Center.  This database and also your treatment records may be 
reviewed by Siteman Cancer Center personnel.  All information will be securely and confidentially 
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If you receive Medicare benefits, are injured as part of your participation in this research study and 
medical treatment relating to this injury is paid by anyone other than you or your insurance company, 
that payer will need to collect personal information about you.  This information includes your name, 
date of birth, gender, social security number, Medicare identification number and information related to 
this research study. The payer will report this information to the Centers for Medicare & Medicaid 
Services (CMS), the federal agency that oversees the Medicare program, during your participation in the 
study and for as long as the payer is required by CMS to report this information.  If you do not want to 
release your personal or treatment related information you have the right to refuse reimbursement by the 
payer for any research injury.  The payer will not use this information for any other purpose. 
 
To help protect your confidentiality, we will ensure that all patients identified and recruited for this 
study are within the HIPAA protected population of the research team at Washington University.  You 
will have an opportunity to ask questions about this study privately.  The research location will be in the 
clinic and treatment areas of the Center for Advanced Medicine where precautions are made to protect 
the privacy of all patients, not only research or non-research patients. Medical records are considered 
confidential and records are kept in a secured area accessible to those involved in the conduct of the 
study.  You will not be identified by name in any publication or presentation of the results of this study 
unless prior written consent is obtained.  Your information that is collected for the purpose of this study 
will be stored as coded information on paper forms in locked cabinets and locked offices or in a 
password-protected database that only the study personnel will have access to which is also maintained 
in a locked office. A master list will be stored off-line (in a locked cabinet in a locked office) and 
available only to the Principal Investigator and his designee(s). If we write a report or article about this 
study or share the study data set with others, we will do so in such a way that you cannot be directly 
identified. 
 
This consent form or similar documentation that you are participating in a research study will be 
included in your clinical medical record.  Anyone with access to your medical record, including your 
health insurance company will be able to see that you are participating in a research study. 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov/, as required by U.S. 
law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
 
Are there additional protections for my health information? 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?”. 
 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   
 


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The research team will only use and share your information as talked about in this form or as permitted 
or required by law.  When possible, the research team will make sure information cannot be linked to 
you (de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact the University’s Privacy Officer at 866-747-4975.  
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
• your treatment or the care given by your health provider. 
• your insurance payment or enrollment in any health plans.   
• any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
• You authorize the use of your PHI for this research 
• This authorization does not expire. 
• You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of 
the 
Human 
Research 
Protection 
Office 
website 
at 
http://hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
Investigator send you a copy of the letter. 
 
o If you revoke your authorization: 
 The research team may only use and share information already collected for 
the study. 
 Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons.  
 You will not be allowed to continue to participate in the study. 
 
IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time.  Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed. 
 
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify. 
 
What if I decide to withdraw from the study? 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
http://hrpo.wustl.edu/participants/withdrawing-from-a-study/ under Withdrawing from a Research 
Study. 
 
 


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If you decide to leave the study early, we will ask you to tell the study doctor if you are thinking about 
stopping so any risks can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
Will I receive new information about the study while participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
Under certain circumstances, the researchers might decide to end your participation in this research 
study earlier than planned.  This might happen because staying in the study would be harmful, you need 
treatment that is not allowed while on the study, you fail to follow instructions, you become pregnant, 
you develop a major side effect, or the study is canceled. 
 
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Dr. Cynthia Ma, (314) 362-8903. If you experience a research-related injury, please contact Dr.  
 
Ma as well; if this is after hours, you will be directed to the exchange number which will be covered by 
a resident or fellow on call.  Please tell this person that you are a research participant. 
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office, 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, 1-(800)-438-0445, or email hrpo@wustl.edu. General information about being a research 
participant can be found on the Human Research Protection Office website, http://hrpo.wustl.edu.  To 
offer input about your experiences as a research subject or to speak to someone other than the research 
staff, call the Human Research Protection Office at the number above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study.  
As a participant you have rights and responsibilities as described in this document and including: 
• To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
• To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
• To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
• To give the research team accurate and complete information. 
• To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
  
Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 01/13/22. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
 
 
Statement of Person Who Obtained Consent 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that they understand the 
risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed)