Conditions: HER2 Positive Breast Carcinoma Stage IV Breast Cancer AJCC v6 and v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
This phase II trial studies the side effects of and how well neratinib works in treating older patients with stage IV HER2-positive breast cancer. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the safety and tolerability of neratinib in adults age 60 or older with locally advanced or metastatic HER2 over-expressing breast cancer.

SECONDARY OBJECTIVES:

I. To describe the full toxicity profile including all grade toxicities measured by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0.

II. To estimate the rate of all grades of gastrointestinal (GI) toxicities such as diarrhea, nausea, and vomiting.

III. To estimate the rate of dose reduction, delays and discontinuation related to study drug.

IV. To describe pharmacokinetic parameters of neratinib in adults 60 and older. V. To estimate overall response rate (ORR) and clinical benefit rate (CBR) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

VI. To estimate event free survival (EFS), progression-free survival (PFS) and overall survival (OS).

VII. To evaluate the role of cancer-specific geriatric assessment tool in predicting treatment toxicities.

VIII. To estimate adherence rate to neratinib in older adults (percentage of doses of neratinib taken).

IX. To explore the association of pharmacokinetic (PK) parameters and geriatric assessment findings.

X. To explore if serum biomarkers of aging (interleukin \[IL\]-6, C-reactive protein \[CRP\], and D-dimer) are associated with treatment toxicities.

OUTLINE:

Patients receive neratinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then periodically thereafter.

Arms:
arm 1: Patients receive neratinib 240mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Comprehensive Geriatric Assessment intervention 2: Laboratory Biomarker Analysis intervention 3: Neratinib intervention 4: Pharmacological Study
Intervention descriptions: intervention 1: Ancillary studies intervention 2: Correlative studies intervention 3: Given PO intervention 4: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
IRB #: 15342 
04/30/19 
Packet: 26
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY AND MOLECULAR THERAPEUTICS 
TITLE: Phase II Study of Neratinib in Patients 60 and Older with HER2 Positive Metastatic Breast Cancer 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 15342 
PROTOCOL 
DATE: 04/30/2019 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
COH Initial Approval 
Protocol Dated 02/09/2016 
Version: 00 
COH Amendment 01 
Protocol Dated 02/25/2016 
Version: 01 
COH Amendment 02 
Protocol Dated 04/01/2016 
Version: 02 
COH Amendment 03 
Protocol Dated 04/20/2016 
Version: 03 
COH Amendment 04 
Title Page Change dated 06/07/2016 
Version: 04 
COH Amendment 05 
Protocol, dated 10/13/2016 
Version: 05 
COH Amendment 06 
Title Page Change dated 11/30/16 
Version: 06 
COH Amendment 07 
Title Page Change dated 01/24/2017 
Version: 07 
COH Amendment 08 
Title Page Change dated 04/10/2017 
Version: 08 
COH Amendment 09 
Protocol dated 04/10/2017 
Version: 09 
COH Amendment 10 
Protocol dated 08/18/17 
Version: 10 
COH Amendment 11 
Protocol dated 10/24/17 
Version: 11 
COH Amendment 12 
Protocol dated 11/03/17 
Version: 12 
COH Amendment 13 
Protocol dated 11/10/17 
Version: 13 
COH Amendment 14 
Protocol dated 02/07/18 
Version: 14 
COH Amendment 15 
Title Page Change dated 02/22/2018 
Version: 15 
COH Amendment 16 
Protocol dated 03/05/18 
Version: 16 
COH Amendment 17 
Title Page Change dated 04/20/2018 
Version: 17 
COH Amendment 18 
Protocol v17 dated 03/23/2018 
Version: 18 
COH Amendment 19 
Title Page Change dated 10/06/2018 
Version: 19 
COH Amendment 20 
Title Page Change dated 11/16/2018 
Version: 20 
COH Amendment 21 
Protocol dated 12/03/2018 
Version: 21 
COH Amendment 22 
Protocol dated 01/08/2019 
Version: 22 
COH Amendment 23 
Protocol dated 04/30/2019 
Version: 23 
COH Amendment 24 
Title Page dated 10/08/2019 
Version: 24 
COH Amendment 25 
Personnel Change dated 07/22/2020 
Version: 25 
COH Amendment 26 
Protocol dated 04/30/2019 [Title page only change] 
 Packet: 26 
SITE:  
Breast 
STAGE (If applicable): 
IV 
MODALITY:  
Chemotherapy 
TYPE:  
Phase II 
PRINCIPAL INVESTIGATOR: 
Yuan Yuan, M.D., Ph.D. 
COLLABORATING INVESTIGATOR(S): 
Tim Synold, Pharm.D., Sumanta Pal, M.D., Nazli Dizman, 
M.D., Zeynep Zengin, M.D.


 
IRB #: 15342 
 
04/30/19 
Packet: 26 
PARTICIPATING CLINICIANS: 
 
 
Joanne Mortimer, M.D., James Waisman, M.D., Jana 
Portnow, M.D., Stephen Koehler, M.D., Samuel Chung, 
M.D., Christina Yeon, M.D., Daphne Stewart, M.D., 
Daneng Li, M.D., Cary Presant, M.D., Gargi Upadhyaya, 
M.D., Behnam Ebrahimi, M.D., Naveen Gupta, M.D., 
Swapnil Rajurkar, M.D., Misagh Karimi, M.D., 
Mohammadbagher Ziari, M.D., Niki Patel, M.D., Mina 
Sedrak, M.D., Shanmuga Subbiah, M.D., James Shen, 
M.D., Shamel Sanani, M.D., Benjamin Leach, M.D., Philip 
Chatham, M.D., Thomas Joseph, M.D., Sayeh Lavasani, 
M.D. 
 
Radiology: 
Arnold Rotter, M.D. 
 
Statistician: 
Suzette Blanchard, Ph.D. 
 
        RESEARCH STAFF:      Susan Yost, PhD  
 
Participating Sites: 
City of Hope, Duarte, CA 
City of Hope, South Pasadena, CA 
City of Hope, West Covina, CA 
City of Hope, Antelope Valley, CA 
City of Hope, Rancho Cucamonga, CA 
City of Hope, Mission Hills, CA 
City of Hope, Corona, CA 


 
 
 
 
 
 
 
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Page 1 of 145 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY AND MOLECULAR THERAPEUTICS 
PHASE II STUDY OF NERATINIB IN PATIENTS 60 AND OLDER WITH HER2 POSITIVE 
METASTATIC BREAST CANCER 
IRB PROTOCOL NUMBER: 15342 
VERSION: 23 
DISEASE SITE: 
Breast 
STAGE: 
III-IV 
MODALITY 
Oral 
PHASE 
Phase II 
PRINCIPAL INVESTIGATORS: 
Yuan Yuan, M.D. Ph.D. 
COLLABORATING 
INVESTIGATORS: 
Tim Synold, Pharm.D. 
 
 
 
PARTICIPATING 
INVESTIGATORS: 
Shamel Sanani, M.D., 
Benjamin Leach, M.D., 
Phiip Chatham, M.D., 
Thomas Joseph, M.D. 
Arnold Rotter, M.D. 
Joanne Mortimer, M.D. 
James Waisman, M.D. 
Jana Portnow, M.D. 
Stephen Koehler, M.D.  
Samuel Chung, M.D. 
Behnam Ebrahimi, M.D. 
Swapnil Rajurkar, M.D. 
Mohammadbagher 
Ziari, M.D. 
Mina Sedrak, M.D. 
George Hajjar, M.D. 
Christina Yeon, M.D. 
Daphne Stewart, M.D. 
Waheed Murad, M.D. 
Mohammad Fekrazad, 
M.D. 
Daneng Li, M.D. 
Cary Presant, M.D. 
Gargi Upadhyaya, M.D. 
Naveen Gupta, M.D. 
Misagh Karimi, M.D. 
Niki Patel, M.D. 
(formerly Tank) 
Shanmuga Subbiah, M.D. 
James Shen, M.D. 
Sayeh Lavasani, M.D. 
STUDY STATISTICIAN: 
Suzette Blanchard, Ph.D. 
PARTICIPATING SITE: 
City of Hope (Duarte, South Pasadena, West Covina, 
Antelope Valley, Mission Hills, Rancho Cucamonga 
and Corona). 
STUDY SPONSOR AND MONITOR: 
City of Hope National Cancer Center 
AGENT NSC# AND IND#: 
Neratinib, 066783 


 
 
 
 
 
 
 
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COORDINATING CENTER: 
Data Coordinating Center 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Phone: 626-256-4673 x 83968 
e-mail: DCC@coh.org 


 
 
 
 
 
 
 
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Experimental Design Schema 
 
Pre-Study 
(up to  
28 days 
prior to 
enrolling)i 
Cycle 1 
Day 1 
(28 day  
cycle) 
Cycle 1 
Day 8  
(± 1 day) 
Cycle 1 
Day 15 
(± 1 day) 
Cycle 2  
Day 1  
(± 3 days) 
Cycle 2 
Day 15 
(± 3 days) 
Cycle 3 
Day 1 
(± 3 days) 
Cycle 4 
Day 1 
(± 3 days) 
Cycle 5 
Day 1 
(±3 days) 
Cycle 6  
Day 1 
(±3 days) 
Every 
Cycle  
Thereafter 
(± 3 days) 
Every 3 
cycles 
(±7 days) 
Off  
treatmenth 
Neratinib  
(day 1-28 every 4 weeks a,b 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Physical exam  (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Vital signs (± 1 wk)  
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (± 1 wk) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Performance Status (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
CBC w/diff, plts (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Complete Metabolic Panelc  
(± 1 wk) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diarrhea Checklist  
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
Nurse brief toxicity 
evaluation 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic samples j 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Adherence evaluation (pill 
count, diaries) (± 1 wk) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event evaluation 
(± 1wk) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Tumor measurements using 
CT or PET-CT (± 1 wk) 
Xd 
 
 
 
 
 
 
X 
 
 
 
Xe 
Xf 
LVEF Assessment 
Xd 
 
 
 
 
 
 
Xe 
 
 
 
Xe 
Xf 


 
 
 
 
 
 
 
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Geriatric Assessment 
Survey(±1 wk) k 
X 
 
 
 
 
 
 
X 
 
 
 
 
Xg 
Peripheral Blood 
Correlativesk 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Bacteriomic profiling 
Xm 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
a: Dose as assigned; neratinib 240mg orally daily; Doses held due to toxicity will not be made up. 
b: If baseline laboratory tests are done within 14 days of start of treatment, these labs do not need to be repeated prior to Day 1. 
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
d: Baseline assessment may be done up to 30 days prior to study enrollment. 
e: Tumor measurements and LVEF assessment are repeated every 3 cycles  ± 1 wk until patient comes off study. Documentation (radiologic or clinical) must be provided for patients 
removed from study for progressive disease. 
f: Off-study radiologic evaluation will only be done if clinically indicated. 
g: Geriatric assessment will be performed at baseline prior to study, after 3 cycles and at end of study. Geriatric assessment will be repeated off study ONLY if it had not been administered 
within the previous month. If patient’s native language was not covered by the current language forms, Geriatric assessment form can be omitted with clear documentation. 
h: Patients will be followed for 30 days following discontinuation of therapy in order to capture toxicity attributable to therapy. 
i. Chart review data must be within 28 days to determine if patient meets study criteria. Once patient meets study criteria, then all criteria must be within window specified in protocol 
from Day 1 as indicated in column one in the schema above. 
j: Pharmacokinetics samples will be collected at the following time points:  Cycle 1 Day 15 pre-dose (± 20 minutes) and  6 hours post-dose (± 60 minutes); pre-dose (± 20 minutes) on 
Cycle 3 Day 1 and Cycle 4 Day 1.All pre-dose samples should be collected within 30 minutes before the daily dose, in 10 ml purple-top tube. 
k: Peripheral blood correlatives for inflammatory marker measurement (IL-6, CRP and D-dimer) and ctDNA will be collected at baseline, after 3 cycles (Cycle 4 Day 1,±7days ), and 
at end of  study (±7days) when patient receives geriatric assessment in 10 ml purple-top tube. 
L: An “Optimal Management of Diarrhea Checklist” will be reviewed and signed by study investigator or study nurse on Cycle 1 Day1. The study team will call patients at 1day, 2 
days and 3 days after first dose of neratinib to assess tolerance. 
m. Stool samples must be collected within 7 days prior to start of neratinib, at onset of first episode of diarrhea (same day), C1Day 15 (+/-3 days), C2Day1 (+/-3 days), C2Day15 (+/-3 
days), C3Day1 (+/-3 days). 
 


 
 
 
 
 
 
 
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Study Schema 
 
 


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Protocol Synopsis 
Protocol Title: 
PHASE II STUDY OF NERATINIB IN PATIENTS 60 AND OLDER WITH HER2 
POSITIVE METASTATIC BREAST CANCER 
Brief Protocol Title for the Lay Public (if applicable): 
Neratinib in Older Adults 
Study Phase: 
Phase II 
Participating Sites: 
City of Hope Comprehensive Cancer Center 
Rationale for this Study: 
Limited evidence exists to guide therapy with targeted agents in the older adult because 
these patients have been under-represented in clinical trials. Adults age 70 and older make 
up only 20% of subjects enrolled in FDA registration trials, but 46% of all patients with 
cancer are older adults. Dose-finding studies specifically in older adults are not routinely 
performed despite changes in drug metabolism, absorption, and distribution with increasing 
age.  
Neratinib is a potent oral small molecule that inhibits HER1, HER2 and HER4 at the 
intracellular tyrosine kinase domains through irreversible binding at a targeted cysteine 
residue in the ATP binding pocket of the receptor. Both the ability of neratinib to 
concurrently block signal transduction through the three active tyrosine kinase HER 
receptors, and its irreversible binding and prolonged inhibition of these growth-promoting 
pathways, provide the opportunity to further improve the clinical benefit of its use in 
HER2+ MBC patients. Early clinical data have demonstrated the activity of neratinib in 
patients who have already progressed through treatment with other small molecule or 
antibody-based HER2 targeted therapies. With the promising results from multiple clinical 
trials, neratinib has the potential to emerge as a novel therapy for patients with HER2 
positive breast cancer. There is significant interest in studying this drug among older adults, 
as it is a targeted therapy which is convenient to prescribe and easy to administer.  However, 
there is a significant amount of GI toxicity. In particular, grades 1-4 diarrhea occurred in 
92% of patients.  Grade 3-4 diarrhea occurred in over 30%  of patients and dose reductions 
secondary to diarrhea range from 20-53% across 9 trials of neratinib alone or in 
combination with other therapy [1-9]. This particular side effect is likely to be significant in 
the population of older adults who are particularly vulnerable to diarrhea.  Currently, there 
are 6 trials of neratinib therapy with a total enrollment of 291 patients, but only 38 patients 
are 65 and older (data provided by PUMA). Therefore, there is a significant gap of 
knowledge regarding the toxicity profile of neratinib in older adults, as well as the optimal 
supportive care medications to minimize side effects. 


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Objectives: 
Primary Objective: 
To estimate the rate of grade 2 or higher toxicities attributed to neratinib in adults 60 years 
and older with HER2 overexpressing breast cancer.  
Secondary Objectives: 
 To describe the full toxicity profile including all grades as measured by NCI CTCAE 
v.4.0. 
 To estimate the rate of all grades of GI toxicities such as diarrhea, nausea, and vomiting. 
 To estimate the rate of dose reduction, holds and hospitalizations. 
 To describe pharmacokinetic parameters of neratinib in adults 60 and older. 
 To estimate overall response rate (ORR) and clinical benefit rate (CBR) defined by 
RECIST 1.1. 
 To estimate event free survival (EFS), progression free survival (PFS) and overall 
survival (OS). 
 To evaluate the role of cancer-specific geriatric assessment tool in predicting treatment 
toxicities.  
 To estimate adherence rate to neratinib in older adults.  
 To explore the association of PK parameters and geriatric assessment findings. 
 To explore if serum biomarkers of aging (IL-6, CRP, and D-dimer) are associated with 
treatment toxicities. 
Endpoints: 
Primary: Grade 2 or higher toxicities. 
Secondary: 
 All grade toxicities as measured by NCI CTCAE v.4.0. 
 All grades of GI toxicities such as diarrhea, nausea, and vomiting. 
 Dose reduction, holds and hospitalizations.  
 Effect of age on PK parameters: clearance and volume of distribution and exposure-
response relationships on efficacy and safety of neratinib. 
 Response as defined by RECIST. 
 EFS(where the event is toxicity or progression), PFS, OS. 
 Geriatric assessment score  
 Adherence as defined by pill count. 
 IL-6 
 CRP 
 
D-dimer 
Study Design: 
The study will be an open label, single arm, phase II toxicity study of single agent neratinib 
in order to describe the toxicity profile in patients age 60 and older with HER2 positive 


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breast cancer. We plan to study 40 subjects, stratified by patient age (with at least 5 patients 
age 75 years or older, and no more than 15 patients 60-70, in order to assure that we study 
the entire age range of older adults). As diarrhea has been seen with neratinib, we have 
established additional guidelines and criteria which will be used to flag an unexpected 
number of patients that experience grade 3 diarrhea within the 2 cycles on neratinib 
treatment in the presence of aggressive mandatory anti-diarrhea management which will 
lead to a careful data review.  There will also be one interim analysis of the toxicity profile 
after 20 subjects have been on drug for at least one cycle. 
Patients are anticipated to participate in the study for an average of 48 months. This includes 
approximately 0.5 months for screening, an estimated average of 9.5 months for the active 
treatment phase, and an estimated average of 38 months for the long-term follow-up phase. 
Treatment is to be given for as long as it is tolerated and while there is no disease 
progression. Patients who permanently discontinue treatment will enter the long-term 
follow-up phase until death or withdrawal of consent. 
Sample Size: 
40 
Estimated Duration of the Study 
48 months 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
1. Female or male patient age > 60 years. 
2. ECOG performance 0-2. (see Appendix A for ECOG criteria) 
3. Life expectancy of greater than 12 weeks. 
4. Histologically or cytologically proven metastatic breast cancer (metastases can be 
proven with imaging results in certain circumstances provided that the initial tumor 
was demonstrated histologically). 
5.  Stage IV Her2/Neu positive breast cancer patients who failed previous anti-HER2 
targeted therapies. 
6. HER2 positivity as defined by ASCO/CAP guidelines. 
If HER2 negative by IHC or FISH, but activating somatic mutations of HER2 gene 
identified through genomic sequencing (CLIA certified lab test) including but not limited to 
the following: Missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, 
R678Q, V697L, T733I, L755S, L755P, D769H, D769Y, D769N, G776V, G776C, V777L, 
L841V, V842I, R849W, L869R); Insertions/deletions (A775_G776insYVMA aka 
Y772_A755dup, G776VinsC, G776AinsVGC, G778_S779insCPG, P780_781insGSP aka 
G778_P780dup, L755_T759del) and/or HER3 activating mutations. 
1. There is no limitation on the number of prior lines of systemic therapy or HER2-
targeted therapies (prior neratinib not allowed). 
2. Both measurable as well as non-measurable disease will be allowed. 
3. Adequate organ and bone marrow functions defined below within 4 weeks of pre-


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registration:  
o Hemoglobin: ≥9 g/dL (after transfusion, if necessary). 
o Total bilirubin: within normal institutional limits. 
o AST (SGOT)/ALT (SGPT): ≤ 2.5 X institutional upper limit of normal. 
o Creatinine clearance ≥ 30 mL/min as calculated by Cockroft-Gault formula. 
4. Baseline left ventricular ejection fraction LVEF > 50% as evaluated by 
echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA).  
5. All grade >2 toxicities other than alopecia from prior therapy have resolved by the 
time of study commencement. 
6. Patient must have completed radiation therapy with adequate recovery of bone 
marrow and organ functions, before starting neratinib. 
7. Patient with stable or treated brain metastases are eligible. Asymptomatic patients 
with metastatic brain disease who have been on a stable dose of corticosteroids for 
treatment of brain metastases for at least 14 days are eligible to participate in the 
study. 
8. Provide written, informed consent to participate in the study and follow the study 
procedures. 
Exclusion Criteria: 
1. Prior treatment with neratinib. 
2. Concurrent usage of other investigational agents, chemotherapy, or hormone 
therapy. Prior chemotherapy, hormonal therapy, targeted therapy, and investigational 
agents are allowed but all toxicities grade ≥2 must have resolved by the time of 
study commencement (except alopecia). 
3. Any major surgery ≤ 28 days prior to the initiation of investigational products. 
4. Received chemotherapy or biologic therapy ≤3 weeks prior to the start of neratinib 
5. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart 
failure (New York Heart Association functional classification of  ≥2, including 
individuals who currently use digitalis specifically for congestive heart failure ),  
unstable angina, myocardial infarction within 12 month of enrollment or ventricular 
arrhythmia. 
6. Concurrent use of digoxin due to cardiac disease. QTc interval ≥ 450 milliseconds in 
men or QTc interval ≥ 470 milliseconds in women  within 2 weeks of registration or 
known history of QTc prolongation or Torsades de Pointes. 
7. Inability to take oral medication. 
8. Other malignancy within the past 3 years with the exception of: a) adequately treated 
basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or 
vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely 
to impact survival during the duration of the study, such as localized transitional cell 
carcinoma of the bladder, or benign tumors of the adrenal or pancreas.  
9. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., 
Crohn’s disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] 
diarrhea of any etiology at baseline). 
10. Known clinically active infection with hepatitis B or hepatitis C virus. 


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11. Evidence of significant medical illness, abnormal laboratory finding or psychiatric 
illness/social situations that would, in the Investigator’s judgment, makes the patient 
inappropriate for this study. 
Investigational Product Dosage and Administration: 
Neratinib will be given as 240 mg (six 40 mg tablets) orally, once daily with food, 
preferably in the morning, continuously throughout the study period, with no rest between 
cycles. This medication will be continued until disease progression, death, drug intolerance 
or other limiting factors, removal from protocol due to patient or physician preference, or 
loss to follow-up. 
Clinical Observations and Tests to be Performed: 
Patients who fulfill the eligibility criteria described above will undergo the full informed 
consent process. Prior to starting treatment, all subjects will undergo history and physical 
exam, and laboratories including CBC, chemistry, and liver function tests. Pathology will be 
reviewed and HER2 receptor status will be documented. HER 2 receptor somatic mutations 
will be documented if available. Baseline disease will be documented with CT scan of chest, 
abdomen and pelvis, or PET-CT as long as there is a diagnostic CT component (within 30 
days prior to starting treatment). All subjects will have cardiac function evaluation (within 
30 days prior to starting treatment) using either an echocardiogram or MUGA scan and an 
EKG.  
Each cycle will be four weeks with neratinib 240 mg orally continued daily.  During each 
cycle, history and physical, CBC and CMP (BMP, LFTs) will be performed once every 4 
weeks (+/- 1 wk). Toxicity will be evaluated at these appointments as well between visits if 
the subject contacts the participating clinician with concerns. Evaluations will continue once 
per cycle until disease progression, death, discontinuation of the drug, or loss to follow-up. 
Due to the risk of diarrhea in this population, research nurse will contact the patient on each 
day days 1-3 to check on diarrhea and loperamide compliance. During the first cycle (Cycle 
1 Day 8 and Day 15)  and part of the second cycle (Cycle 2 Day 15, the patient will be seen 
at a brief nurse visit during those weeks in which no full physician assessment is required. 
During these visits, adverse events,  limited history and physical exams will be done to 
ensure that any severe side effects that could benefit from intervention are identified.  
While on study, CT of the chest, abdomen, and pelvis (or PET-CT as above); and LVEF 
evaluation will be performed at the end of every three cycles (every 12 weeks). The 
modality of cardiac evaluation must be consistent throughout the study for each individual 
patient. 
A cancer specific geriatric assessment will be performed at baseline, after 3 cycles, and at 
the end of the study. The comprehensive cancer-specific geriatric assessment includes an 
evaluation of functional status, co-morbidity, cognition, psychological status, social 
functioning and support, and nutritional status.[10] Patients receiving at least 1 dose of 
investigational product will be evaluable for safety. Safety will be assessed based on 
medical history, vital sign measurements, physical examination findings, ECG results, 
MUGA or ECHO and laboratory assessments. Adverse events (AEs) will be graded 


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according to the NCI CTCAE v.4.0. AEs and SAEs will be reported until 28 days after the 
last dose of investigational product and will be followed until resolution or until condition 
stabilizes. Should an investigator be made aware of any neratinib-related SAE occurring any 
time after the reporting period, it should be promptly reported. 
Adherence to neratinib will be measured by pill count at each appointment as well as by 
patient self-report in dedicated patient diaries, also to be evaluated at each interim visit.  
Neratinib log will also be utilized to track the use of the pill.  In the event of discrepancy in 
these measures of adherence, we will follow whichever indicates the lower measure of 
adherence (i.e. if patient states they took 13 of 14 doses, but only 10 doses are missing, we 
will count the patient as having taken only 10 days.  Alternatively, if 14 doses are missing, 
but the patient stated she only took 11 doses, we will count the patient as having taken only 
11 doses.) Measures of patient initiated dose reduction will be exclusively measured by 
patient self-report. All toxicity related dose interruptions or reductions, hospitalizations, and 
adverse events will be noted. Subjects will be followed for toxicity outcomes for an 
additional 30 days after stopping the drug and until resolution of all grade >2 toxicities. 
Pharmacokinetic measures will be determined in all study participants. Based on a neratinib 
half-life of 11-20 hours at steady state, PK samples will be collected at the following time 
points:  Cycle 1 Day 15 pre-dose (± 20 minutes),  6 hours post-dose ± 60 minutes ) and Day 
1 of Cycle 3 and 4 pre-dose (± 20minutes). All pre-dose samples should be collected within 
30 minutes before the daily dose. In the event that the neratinib dose is held or the dose 
level is changed, pharmacokinetic sample will be rescheduled accordingly.  
Mandatory Peripheral blood biomarkers (IL-6, CRP, and D-dimer) and proteomics analysis 
will be performed at baseline, after 3 cycles, and at the end of the study. 
Statistical Considerations: 
Tables will be created to summarize the toxicities and side effects by organ system, 
attribution and severity for all participants that receive at least one dose of neratinib. Rates 
and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated 
for 1) grade 2 or higher toxicities attributed to neratinib, 2) all grade GI toxicities (diarrhea, 
nausea and vomiting),  3) dose reductions, holds  and hospitalizations,  and 4) the objective 
response  (CR+PR) and clinical benefit  (CR+PR+SD) and 5) 16 week progression free 
survival(PFS). EFS, PFS and OS will be estimated using the product limit method of 
Kaplan and Meier. Descriptive statistics will be provided for pharmacokinetic parameters, 
drug adherence and participant demographics. Generalized linear models and graphical 
methods will be used to explore factors as identified by a cancer-specific geriatric 
assessment and serum biomarkers that may be predictive of toxicity dose reductions, dose 
holds or hospitalizations. We will use generalized linear models to determine if any of these 
factors independently predict toxicity, response, and/or pharmacokinetic parameters of 
interest. 
Sponsor/Licensee: 
Puma Biotechnology Inc. 
Case Report Forms 


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Paper or via Medi-data Electronic Data Collection (EDC) 


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Table of Contents 
SECTION...................................................................................................... PAGE 
1.1 
Introduction/Rationale for Development .................................................. 18 
1.2 
Overview of Proposed Study: Cancer and Aging ..................................... 18 
1.3 
Epidermal Growth Factor Receptor (ErbB Receptors) Family ................. 18 
1.4 
Human Studies – HER2 Targeted Therapies in Breast Cancer ................ 19 
1.4.1 Trastuzumab .................................................................................. 19 
1.4.2 Pertuzumab ................................................................................... 19 
1.4.3 Ado-Trastuzumab Emtansine (T-DM1 [Kadcyla]) ....................... 20 
1.4.4 Lapatinib ....................................................................................... 20 
1.4.5 Neratinib in HER2 Positive Breast Cancer ................................... 21 
1.4.6 Clinical Trials of Neratinib ........................................................... 25 
1.5 
Aging and Decreased Tolerance of Chemotherapy .................................. 27 
1.6 
Factors Predicting Chemotherapy Tolerance ............................................ 28 
1.6.1 Measures of Biological Age.......................................................... 28 
1.6.2 Biomarkers of Aging: Inflammatory Markers (IL-6, CRP) and a 
Coagulation Marker (D-dimer) ................................................................. 29 
1.7 
Neratinib in the Older Patient Population Study Rationale ...................... 30 
2.0 
Specific Objectives and Goals .............................................................................. 31 
2.1 
Primary Objective ..................................................................................... 31 
2.2 
Secondary Objectives................................................................................ 31 
3.0 
Study Endpoint...................................................................................................... 31 
3.1 
Primary Endpoint ...................................................................................... 31 
3.2 
Secondary Endpoints ................................................................................ 31 
4.0 
Study Design and Schema .................................................................................... 32 
5.0 
Patient Eligibility .................................................................................................. 33 
5.1 
Inclusion Criteria ...................................................................................... 33 
5.2 
Exclusion Criteria ..................................................................................... 34 
5.3 
Inclusion of Women and Minorities ......................................................... 35 
6.0 
Screening, Registration, and Follow-up Studies ................................................... 35 
6.1 
Screening Procedures ................................................................................ 35 
6.1.1 General Guidelines........................................................................ 35 


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6.1.2 Procedure for On-study and Treatment Deviations ...................... 35 
6.2 
Informed Consent...................................................................................... 35 
6.3 
Participant Registration ............................................................................. 36 
6.3.1 COH DCC Availability and Contact Information ....................................... 36 
6.3.1 Slot verification and reservation ................................................... 36 
6.3.2 Registration procedure .................................................................. 36 
6.4 
Dose Assignment ...................................................................................... 37 
7.0 
Study Treatment Protocol ..................................................................................... 37 
7.1 
Treatment Overview ................................................................................. 37 
7.1.1 Neratinib ....................................................................................... 37 
7.2 
Dose Adjustment ....................................................................................... 37 
7.3 
Planned Duration of Therapy .................................................................... 37 
7.4 
Criteria for Removal from Treatment ....................................................... 37 
7.5 
Subject Follow-Up .................................................................................... 38 
7.6 
Supportive Care, Other Concomitant Therapy, Prohibited Medications .. 38 
7.6.1 Required Concomitant Treatment ................................................. 38 
7.6.2 Permitted Concomitant Treatment ................................................ 42 
7.6.3 Concomitant Treatment Prohibited in Combination with Neratinib43 
7.6.4 Other concomitant medications with potential for interaction ..... 43 
7.7 
Laboratory Studies/Monitoring Studies .................................................... 44 
7.7.1 Required Clinical, Laboratory and Disease Evaluation at Baseline44 
7.7.2 Studies Obtained During the Trial ................................................ 45 
7.7.3 Monitoring Studies........................................................................ 45 
8.0 
Dose Delays/Modifications for Adverse Events ................................................... 46 
8.1 
General Toxicities ..................................................................................... 47 
8.2 
Gastrointestinal Toxicity ........................................................................... 47 
8.3 
Pulmonary Toxicity .................................................................................. 47 
8.4 
Liver Toxicity ........................................................................................... 49 
8.5 
Left Ventricular Ejection Fraction Toxicity ............................................. 49 
9.0 
Data and Safety Monitoring Plan .......................................................................... 52 
10.0 
Agent Information and Risks ................................................................................ 57 
10.1 
Neratinib ................................................................................................... 57 


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10.1.1 Description .................................................................................... 57 
10.2 
Adverse Drug Reactions ........................................................................... 58 
10.2.1 Diarrhea and Other Gastrointestinal Toxicities ............................ 58 
10.2.2 Dermatologic Toxicities................................................................ 59 
10.2.3 General Disorders (Fatigue and Asthenia) .................................... 60 
10.2.4 Metabolic and Nutritional Disorders (Decreased Appetite and 
Dehydration) ............................................................................................. 60 
10.2.5 Nervous System Disorders (Headache) ........................................ 60 
10.2.6 Hematologic Toxicities ................................................................. 60 
10.2.7 Hepatotoxicity ............................................................................... 61 
10.2.8 Pulmonary Toxicity ...................................................................... 61 
10.2.9 Cardiac Toxicities ......................................................................... 61 
11.0 
Correlative/Special Studies ................................................................................... 62 
11.1 
11.1 PK Analysis ...................................................................................... 62 
11.2 Peripheral Blood Biomarkers Predicting Chemotherapy Tolerability .......... 63 
11.3 
Specimen Labeling and Shipping ............................................................. 64 
11.4 
Bacteriomic Profiling ................................................................................ 64 
11.4.1 Stool Specimen Collection ........................................................................ 64 
11.4.2 Laboratory Processing and Analysis .......... Error! Bookmark not defined. 
12.0 
Experimental Design Schema ............................................................................... 66 
13.0 
Endpoint Evaluation Criteria/Measurement of Effect .......................................... 68 
13.1 
Response Criteria ...................................................................................... 68 
13.2 
Disease Parameters ................................................................................... 68 
13.3 
Methods for Evaluation of Measurable Disease ....................................... 69 
13.4 
Response Criteria ...................................................................................... 70 
13.4.1 Evaluation of Target Lesions ........................................................ 70 
13.5 
Evaluation of Non-Target Lesions (see Table 15) .................................... 70 
13.5.1 Evaluation of Best Overall Response ........................................... 71 
13.6 
Duration of Response ................................................................................ 72 
13.7 
Progression-free Survival.......................................................................... 72 
13.8 
Overall Survival ........................................................................................ 72 
13.9 
Clinical Benefit Rate ................................................................................. 73 


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14.0 
Data Reporting/Protocol Deviations ..................................................................... 73 
14.1 
Data Reporting .......................................................................................... 73 
14.1.1 Confidentiality and Storage of Records ........................................ 73 
14.1.2 Subject Consent Form ................................................................... 73 
14.1.3 Data Collection Forms and Submission Schedule ........................ 73 
Table 16: Data Submission Schedule ................................................................... 73 
14.2 
Protocol Deviations ................................................................................... 74 
14.2.1 Deviation Policy............................................................................ 74 
14.2.2 Reporting of Deviations ................................................................ 74 
14.2.3 Resolving Disputes ....................................................................... 74 
15.0 
Statistical Considerations ...................................................................................... 75 
15.1 
Stratification ............................................... Error! Bookmark not defined. 
15.2 
Sample Size and Accrual Rate .................................................................. 75 
15.3 
Interim Analyses and Stopping rules ........................................................ 75 
15.3.1 Interim Analyses ........................................................................... 75 
15.3.2 Stopping Rules (see Table 17) ..................................................... 75 
15.4 
Data Analysis ............................................................................................ 76 
16.0 
Human Subject Issues ........................................................................................... 77 
16.1 
Institutional Review Board ....................................................................... 77 
16.2 
Recruitment of Subjects ............................................................................ 77 
16.3 
Advertisements ......................................................................................... 78 
16.4 
Study location and Performance Sites ...................................................... 78 
16.5 
Confidentiality .......................................................................................... 78 
16.6 
Financial Obligations and Compensation ................................................. 79 
16.7 
Informed Consent Processes ..................................................................... 79 
17.0 
References ............................................................................................................. 79 
Patient’s Maximum Final Response Errors Score Weight Score ....................... 120 
Memory Phrase ..................................................................................... 120 
Information to provide when talking to your doctor ....................................................... 126 
Medications to treat diarrhea .................................................................. 127 
Changes to my diet to treat diarrhea ....................................................... 128 
1.2.1 Study Medication adjustments .................................................... 129 


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Background/ Study Rationale 
1.1 Introduction/Rationale for Development 
Approximately 15-20% of women with breast cancer have HER2+ cancer, which is associated 
with aggressive disease and poor prognosis. The goal of this study is to utilize a phase II design 
to examine the tolerability of neratinib, a potent oral small molecule tyrosine kinase inhibitor 
targeted at ERBB1, 2, and 4 among older adults with HER2 overexpressing breast tumors. There 
is significant interest in studying this drug among the older adults as it is an oral targeted therapy. 
However, there is concern that without definitive studies in the older adult population, 
oncologists may have reservations in giving neratinib, or will dose reduce the agent without 
guidance.  
1.2 Overview of Proposed Study: Cancer and Aging 
Cancer is a disease that disproportionately affects older patients. People age 65 and older have an 
11-fold increase in the incidence of cancer and a 15-fold increase in cancer mortality in 
comparison to people younger than age 60 [11, 12]. Older adults are an important population to 
study because 60% of all cancer cases and 70% of cancer mortality occur in patients over the age 
of 60 [13]. The number of older people with cancer is continuously growing as the population is 
aging. By the year 2030, the total projected cancer incidence will increase by approximately 
45%, from 1.6 million in 2010 to 2.3 million in 2030. A 67% increase in cancer incidence is 
anticipated for older adults, compared with an 11% increase for younger adults [14]. Older adults 
with cancer are an understudied population. Cancer patients age 70 or greater made up only 20% 
of subjects enrolled in FDA registration trials from 1995 to 1999, though they made up fully 
46% of the U.S. cancer population [15]. 
While several studies have demonstrated that older adults are more likely to experience 
chemotherapy toxicity [16-18], the comparative risk of targeted therapies has been under- 
studied. Though chronological age does not entirely correlate with physiologic age, older adults 
do have changes in physiology that can predispose to drug toxicity [19]. A progressive reduction 
in the functional reserve of various organ systems may alter the pharmacokinetics of anti-cancer 
therapies[20] and increase the susceptibility of older individuals to complications of 
treatment[21, 22] Normal tissues may be less able to repair the molecular damage caused by 
antineoplastic agents due to cellular senescence, resulting in greater potential cardiac toxicity, 
neurotoxicity, mucositis, and hematologic toxicities [19]. And finally, there may be age-related 
changes in the biology of cancer which may impact the therapeutic efficacy and approach to 
treatment [23-26].  
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
the applicable regulatory requirements. 
1.3 Epidermal Growth Factor Receptor (ErbB Receptors) Family 
The human epidermal growth factor receptor 2 (HER2)/Neu gene is a member of the family of 
EGFR/ErbB genes. Amplification or over-expression is associated with an aggressive disease 
biology, including enhanced cell proliferation, and reduced progression-free survival (PFS) and 
overall survival (OS) [27] [28-30]. The human HER (ErbB) receptor family consists of four 
closely related transmembrane tyrosine kinase receptors: epidermal growth factor receptor ErbB1 
(HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). These membrane-spanning 


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proteins receive extracellular signals from small peptide ligand molecules, including epidermal 
growth factor-like molecules, transforming growth factor-α and neuregulins. Ligand binding 
triggers intracellular signaling through a complex and tightly controlled array of signaling 
pathways that together drive and regulate many cellular functions, including cell proliferation, 
organ development, and repair. Binding of ligands to extracellular parts of HER1, HER3 and 
HER4 result in dimerization and initiation of  a series of signaling cascades that include mitogen-
activated protein kinase (MAPK), phosphoinositide-3kinase (PI3K), protein kinase B (PKB or 
Akt), and mammalian target of rapamycin (mTOR) [31].   
HER receptor dimerization is an essential requirement for signaling activity and can occur 
between two different HER receptors (heterodimerization) or two molecules of the same receptor 
(homodimerization) [32, 33]. HER homodimers weakly perpetuate signals compared with 
heterodimers [34]. Ligands have been identified for the HER1 (EGFR), HER3 and HER4 
receptors. No ligand has yet been identified for HER2 (also known as Her-2/Neu) which is the 
preferred dimerization partner for HER1, HER3, and HER4[34]. The HER2 receptor is presumed 
to exert its effects through formation of heterodimers with other HER family members.  HER3 
possesses a defective tyrosine kinase and requires heterodimerization with another HER member 
to be activated. HER4 has an active tyrosine kinase, but its role in breast cancer is currently 
unknown. HER1 (EGFR) and HER2 receptors are often upregulated in many human cancers 
[35].  Many therapeutic strategies have therefore been employed to block the HER signaling 
pathways as a means to improve the therapeutic efficacy of hormonal and chemotherapy 
regimens. 
1.4 Human Studies – HER2 Targeted Therapies in Breast Cancer 
1.4.1 Trastuzumab 
Human epidermal growth factor receptor 2 (HER2) amplification is seen in approximately 15-
20% of breast cancers and is associated with more aggressive disease and worse prognosis. 
Trastuzumab, the first agent approved for treatment of HER2+ breast cancer, is a monoclonal 
antibody against the extracellular juxtamembrane portion of the HER2 receptor. Treatment 
results in improved DFS and OS in patients with HER2-over-expressing tumors in both the 
adjuvant and metastatic settings [36]. In adjuvant trials, trastuzumab has been shown to decrease 
the risk of recurrence of breast cancer by 39-52% [37-39]and decreases the risk of death by 33% 
[38]. Trastuzumab has also been found effective in the neoadjuvant setting [16, 18]. 
The mechanisms of action of trastuzumab include prevention of HER2-receptor dimerization, 
increased endocytotic destruction of the receptor, inhibition of shedding the extra-cellular 
domain, and immune activation [40] by recruiting immune effector cells that are responsible for 
antibody-dependent cytotoxicity[41]. Trastuzumab was first approved for use in the treatment of 
HER2-amplified breast cancer in the U.S. in 1998. More recently, additional HER2-targeted 
therapies including lapatinib (a tyrosine kinase inhibitor), pertuzumab (a humanized anti-HER2 
monoclonal antibody)   and TDM-1 have shown promising results in metastatic HER2 positive 
breast cancer. 
1.4.2 Pertuzumab 
Pertuzumab is a monoclonal antibody that binds HER2 at a different epitope of the HER2 
extracellular domain (subdomain II) than trastuzumab [42] and prevents HER2 from dimerizing 


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with other ligand-activated HER receptors, most notably HER3 [43, 44].  Adding pertuzumab to 
combination therapy has led to improved PFS in patients with HER2 metastatic breast cancer 
(MBC) and higher RR in pre-operative setting[45]. The clinical evaluation of pertuzumab and 
trastuzumab (CLEOPATRA) assessed the efficacy and safety of pertuzumab plus trastuzumab 
and docetaxel, as compared with placebo plus trastuzumab and docetaxel (control group), as 
first-line treatment for patients with HER2+ MBC who had not received chemotherapy or 
biologic therapy for their metastatic disease [42]. Based on an interim analysis (on 43% of the 
total number of events planned for the final analysis), treatment with pertuzumab plus 
trastuzumab and docetaxel compared with the control group resulted in a significant reduction in 
the risk of progression or death, and an increase of 6.1 months in median [42]. The median PFS 
in the control group (12.4 months) was similar to that among HER2+ MBC patients in two other 
randomized studies who were treated with the combination of trastuzumab and docetaxel (11.7 
months[46] and 11.1 months[39]). CLEOPATRA findings suggest that targeting HER2+ tumors 
with two anti-HER2 monoclonal antibodies (dual HER2 targeting) that have complementary 
mechanisms of action results in a more comprehensive blockade of HER2. These findings 
highlight the clinical importance of preventing the ligand-dependent formation of HER2 dimers 
in order to silence HER2 signaling to the greatest extent possible [34, 43]. Pertuzumab received 
approval in the U.S. in 2012 for use in combination with trastuzumab and docetaxel for the 
treatment of patients with HER2+ MBC who have not received prior anti-HER2 therapy or 
chemotherapy for metastatic disease. 
1.4.3 Ado-Trastuzumab Emtansine (T-DM1 [Kadcyla]) 
T-DM1is an antibody-drug conjugate that combines HER2-targeted delivery of the potent 
antimicrotubule agent emtansine (DM1, a derivative of the antimicrotubule agent maytansine), 
with the antitumor activity of trastuzumab [47, 48]. In T-DM1, trastuzumab and DM1 are 
covalently linked via a stable thioether linker (N-maleimidomethyl) cyclohexane-1-carboxylate, 
which is thought to limit the exposure of normal tissue to DM1[49]. Antitumor activity was 
established in a proof-of-concept Phase 2 study of single-agent T-DM1 in patients with HER2+ 
MBC, who had progressed while receiving HER2-directed therapy[50]. Furthermore, in a single-
arm phase 2 study, T-DM1 demonstrated efficacy in patients with HER2+ MBC who previously 
received all standard HER2-directed therapies (trastuzumab, lapatinib, an anthracycline, a 
taxane, and capecitabine) [51]. 
1.4.4 Lapatinib 
Another HER2-targeted agent is lapatinib, an oral, selective, reversible, small molecule that 
targets the tyrosine kinase domains of both HER1 and HER2 [52]. In vitro studies confirmed that 
lapatinib inhibits growth [52]  and can lead to cell arrest or apoptosis[53]  in human tumor cells 
overexpressing HER1 or HER2. Furthermore, lapatinib treatment has been shown to inhibit the 
growth of HER2-overexpressing human breast cancer cells that do not respond to trastuzumab 
after long-term conditioning[54]. Investigations of lapatinib monotherapy conducted in highly 
refractory MBC patients showed modest cytoreduction and disease stabilization in a 
trastuzumab-refractory setting [55]. A randomized phase III clinical trial including women with 
HER2-overexpressing advanced breast cancer who had progressed on a regimen containing 
trastuzumab, showed that lapatinib in combination with capecitabine was superior to 
capecitabine alone[19] This study ultimately resulted in FDA approval for lapatinib in 2007 in 


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combination with capecitabine. Additionally, a Phase III trial showing that lapatinib in 
combination with letrozole, an aromatase inhibitor, was effective in the first-line metastatic 
setting in a subset of 219 patients whose breast cancer was HER-2 positive and hormone receptor 
positive. Median progression-free survival was 8.2 months for those receiving letrozole and 
lapatinib versus 3.0 months for those getting letrozole alone (HR 0.71 [0.53-0.96], p=0.019) 
[27]. 
Currently there is an on-going designated study accessing the tolerance and efficacy of lapatinib 
plus trastuzumab in patients who are 60 and older with locally advanced or metastatic HER2 
overexpressing breast cancer (NCT01273610). 
1.4.5 Neratinib in HER2 Positive Breast Cancer 
Neratinib (PB-272, HKI-272) is a potent irreversible pan–erythroblastic leukemia viral oncogene 
homolog (ERBB) tyrosine kinase inhibitor (TKI) that blocks signal transduction through 3 
epidermal growth factor receptors (EGFRs): EGFR (encoded by ERBB1), HER2 (encoded by 
ERBB2) also known as human epidermal growth factor receptor 2, and HER4 (encoded by 
ERBB4), or their active heterodimers with HER3 (encoded by ERBB3). Treatment with neratinib 
results in sustained inhibition of these growth-promoting pathways in subjects with HER2-
positive or HER2-mutant breast and other cancers due to activating mutations in these ERBB 
genes. The ability of neratinib to concurrently block signal transduction through the three active 
tyrosine kinase HER receptors, and prolong inhibition of these growth-promoting pathways 
provides the opportunity to further improve the clinical benefit of its use in HER+ MBC patients.  
1.4.5.1 Preclinical Data 
Preclinical data suggest that neratinib has antitumor activity in HER1 and/or HER2-expressing 
carcinoma cell lines, with cellular IC50 <100 nM[18]. Neratinib may have advantages over other 
HER2 inhibitors, due to its ability to inhibit both HER1 and HER2, and to inhibit irreversibly. 
Breast cancer cells may become resistant to trastuzumab on the basis of ECD truncated HER2 
receptor, which can no longer be recognized by the antibody[56], or because of co-activation of 
HER1 signaling [57]. However, since neratinib acts on the intracellular tyrosine kinase domain, 
such cells are likely to maintain sensitivity to neratinib [16].  In vivo, neratinib is active in HER2 
and HER1-dependent tumor xenograft models, when administered orally on a once daily 
schedule. Overall, neratinib is less potent against HER1-dependent tumors than HER2-dependent 
tumors in vivo, although it has equivalent activity against the two kinases in vitro. The ability of 
neratinib to specifically inhibit HER1, HER2, and HER4 is unique among the small molecule 
TKIs and contrasts with the effects of the licensed TKIs gefitinib and erlotinib, which target 
EGFR only, and lapatinib, which reversibly targets HER1 and HER2[17]. Additional clinical 
benefit may be derived from agents such as neratinib that concurrently inhibit 3 HER receptors.  
1.4.5.2 Neratinib Pharmacokinetic Data 
Clinical pharmacokinetic (PK) results from the first-in-human study in healthy volunteers and 
subjects with cancer showed that the exposure of neratinib increased in a dose-dependent manner 
after oral administration of neratinib, and no accumulation of neratinib after daily dosing was 
observed when comparing Day 14 exposure with Day 1 exposure. Neratinib is absorbed within 4 
to 6 hours. The half-life of neratinib, approximately 14 hours, supports a once-daily dose 
regimen. Fecal excretion of radiolabeled neratinib accounted for approximately 97% of the total 


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dose administered, and is the major route of elimination. Data suggested no sex-related effect on 
the PK profile of neratinib. Food appeared to increase neratinib Cmax and area under the plasma 
concentration-versus-time curve (AUC) by approximately 2-fold as shown in a food-effect 
assessment of a single ascending dose study with healthy subjects. A study in healthy volunteers 
suggests that severely hepatically-impaired (Child-Pugh C) subjects had statistically significant 
increased exposure and decreased elimination of neratinib. Results of a study with healthy 
subjects to assess the effects of neratinib on cardiac conduction showed that neratinib was not 
associated with prolongation of the QTc interval in humans at the recommended dose of 
neratinib 240 mg daily with food, or under conditions of supratherapeutic plasma concentrations, 
obtained by the concomitant administration of neratinib 240 mg and ketoconazole 400 mg. 
Neratinib interactions with drugs that affect CYP3A4 and Flavin-containing monooxygenases 
(FMO) were not tested, since the metabolites of neratinib are formed by them in vitro. Systemic 
exposure to digoxin increased by 54% for Cmax and 32% for AUC when a single oral dose of 
digoxin 0.5 mg was coadministered with multiple oral doses of neratinib 240 mg compared with 
systemic exposure when digoxin was administered alone. No drug-drug interactions were 
observed when neratinib was concomitantly administered with paclitaxel or vinorelbine. 
1.4.5.3 Overall Safety Profile – Safety Data of Pooled Single-Agent Studies 
Single-agent unblinded safety data is available for 476 patients treated with neratinib (Neratinib 
Investigator brochure).  Overall, 476 subjects with advanced solid tumors received neratinib 
monotherapy at dosages of 240 mg/day in 7 studies. All AEs (all grades and Grades 3), by 
system organ class and preferred term, occurring in at least 10% of subjects with advanced solid 
malignancies who received neratinib monotherapy at 240 mg (N=476) are presented in Table 1. 
The most commonly reported AE of any toxicity grade was diarrhea (88.2%) followed by nausea 
(46.2%), vomiting (35.5%), fatigue (33.6%), and decreased appetite (30.3%). The most 
commonly reported Grade 3 AE was diarrhea (27.1%). 
1.4.5.4 Adverse Events Leading to Treatment Discontinuation 
For subjects with cancer, diarrhea was the most frequently reported AE that led to the 
discontinuation of neratinib treatment. Pooled data on the incidences of AEs that led to 
discontinuation of subjects with advanced solid malignancies in 12 ongoing studies (N=4242 
combined safety population) are summarized in Table 2. The most common AE that led to 
discontinuation was diarrhea (6.1%), followed by vomiting (1.5%) and nausea (1.2%). Grade 3 
AEs that led to discontinuation were reported for 5.8% of the subjects, and Grade 4 AEs were 
reported for 0.5% of the subjects. The most frequent Grade 3 AEs that led to discontinuation 
were diarrhea (2.8%), vomiting (0.6%), ALT increased (0.3%), and fatigue (0.2%). 
1.4.5.5 Diarrhea Prophylaxis in Neratinib Clinical Studies 
Although in earlier Neratinib trials, patients received standard-of-care diarrhea management on 
occurrence of diarrhea, the studies did not mandate concomitant treatment with loperamide or 
other anti-diarrheal agents at the outset of neratinib therapy for prevention of neratinib-related 
diarrhea. In these studies, 28-39% of patients experienced Grade 3 or Grade 4 diarrhea (Table 3). 
In ongoing neratinib clinical studies that are currently enrolling patients with solid tumors, 
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receiving prophylactic antidiarrheal medication in these studies, 12-16% of patients experienced 
Grade 3 or Grade 4 diarrhea. 
 
 
 


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Table 1: Summary of Adverse Events Reported in ≥10% of Subjects With Advanced Solid 
Malignancies Receiving Single-Agent Neratinib (240 mg, All Subjects). Maximum CTCAE Grade by 
Descending Frequency (Safety Population, Pooled Studies) * 
Adverse Events  
Number of Subjects (N=476) 
Grade 1 to 4 
n (%) 
Grade 3 n 
(%) 
Grade 4 n 
(%) 
Any Adverse Event  
 
Gastrointestinal Disorders  
Diarrhea 
Nausea  
Vomiting  
Abdominal Pain  
 
General Disorders And Administration Site Conditions 
Fatigue  
Asthenia  
Pyrexia  
 
Metabolism And Nutrition Disorders  
Decreased Appetite  
Dehydration  
 
Skin And Subcutaneous Tissue Disorders  
Rash  
 
Respiratory, Thoracic And Mediastinal Disorders 
Dyspnea  
Cough  
 
Musculoskeletal And Connective Tissue Disorders  
Back Pain 
 
Investigations  
Weight Decreased 
 
Nervous System Disorders  
Headache 
 
Blood And Lymphatic System Disorders  
Anemia  
464 (97.5) 
 
440 (92.4) 
420 (88.2) 
220 (46.2) 
169 (35.5) 
104 (21.8) 
 
287 (60.3) 
160 (33.6) 
68 (14.3) 
53 (11.1) 
 
214 (45.0) 
144 (30.3) 
52 (10.9) 
 
208 (43.7) 
83 (17.4) 
 
193 (40.5) 
80 (16.8) 
70 ( 14.7) 
 
173 ( 36.3) 
53 ( 11.1) 
 
171 ( 35.9) 
54 ( 11.3) 
 
163 ( 34.2) 
85 ( 17.9) 
 
91 ( 19.1) 
52 ( 10.9) 
205 (43.1) 
 
145 (30.5) 
129 (27.1) 14 
(2.9) 
18 (3.8) 
7 (1.5) 
 
29 (6.1) 
14 (2.9) 
9 (1.9) 
1 (0.2) 
 
43 (9.0) 
17 (3.6) 
17 (3.6) 
 
4 (0.8) 
0 
 
29 (6.1) 
20 (4.2) 
3 ( 0.6) 
 
18 ( 3.8) 
9 ( 1.9) 
 
31 ( 6.5) 
0 
 
12 ( 2.5) 
5 ( 1.1) 
 
13 ( 2.7) 
5 ( 1.1) 
46 (9.7) 
 
4 (0.8) 
3 (0.6) 
1 (0.2) 
1 (0.2) 
0 
 
9 (1.9) 
0 
1 (0.2) 
0 
 
4 (0.8) 
0 
1 (0.2) 
 
0 
0 
 
13 (2.7) 
9 (1.9) 
0 
 
1 ( 0.2) 
0 
 
2 ( 0.4) 
0 
 
8 ( 1.7) 
0 
 
3 ( 0.6) 
1 ( 0.2) 
*Data provided by Puma Biotechnology Inc. (Investigator’s Brochure) 
 
 


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Table 2: Incidence of Adverse Events Leading to Discontinuation Reported in ≥0.1% of Subjects With Advanced 
Solid Malignancies by System Organ Class and Preferred Term. Maximum CTCAE Grades, Descending 
Frequency (Safety Subjects, Pooled Studies)* 
Adverse Events  
Number of Subjects (N=4242) 
Grade 1 to 4  
n (%) 
Grade 3 
 n (%) 
Grade 4 
n (%) 
Metabolism And Nutrition Disorders  
Decreased Appetite  
Dehydration  
 
Musculoskeletal And Connective Tissue Disorders  
Arthralgia  
Muscular Weakness  
Pain In Extremity  
 
Neoplasms Benign, Malignant And Unspecified 
(Incl Cysts And Polyps)  
Metastases To Central Nervous System  
 
Psychiatric Disorders  
Anxiety  
Depression  
 
Renal And Urinary Disorders  
Renal Failure  
 
Vascular Disorders  
Hypertension 
16 (0.4)  
9 (0.2)  
4 (0.1)  
 
16 (0.4)  
3 (0.1)  
3 (0.1)  
3 (0.1)  
 
14 (0.3)  
 
3 (0.1)  
 
12 (0.3)  
4 (0.1)  
3 (0.1)  
 
10 (0.2)  
5 (0.1)  
 
8 (0.2)  
3 (0.1 
5 (0.1)  
1 (0.0)  
2 (0.0)  
 
4 (0.1)  
0  
1 (0.0)  
1 (0.0)  
 
6 (0.1)  
 
1 (0.0)  
 
2 (0.0)  
1 (0.0)  
1 (0.0)  
 
7 (0.2)  
4 (0.1)  
 
2 (0.0)  
1 (0.0) 
0 
0 
0 
 
0 
0 
0 
0 
 
3 (0.1) 
 
0 
 
0 
0 
0 
 
0 
0 
 
0 
0 
*Data provided by Puma Biotechnology Inc. (Investigator’s Brochure) 
Table 3: Diarrhea incidence in neratinib studies without loperamide prophylaxis * 
Studies 
Patients 
Investigational Product 
Patients N 
Grade 3-4 
Diarrhea n(%) 
3144A1-201-
WW 
Locally advanced 
or HER2+ MBC 
neratinib 240 mg 
66 
21 (32%) 
3144A2-3003-
WW 
Locally advanced 
or HER2+ MBC 
neratinib 240 mg (monotherapy arm) 
116 
33 (28%) 
10-005 
Triple-negative 
or HER2+ MBC 
neratinib (240 mg) + 
temsirolimus IV (once per week) 
35 
10 (29%) 
I-SPY2 
HER2+/HR-Breast 
Cancer 
neratinib (240 mg) + 
paclitaxel (once per week) 
116 
45 (39%) 
*Data provided by Puma Biotechnology Inc. (Investigator’s Brochure) 
1.4.6 Clinical Trials of Neratinib 
Neratinib is currently being developed for treatment of HER2-overexpressed or amplified breast 
cancer as well as HER2-mutant breast, non-small cell lung cancer (NSCLC), and other solid 
tumors. Additionally, clinical activity is being evaluated in EGFR mutation-positive and ERBB3 
mutation-positive solid tumors. Thirteen clinical studies are currently ongoing with neratinib 
both administered as monotherapy and in combination with other marketed drugs. Clinical 


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experience with orally administered neratinib is based on information obtained from 31 studies 
conducted with healthy subjects and in subjects with advanced solid tumors, including breast 
cancer and NSCLC. As of 22-AUG-2014, 5089 subjects have been enrolled in neratinib studies. 
Among the subjects enrolled, 476 subjects with locally advanced or metastatic solid 
malignancies have received at least 1 dose of single-agent neratinib at 240 mg administered once 
a day (QD), and approximately 1400 subjects have been dosed with neratinib 240 mg in the 
ongoing study, a randomized, double-blind, placebo-controlled (1:1 ratio) Phase 3 study of 
neratinib after trastuzumab in women with early-stage HER2-positive breast cancer. 
1.4.6.1 Neratinib Single-agent Activity in Patients with HER2+ Breast Cancer 
Early clinical data have demonstrated the activity of neratinib in patients who have already failed 
other small molecule or antibody-based HER2 targeted therapies.  In the single-agent, first-in-
human phase I study of neratinib in solid tumor, a 32% objective response rate (ORR) was 
observed among patients with trastuzumab refractory HER2+ disease [5]. Specifically, 8 of 25 
patients had partial response (PR). Among the responders, two PRs occurred at neratinib doses of 
120 or 180 mg per day, which was below the recommended monotherapy dose. All of these 
responders had prior trastuzumab therapy, notably six patients had received at least four 
trastuzumab-based therapies. Additionally, all had received prior anthracycline and gemcitabine, 
and the majority (7/8) had received prior taxane therapy. Six patients had also received prior 
capecitabine therapy. 
An open-label, multicenter, Phase 2 study evaluated the efficacy and safety of neratinib 240 mg 
daily, in patients with and without prior trastuzumab treatment, who had advanced HER2+ breast 
cancer. The primary end point, the 16-week PFS rates, was 59% and 78% in prior trastuzumab-
treated patients and trastuzumab-naïve cohorts, respectively [4]. The ORR was 24% and 56%, 
respectively, and the median PFS times were 22.3 and 39.6 weeks, respectively. Mean steady-
state trough concentrations for the 240 mg daily dose exceeded concentrations needed to inhibit 
autophosphorylation of HER2 in preclinical models [18]. 
The most common adverse events (AE) were diarrhea, nausea, vomiting, and fatigue. Diarrhea 
was the most frequent Grade 3 to 4 AE, occurring in 30% of patients with prior trastuzumab 
treatment and in 13% of trastuzumab-naïve patients, which resulted in dose reductions of 29% 
and 4% of patients, respectively. However, treatment discontinuation (TD) occurred in only one 
patient due to diarrhea (Grade 2). No neratinib-related Grade 3 or 4 cardiotoxicity was reported. 
Additional information regarding previous clinical studies of neratinib for treatment of HER2+ 
breast cancer is provided in the current Investigator’s Brochure. 
Neratinib was also studied in combination with other agents such as trastuzumab (RR27%) [7], 
vinorelbine (RR 41% in lapatinib naïve patients) [1], paclitaxel (RR 71-77%)[2, 3], temsirolimus 
(RR 18%, CBR 82%)[9] and capecitabine (RR 57-64%) [8] in women with metastatic HER2 + 
breast cancers. A phase III clinical trial of neratinib for the extended adjuvant treatment of breast 
cancer (ExteNET trial) in early stage HER2-positive breast cancer showed promising DFS 
improvement of 33% compared with placebo (p<0.0046) (pending publication). 
1.4.6.2 Neratinib in Activating Somatic HER2 Gene Mutated Breast Cancer (HER2 non-
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Activating somatic mutations in the HER2 receptor have been identified in human breast cancers 
that lack HER2 gene amplification by immunohistochemistry (IHC) or fluorescence in situ 
hybridization (FISH). These patients are not candidates for HER2-targeted drugs under current 
standards of care due to lack of HER2 over-expression, but preclinical data had strongly suggest 
that these patients will benefit from HER2 targeted tyrosine kinase inhibitors. Neratinib could be 
an effective treatment option for breast cancer that carries an activating mutation in the HER2 
gene [58]. Through cancer genome sequencing, HER2 activating somatic mutations have been 
identified.  
Analysis of the data from eight breast cancer genome sequencing projects identified a total of 13 
somatic HER2 mutations, including seven activating mutations such as G309A, D769H, D769Y, 
V777L, P780ins, V842I, and R896C[59].  These mutations of HER2 receptor are highly 
recurrent, with the most common mutations occurring in the residue 309-310 of the extracellular 
domain or the kinase domain [60]. Approximately 1.6% of all newly diagnosed breast cancers 
may harbor a HER2 mutation, and most of these patients do not have HER2 gene amplification 
or overexpression [59]. This percentage might be higher for patients who have relapsed. 
Interestingly, all functionally characterized mutations were sensitive to neratinib, including those 
that rendered cells resistant to lapatinib in vitro [59]. Additional HER2 mutations such as L755S 
were recently identified as a potential target for neratinib [61]. This provides the rationale for 
testing neratinib in patients with HER2 non-amplified breast cancer with identifiable HER2 
activating mutations. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer 
are currently enrolling patients (NCT01670877; NCT01953926).  
We plan to include patients with these HER2-mutated breast cancers in this study. The following 
HER2 gene alterations identified through genomic sequencing (by CLIA certified lab) will fit the 
eligibility criteria: 
Missense substitutions ( G309A, S310F, S310Y, V659E, R678Q, L755S, L755P, E757A, 
D769H, D769Y, G776V, G776C, V777L, L841V, V842I, L869R, R896C ); Insertions/deletions 
(A775_G776insYVMA, G776 insertions, G778_S779insCPG, P780_781insGSP,  ). (Refer to 
unpublished data provided by Puma Technology Inc.). 
1.5 Aging and Decreased Tolerance of Chemotherapy 
Aging brings about a progressive decrease in physiologic reserve that affects each individual at a 
unique pace [47, 48]. The age-related physiological decline in organ systems typically begins in 
the 3rd decade of life and is not evident at times of rest but becomes most apparent when the 
body is stressed. Either cancer or cancer treatment can be considered a physiological stressor, 
and the age-related decrease in physiologic reserve may affect tolerance to cancer treatment. 
Several studies have demonstrated that older adults are more likely to experience chemotherapy 
toxicity, and older adults are at greater risk for myelosuppression, cardiotoxicity, and 
mucositis[62, 63]. Older adults can, in most cases, tolerate chemotherapy in doses and schedules 
similar to those in younger adults, but side effects need to monitored closely and occasionally 
more aggressive prophylactic measures need to be  employed [32].However, most studies to date 
have determined tolerability of cancer therapies in older adults retrospectively rather than using 
prospective interventional trials. With some therapies it has been suggested that a lower starting 
dose in older adults causes less toxicity and does not impact efficacy [35]. 


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A number of age-related changes in drug absorption, distribution, metabolism, and excretion 
with aging may contribute to differences in treatment tolerance between older and younger 
patients. The absorption of drugs can be affected by decreased gastrointestinal motility, 
decreased splanchnic blood flow, decreased secretion of digestive enzymes, and mucosal 
atrophy[21, 36] With the increased use of oral therapy, medication compliance is an important 
issue as well. As a person ages, body composition changes, with an increase in body fat and 
decrease in lean body mass and total body water. The increase in body fat leads to a rise in the 
volume of distribution for hydrophilic drugs. In the population of older adults with cancer, 
malnutrition and hypoalbuminemia may result in an increased concentration of drugs that are 
albumin-bound [22]. 
Physiologic changes with aging, independent of disease, can affect the pharmacokinetics and 
pharmacodynamics of chemotherapy drugs. As one ages, there is a decrease in hepatic and renal 
mass. Autopsy studies demonstrate a decrease in liver volume with aging by approximately 25-
50%. In addition, there is decreased hepatic blood flow, estimated at a 10-15% decrease in liver 
perfusion, even after taking into account the decrease in liver volume [22, 64]. Normal tissues 
may be less able to repair the molecular damage caused by antineoplastic agents due to cellular 
senescence, resulting in greater potential cardiac toxicity, neurotoxicity, mucositis, and 
hematologic toxicities [62]. And finally, there may be age-related changes in the biology of 
cancer which may impact the therapeutic efficacy and approach [25, 26]. These physiological 
changes with aging can affect drug disposition and tolerability to chemotherapy treatment in 
older patients. While several studies have demonstrated that older adults are more likely to 
experience chemotherapy toxicity [63, 65, 66], the comparative risk of targeted therapies has not 
been studied. 
Older adults are an important population to study because 60% of all cancer cases and 70% of 
cancer mortality occur in patients over the age of 65[67]. Furthermore, the number of older 
adults with cancer is expected to rise significantly with the aging of the U.S. population. Older 
adults with cancer are also an understudied population. Accrual of older adults to clinical trials 
has been shown to be significantly lower than their proportion in the general population in both 
an analysis of SWOG trials [68] as well as in studies of drugs approved by the FDA over a seven 
year period [69]. Cancer patients age 70 or greater made up only 20% of participants enrolled in 
FDA registration trials from 1995 to 1999, though they made up fully 46% of the U.S. cancer 
population[15]. 
1.6 Factors Predicting Chemotherapy Tolerance  
1.6.1 Measures of Biological Age 
While certain declines in organ function are universal as the human body ages, the rate of this 
decline and the consequences on everyday function proceed at a unique pace in each individual. 
Therefore, a more detailed evaluation of older adult patients is needed in order to capture factors 
other than chronological age that predict for morbidity and mortality. A comprehensive cancer-
specific geriatric assessment may serve this purpose, and includes an evaluation of functional 
status, other medical conditions, cognitive function, nutritional status, social support, 
psychological state, and a review of medications. Conclusions from several studies have emerged 
regarding the benefits of performing such an assessment. Interventions based on findings from 
such assessments have been shown to predict both survival[70] and toxicity of therapy[71]. 


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Patients who undergo this assessment have also been shown to have better pain control and 
better mental health and well-being[72].  
Among available clinical models, the Cancer and Aging Research Group (CARG) has developed 
a predictive model for chemotherapy toxicity that includes geriatric assessment variables, tumor 
and treatment variables, and laboratory values that independently predict chemotherapy toxicity 
in older patients with cancer[73]. In a CARG multi-center study, 500 older adults with cancer 
with a mean age of 73 years (range, 65 to 91 years) with stage I to IV lung (29%), GI (27%), 
gynecologic (17%), breast (11%), genitourinary (10%), or other (6%) cancer joined this 
prospective study. Patients were deemed by their treating oncologists to be “fit” for the treatment 
prescribed, and received chemotherapy at their oncologist’s discretion. 53% of the enrolled 
patients experienced severe or life-threatening chemotherapy toxicities (Grade 3–5 toxicity as 
determined by the National Cancer Institute, Common Toxicity Criteria for Adverse Events), and 
among this group there was a 2% incidence of treatment-related mortality. A predictive model 
for grade 3 to 5 toxicity was developed that consisted of geriatric assessment variables, 
laboratory test values, and patient, tumor, and treatment characteristics. A scoring system in 
which the median risk score was 7 (range, 0 to 19) and risk stratification schema (risk score: 
percent incidence of grade 3 to 5 toxicity) identified older adults at low (0 to 5 points; 30%), 
intermediate (6 to 9 points; 52%), or high risk (10 to 19 points; 83%) of chemotherapy toxicity 
(P < .001). The assessment of “fitness” based on Karnofsky Performance Status (KPS) 
(Appendix B) did not adequately identify those at risk, but the CARG predictive model 
independently predicted the risk of toxicity[73]. 
Consensus statements now recommend the inclusion of a geriatric assessment as part of the 
evaluation of an older patient[74].  These tools, which include GA items, can be used to assess 
an older adult’s risk of significant toxicity resulting from chemotherapy and assist with the 
discussion of treatment options between the oncologist and patient. However, the biological 
markers of aging were not included in these earlier studies. Therefore, there is an unmet need for 
evaluating blood-based biomarkers as a possible way to identify older adults at risk for 
chemotherapy toxicity and functional decline. In addition, these earlier studies focused on 
chemotherapy toxicity. The association of geriatric assessment and tolerance to biological 
targeted therapy is not adequately studied. 
1.6.2 Biomarkers of Aging: Inflammatory Markers (IL-6, CRP) and a Coagulation Marker (D-
dimer)  
Elevated markers of chronic inflammation such as IL-6 and CRP, and a coagulation factor D-
dimer correlate with aging and functional decline in geriatric patients. Expression of IL-6 and 
CRP increases with aging and can predict age-associated functional decline, increased 
morbidities and mortality [75-78]. Elevated levels of Il-6 and D-dimer at baseline were 
associated with subsequent functional decline and mortality in a cohort of 1723 older adults [79]. 
Furthermore, serum levels of CRP and D-dimer were associated with clinical frailty among 
4,735 community-dwelling adults age over 65 [80]. In the context of cancer, elevated serum IL-6 
correlates with more advanced cancer stage and poorer response to chemotherapy [81]. Plasma 
levels of CRP, which is considered one of the classic markers of systemic inflammation, 
increased rapidly in response to acute inflammation and are moderately increased in response to 
chronic inflammatory disease. Elevated CRP levels at the time of diagnosis of breast cancer are 


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associated with reduced overall and disease-free survival and with an increased risk of death 
from breast cancer [82]. Among patients with operable breast cancer, elevated plasma D-dimer 
levels were associated with lymphovascular invasion, higher clinical stage, and lymph node 
involvement [83]. Based on this growing evidence, we hypothesize that IL-6, CRP, and D-dimer 
may function as biomarkers of aging, potentially predict the risk of toxicity of cancer therapeutic 
in older adults with cancer. 
As part of this study, we will evaluate the association of the geriatric risk score and biomarkers 
of aging (IL-6, CRP and D-dimer), with neratinib toxicity and PK. 
1.7 Neratinib in the Older Patient Population Study Rationale 
With the promising results from multiple clinical trials [1-9], neratinib has the potential to have a 
large impact on the delivery of targeted cancer treatment to the general population. There is 
significant interest in studying this drug among older adults as it is convenient to prescribe and 
easy to administer. However, neratinib appears to have all grades diarrhea rate of 92%. Grade 3-
4 diarrhea was over 30% and dose reduction rate due to diarrhea were 20-53% across 9 trials of 
neratinib therapy (Table 4)[1-9]. This particular side effect is likely to have a great impact in the 
population of older adults.  Due to high rates of all grades diarrhea, there is concern that without 
definitive studies in the older adult population, oncologists may have reservations in giving 
neratinib to elderly patients due to significant GI toxicities, especially diarrhea, or in dose 
reducing the agent without guidance. Currently, of 6 trials of neratinib study with a total 
enrollment of 291 patients, only 38 patients were 65 and older (PUMA Biotechnology Inc. 
provided data). We specifically designed this study to address this important area and develop 
strategies to effectively deliver this potent therapy to older patients. 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
the applicable regulatory requirements.  
Table 4: Common Adverse Effects Occurring in Subjects Receiving Neratinib (N=476)* 
System Organ 
Class  
All 
Causality 
Frequency  
Preferred Term  
N=476 
All grades N 
(%)  
Grade 3/4 N 
(%)  
Gastrointestinal 
disorders 
Very 
common 
Diarrhea  
420 (88.2)  
132 (27.7)  
Nausea  
220 (46.2)  
15 (3.1)  
Vomiting  
169 (35.5)  
19 (4)  
Abdominal pain (includes abdominal pain 
upper/lower, abdominal discomfort, abdominal 
distension) 
170 (35.6) 
9 (1.9) 
Common 
Dyspepsia 
33 (6.9)  
0 (0)  
Skin and 
subcutaneous 
tissue disorders  
Very 
common 
Dermatologic toxicities (includes rash, dry skin, 
pruritus, dermatitis acneiform, erythema, palmar-
plantar erythrodysaesthesia syndrome, alopecia, nail 
disorder, and paronychia  
206 (43.3) 
0 (0) 
General disorders 
and 
administration 
site conditions  
Very 
common 
Fatigue 
160 (33.6)  
14 (2.9)  
Asthenia 
68 (14.3)  
10 (2.1)  


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Metabolism and 
nutrition 
disorders  
Very 
common 
Decreased appetite  
144 (30.3)  
17 (3.6)  
Dehydration  
52 (10.9)  
18 (3.8)  
Nervous system 
disorders 
Very 
common 
Headache 
85 (17.9) 
5 (1.1) 
Blood and 
lymphatic 
disorders 
Very 
common 
Anaemia (includes haemoglobin decreased) 
70 (14.7) 
7 (1.5) 
Investigations  
Common 
Aspartate aminotransferase (AST) increased  
38 (8)  
9 (1.9)  
Alanine aminotransferase (ALT) increased  
38 (8)  
12 2.5)  
* Information provided via Investigator’s Brochure 
2.0 Specific Objectives and Goals 
2.1 Primary Objective 
To estimate the safety and tolerability of neratinib in adults age 60 or older with locally advanced 
or metastatic HER2 over-expressing breast cancer 
2.2 Secondary Objectives 
 To describe the full toxicity profile including all grade toxicities measured by NCI 
CTCAEv.4.0. 
 To estimate the rate of all grades of GI toxicities such as diarrhea, nausea, and vomiting. 
 To estimate the rate of dose reduction, delays and discontinuation related to study drug. 
 To describe pharmacokinetic parameters of neratinib in adults 60 and older. 
 To estimate overall response rate (ORR) and clinical benefit rate (CBR) defined by 
RECIST 1.1. 
 To estimate event free survival (EFS), progression-free survival (PFS) and overall 
survival (OS). 
 To evaluate the role of cancer-specific geriatric assessment tool in predicting treatment 
toxicities. 
 To estimate adherence rate to neratinib in older adults (percentage of doses of neratinib 
taken). 
 To explore the association of PK parameters and geriatric assessment findings. 
 To explore if serum biomarkers of aging (IL-6, CRP, and D-dimer) are associated with 
treatment toxicities. 
3.0 Study Endpoint 
3.1 Primary Endpoint 
Grade 2 or higher toxicities 
3.2 Secondary Endpoints 
 All grade toxicities as measured by NCI CTCAE v.4.0 
 All grades of GI toxicities such as diarrhea, nausea, and   vomiting 
 dose reduction, holds and hospitalizations  


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 Effect of age on PK parameters:  clearance and volume of distribution and exposure-
response relationships on efficacy and safety of neratinib 
 Response as defined by RECIST 
 EFS (where the event is toxicity or progression), PFS, OS 
 Geriatric assessment score  
 Adherence as defined by pill count  
 IL-6 
 CRP 
 D-dimer 
4.0 Study Design and Schema 
The study will be an open label, single arm, phase II toxicity study of single agent neratinib in 
order to describe the toxicity profile in women age 60 and older with HER2 positive breast 
cancer. We plan to study 40 subjects, stratified by patient age (with at least 5 patients age 75 
years or older, and no more than 15 patients 60-70, in order to assure that we study the entire age 
range of older adults). As diarrhea has been seen with neratinib, we have established additional 
guidelines and criteria which will be used to flag an unexpected number of patients that 
experience grade 3 diarrhea within the 2 cycles on neratinib treatment in the presence of 
aggressive mandatory anti-diarrhea management which will lead to a careful data review.  There 
will also be one interim analysis of the toxicity profile after 20 subjects have been on drug for 
one cycle. 
Patients are anticipated to participate in the study for an average of 48 months. This includes 
approximately 0.5 months for screening, an estimated average of 9.5 months for the active 
treatment phase, and an estimated average of 38 months for the long-term follow-up phase. 
Treatment is to be given for as long as it is tolerated and while there is no disease progression. 
Patients who permanently discontinue treatment will enter the long-term follow-up phase until 
death or withdrawal of consent. 
The study schema is shown below: 


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5.0 Patient Eligibility 
5.1 Inclusion Criteria 
1. Female or male patient age > 60 years. 
2. ECOG performance 0-2 (see Appendix A for ECOG criteria) 
3. Life expectancy of greater than 12 weeks. 
4. Histologically or cytologically proven metastatic breast cancer (metastases can be proven 
with imaging results in certain circumstances provided that the initial tumor was 
demonstrated histologically). 
5.  Stage IV Her2/Neu positive breast cancer patients who failed previous anti-HER2 
targeted therapies. 
6. HER2 positivity as defined by ASCO/CAP guidelines. 
7. If HER2 negative by IHC or FISH, but activating somatic mutations of HER2 gene 
identified through genomic sequencing including but not limited to the following (CLIA 
certified lab test): Missense substitutions ( G309A, G309E, S310F, S310Y, S653C, 
V659E, R678Q, V697L, T733I, L755S, L755P,  E757A, D769H, D769Y, D769N, 
G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C ); Insertions/deletions 
(A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC,G776 
insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) 
and/or HER3 activating mutations. There is no limitation on the number of prior lines of 
systemic therapy or HER2-targeted therapies (prior neratinib not allowed). 
8. Both measurable as well as non-measurable disease will be allowed. 
9. Adequate organ and bone marrow functions defined below within 4 weeks of pre-
registration:  
o Hemoglobin: ≥9g/dL (after transfusion, if necessary). 
o Total bilirubin: within normal institutional limits. 


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o AST (SGOT)/ALT (SGPT): ≤ 2.5 X institutional upper limit of normal. 
o Creatinine clearance ≥ 30 mL/min as calculated by Cockroft-Gault 
formula. 
10. Baseline left ventricular ejection fraction LVEF > 50% as evaluated by echocardiogram 
(ECHO) or multiple-gated acquisition scan (MUGA).  
11. All grade >2 toxicities other than alopecia from prior therapy have resolved by the time of 
study commencement. 
12. Patient must have completed radiation therapy with adequate recovery of bone marrow 
and organ functions, before starting neratinib. 
13. Patient with stable or treated brain metastases are eligible. Asymptomatic patients with 
metastatic brain disease who have been on a stable dose of corticosteroids for treatment of 
brain metastases for at least 14 days are eligible to participate in the study. 
14. Provide written, informed consent to participate in the study and follow the study 
procedures. 
5.2 Exclusion Criteria 
1. Prior treatment with neratinib. 
2. Concurrent usage of other investigational agents, chemotherapy, or hormone therapy. 
Prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are 
allowed but all toxicities grade ≥2 must have resolved by the time of study 
commencement (except alopecia). 
3. Any major surgery ≤ 28 days prior to the initiation of investigational products. 
4. Received chemotherapy or biologic therapy ≤ 3 weeks prior to the start of neratinib 
5. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure 
(New York Heart Association functional classification of  ≥2, including individuals who 
currently use digitalis specifically for congestive heart failure ),  unstable angina, 
myocardial infarction within 12 month of enrollment or ventricular arrhythmia. 
6. Concurrent use of digoxin due to cardiac disease. QTc interval ≥450 milliseconds in men 
and ≥ 470 milliseconds in women within 2 weeks of registration or known history of QTc 
prolongation or Torsades de Pointes. 
7. Inability to take oral medication 
8. Other malignancy within the past 3 years with the exception of: a) adequately treated 
basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva 
carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact 
survival during the duration of the study, such as localized transitional cell carcinoma of 
the bladder, or benign tumors of the adrenal or pancreas.  
9. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., 
Crohn’s disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any 
etiology at baseline). 
10. Known clinically active infection with hepatitis B or hepatitis C virus. 
11. Evidence of significant medical illness, abnormal laboratory finding or psychiatric 
illness/social situations that would, in the Investigator’s judgment, makes the patient 
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5.3 Inclusion of Women and Minorities 
The study is open to everyone, regardless of gender or ethnicity. Although majority of the 
participant of this study is women, male patients who meet the inclusion criteria will be offered 
enrollment for participation. Efforts will be made to extend the accrual to a representative 
population, but in a trial which will accrue approximately 40 subjects, a balance must be struck 
between subject safety considerations and limitations on the number of individuals exposed to 
potentially toxic or ineffective treatments and the need to explore gender, racial, and ethnic 
aspects of clinical research.  If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to 
investigate those differences more fully. 
6.0 Screening, Registration, and Follow-up Studies  
6.1 Screening Procedures 
6.1.1 General Guidelines 
Eligible patients will be entered on study at the participating sites and centrally at the City of 
Hope Comprehensive Cancer Center. See Appendix C for Multicenter Guidelines. An Eligibility 
Screening Worksheet is attached as Appendix G. 
Following registration, patients should begin protocol treatment after receiving the oral 
medication and after being told to do so by the study team. Issues that would cause treatment 
delays should be discussed with the Principal Investigator. If a patient does not receive protocol 
therapy following registration, the patient’s registration on the study may be canceled. The Data 
Coordinating Center  should be notified of cancellations as soon as possible. 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will 
be done only after obtaining written informed consent. Studies or procedures that were 
performed within 2 weeks for clinical indications (not exclusively to determine study eligibility) 
may be used for baseline values, even if the studies were done before informed consent was 
obtained. 
6.1.2 Procedure for On-study and Treatment Deviations 
Any amendments to the study protocol need to be approved by the institutional review board 
(IRB) at both the study sponsor site as well as at all participating centers. All deviations or single 
subject exceptions to the study protocol must be reported to the primary IRB of the participating 
site, and to Dr. Yuan Yuan. 
6.2 Informed Consent  
The investigational nature and objectives of the trial, procedures and treatments involved, 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to 
the subject and a signed informed consent will be obtained. Documentation of informed consent 
for screening will be maintained in the subject’s research chart and medical record.   
 
The participating clinicians who are approved at City of Hope must obtain informed consent and 
confirm in the electronic medical record that the patient has received the Notice of Privacy 


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Practice. This must be obtained before confirming eligibility, registration and the subject 
receiving any study treatment.  
 
6.3 Participant Registration 
6.3.1 COH DCC Availability and Contact Information 
Eligible subjects will be registered on the study centrally by the Data Coordinating Center (DCC) 
at City of Hope.  DCC staff is available between the hours of 8:00 a.m. and 5:00p.m. PST, 
Monday through Friday (except holidays).   DCC contact information is as follows: 
 phone: (626) 256-4673 ext. 83968 
 e-mail: DCC@coh.org 
6.3.1 Slot verification and reservation 
As the study nears completion of accrual, study team personnel (including physicians, protocol 
nurses and/or CRCs) may wish to contact the DCC to verify slot availability and to reserve an open 
slot or be placed in queue for slot opening.  Slots may only be held for a limited time which will 
be determined by the PMT. The Data Coordinating Center should be notified of cancellations of 
prospective participants holding slots as soon as possible. 
6.3.2 Registration procedure 
To register a participant, the subsequent procedure is to be followed. 
1. City 
of 
Hope 
staff 
or 
the 
participating 
institution’s 
data 
manager/coordinator/research nurse should contact the DCC via telephone or email 
to provide notification regarding the pending registration and communicate desired 
timeline of the registration, especially if it must be completed promptly. 
2. Documentation of current IRB approval must be on file with the DCC prior to 
registration of patients on this study for participating institutions. 
3. The data manager/coordinator/research nurse should then e-mail copies to 
DCC@coh.org  of the following documents to the DCC:  
o Registration Cover Sheet (Appendix N) 
o Completed Eligibility Criteria List (printed from Section 3.1-2 of 
the protocol) 
o Source documentation to support eligibility criteria**  
o Signed informed consent document 
o Signed HIPAA authorization form (if separate from the informed 
consent document) 
o Signed subject’s Bill of Rights (COH only)  
**For COH participants, provide copies of source documentation only if not readily 
available as a finalized record in the COH EMR  
4. After having received all transferred documentation, the DCC will complete the 
review the documents to verify eligibility, working with the COH staff and/or 


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participating institution as needed to resolve any missing required source elements. 
A subject failing to meet all protocol eligibility requirements will not be registered.  
5. Once eligibility has been confirmed, DCC staff will register the participant by: 
assigning a subject accession number, register the subject on study centrally into 
MIDAS for all outside institutions (the COH CRC will directly accession into 
MIDAS), and enter the subject into the eCRF system, Medidata RAVE. 
6. Once registration has been completed, DCC staff will send a Confirmation of 
Registration Form, including the participant study number and planned start date of 
treatment to:  
o the participating institution’s study team: site PI, treating physician, 
protocol nurse, CRC and pharmacy.   
o the sponsor team: (Dr. Yuan, Dr. Blanchard, COH CRN and COH 
CRC).  
6.4 Dose Assignment 
Study patients will receive the same initial dose of study agents (see Section 7.0). Dose reductions 
can occur if medically necessary as described below (see Section 8). 
7.0 Study Treatment Protocol 
7.1 Treatment Overview 
Treatment will be administered in an outpatient setting. 
7.1.1 Neratinib  
7.2 Neratinib investigational product will be supplied as 40 mg film-coated tablets 
packaged in bottles with desiccant. Neratinib (240 mg initial dose; provided as six 40 
mg tablets) will be self-administered orally by patients on a daily basis, starting with 
Cycle 1/Day 1. Neratinib must be taken with food, in the morning. Neratinib is to be 
taken continuously in 28-day cycles, with no rest between cycles. Doses missed for 
toxicity will not be made up. Dose Adjustment 
Management and dose modification associated with adverse events are outlined in Section 8. 
7.3 Planned Duration of Therapy 
The treatment will be continued until one of the following occurs: 
 Progression of disease. 
 Concurrent illness that prevents further administration of treatment.  
 Unacceptable adverse event(s) as defined in Section 6 below.  
 Patient decides to withdraw from the study. 
 General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
7.4 Criteria for Removal from Treatment 
 Adverse Events. 


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 Current illness that prevents further administration of treatment. 
 General or specific changes in the patient's condition which render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 Clinical disease progression confirmed by imaging. 
 Withdrawal of consent. 
7.5 Subject Follow-Up 
Throughout the study, reconciliation will be made between the amount of investigational product 
supplied, dispensed, returned, and subsequently destroyed or returned to IDS pharmacy. All 
investigational products that were supplied by the sponsor will be returned to IDS pharmacy, or 
destroyed at the site in accordance with COH guidelines. Individual patient dosing compliance 
should be reviewed at each study visit by study site staff. If patient non-compliance is noted, the 
patient should be re-instructed regarding proper dosing procedures in order to continue in the 
study. If repeated non-compliance is noted, additional steps may be taken, including withdrawal 
of the patient from the study. Subjects will be followed for toxicity outcomes for an additional 30 
days after stopping the drug and until resolution of all grade >2 toxicities. Patients removed from 
study for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event, even after disease progression is noted. All patients will be passively followed 
until death, though active follow-up will cease upon removal from study. 
7.6 Supportive Care, Other Concomitant Therapy, Prohibited Medications 
All concomitant treatments, therapies and medications will be captured from the signing of the 
ICF until the end of the treatment. This will include the start date, stop date, generic name, route 
of administration, dose and indication for treatment. At screening, patients will be asked what 
medications they have taken during the last 30 days, which medications are ongoing at the time 
of screening, any medical conditions that require medication, and all prior cancer therapies. At 
each subsequent study visit, patients will be asked what concomitant medications they are 
currently taking. 
All concomitant medications taken during the study treatment will be recorded in the Case 
Report Form. The minimum requirements are drug name and dates of administration. All 
prescription and over-the-counter medications that have been taken within one month prior to the 
first dose of investigational treatment should also be reported in the Case Report Form. Patients 
should receive full supportive care during the study, including treatment with antibiotics, 
antiemetics, blood transfusions, antidiarrheals, and analgesics as appropriate, with the exception 
of drugs listed in Section 7.6.3 and 7.6.4. 
7.6.1 Required Concomitant Treatment 
7.6.1.1 Loperamide Antidiarrheal Therapy 
Diarrhea is the major dose-limiting toxicity of neratinib with onset typically occurring early in 
the course of treatment (during the first few weeks). Primary prophylactic use of antidiarrheal 
medication is mandatory for all enrolled patients in the neratinib study.  
Loperamide is the recommended standard therapy to treat diarrhea in this study. If alternative 
antidiarrheal medication is proposed, this should be discussed with the PI and the reason 
documented in the source documents. Second-line antidiarrheal treatments and adjunctive 


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therapies (i.e., octreotide [SANDOSTATIN®]) (or equivalent as approved by the PI) are also 
recommended for use when appropriate. 
All patients are required to receive intensive diarrhea prophylaxis:   
 For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered 
orally by patients 3 times a day (total 12 mg a day). The initial dose of loperamide 4 mg 
will be self-administered orally with the first dose of neratinib.  
 After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered 
orally twice a day (total 8 mg a day) through the first cycle of therapy (Day 28) from start 
of neratinib dosing.  
 Thereafter, loperamide will be administered as needed (not to exceed 16 mg per day). 
The goal is to titrate to 1-2 bowel movements a day. Recommended loperamide dosing is 
listed below in Table 5.  
 
Table 5: Loperamide Dosing  
Day 
Loperamide Dose 
1 
4mg at time of first dose of neratinib, then 12mg in 3 divided dose 
of 4mg tid 
2-14 
Daily dose of 12 mg in 3 divided doses of 4 mg tid 
15-28 
Daily dose of 8 mg in 2 divided doses of 4 mg bid 
29+ 
Daily dose as needed (not to exceed 16 mg per day)  
 
Patients must use a diary to record intake of loperamide. Loperamide pill counts will be 
conducted during the first 2 cycles (56 days) of therapy. 
Loperamide Dose Adjustment: 
Patients are expected to take loperamide prophylaxis as directed. However, patients may require 
individualization of loperamide prophylaxis dose (up to a maximum dose of 16mg per day) with 
the goal of titrating to 1-2 bowel movements a day.  
 For patients who develop diarrhea during Cycles 1-2, loperamide should be increased up 
to a maximum of 16 mg a day.  
 If a patient is unable to tolerate loperamide due to symptomatic constipation, loperamide 
should be held until after the first bowel movement and then resumed at a dose reduced 
by one level.  
 For recurrent symptomatic constipation events, hold loperamide until after the first bowel 
movement and then resume at a dose reduced to the next lower dose level.  
 If a patient is unable to tolerate once-daily loperamide due to constipation, hold 
loperamide and discuss subsequent loperamide dosing with the Medical Monitor.  
 Neratinib dosing should continue if loperamide is held.  
Recommended dose reductions for the -1 and -2 dose levels of loperamide are listed in Table 6. 


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Table 6: Loperamide Dose Reduction Levels for Constipation 
Dose Level 
Loperamide Dose 
Tablets/Capsules per Day 
 0 
4 mg TID 
6 tablets/capsules a day 
-1 
4 mg BID 
4 tablets/capsules a day 
-2 
2 mg TID 
3 tablets/capsules a day 
-3 
2 mg BID 
2 tablets/capsules a day 
-4 
2 mg once a day 
1 tablet/capsule a day 
Abbreviations: BID = twice daily; mg = milligrams; TID = three times daily 
The Investigator/study nurse must review with the patient the patient instructions (Appendix 
K) for the management of diarrhea and the Patient Diary (Appendix M) for the patient’s daily 
recording of investigational product during the first 2 cycles, number of stools, and use of 
loperamide and/or other anti-diarrheals. Both the patient and the Investigator/study nurse must 
sign the patient instructions for the management of diarrhea. The Patient Instructions and Patient 
Diary are to be handed to the patient before leaving the site with investigational product on or 
before Cycle 1/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.  
An “Optimal Management of Diarrhea Checklist” (Appendix L)  will be reviewed and signed by 
study investigator or study nurse on Cycle 1 Day1. The study team will call patients at 1day, 2 
days and 3 days after first dose of neratinib to assess tolerance. 
Documentation of any occurrences of stools or diarrhea must be as precise as possible and 
captured in the Patient Diary. For AE recording, documentation of “intermittent” events of 
diarrhea is limited to Grade 1. If events of Grade 1 diarrhea are separated by 3 days without any 
diarrhea, then each event must be documented as separate AEs with corresponding start and stop 
dates. 
The entries on the Patient Diary should be reviewed together with the patient for the first 2 
cycles. If the patient has experienced diarrhea since the last visit, details of the daily number of 
stools provided on the diary help to grade the diarrhea as precisely as possible (per NCI CTCAE 
v.4.0). Also, the daily dose of loperamide (or other anti-diarrheals, if applicable) noted on the 
diary for patients in the neratinib treatment will be reviewed and recorded on the CRF.  
Loperamide will be dispensed directly by the site on or before Cycle 1/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. 
7.6.1.2 Prophylactic dosing instructions for Cycle 1  
 Inform patients that they will experience diarrhea while taking neratinib. 
Administer loperamide:  
o For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be 
self-administered orally by patients three times a day (total 12 mg a day). The 
initial dose of loperamide 4 mg will be  
self-administered orally with the first 
dose of neratinib.  
o After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be 
self-administered orally twice a day (total 8 mg a day) through the first cycle of 
therapy (Day 28) from start of neratinib dosing.  


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o Thereafter, loperamide will be administered as needed (not to exceed 16 mg per 
day).  
o The goal is to maintain the loperamide prophylaxis dose with a goal of titrating to 
1-2 bowel movements a day. 
 For patients who develop diarrhea during Cycles 1, loperamide should be increased up to 
a maximum of 16 mg a day.  
 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 to 8 hours may be added (or equivalent as approved by PI).  
 For Grade 2 diarrhea during Cycle 1 (4 to 6 stools per day above baseline, despite 
intensive loperamide): add lomotil 2.5mg every 6 to 8 hours, consider adding octreotide 
(short-acting) 150 μg subcutaneous [SC] injection 3 times a day, or after initial dose of 
short-acting octreotide, if well tolerated, a single dose of octreotide LAR 20 mg by 
intramuscular injection (equivalent medication may be used with approval of the 
Investigator). For persisting Grade 2 diarrhea during Cycle 1 despite the use of both 
immodium and lomotil: add octreotide as directed above.   
 For Grade 3 diarrhea management during Cycle1: please refer to Table 7 and 8 for dose 
hold and reduction.  
 For Grade 4 diarrhea management during  Cycle 1:  recommend permanently discontinue 
neratinib 
The sites must contact the patient by phone at 1 day, 2 days, and 3 days after the first dose of 
neratinib:  
 To inquire about any diarrhea and about potential AEs; 
 To provide guidance to the patients for immediate and appropriate management of AEs, 
including diarrhea as specified in this protocol;  
 To confirm that patient has loperamide available, in cased needed; 
 To inquire about the first date of neratinib intake; the Investigator/research staff must 
update the electronic CRF (eCRF) within 3 days of receipt of this information.  
(These phone calls are mandatory and must be recorded in the study chart together with 
response from the patient and action taken.)  
 Instruct patients to promptly report diarrhea symptoms.  
 Instruct patient to record the number of stools per day and the dose of anti-diarrheal 
medication taken each for the first 2 cycles. 
7.6.1.3 New onset uncomplicated Grade 1 or Grade 2 diarrhea for 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 until 
resolution of diarrhea. 
Pharmacological Treatment: 


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 Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first bout of 
diarrhea followed by 2 mg (1 tablet/capsule) 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.  
 For patients with persistent Grade 1 diarrhea on loperamide, Lomotil (diphenoxylate 
hydrochloride and atropine sulfate) 1 tablet (2.5 mg) every 6 to 8 hours may be added (or 
equivalent as approved by the Sponsor).  
 For Grade 2 diarrhea (4 to 6 stools per day above baseline, despite intensive antidiarrheal 
therapy), consider adding octreotide (short-acting) 150 μg SC three times daily (TID); or 
after initial dose of short-acting octreotide, if well tolerated, a single dose of octreotide 
LAR 20 mg intramuscular (IM) (equivalent medication may be used with approval of the 
Investigator). 
7.6.1.4 For Grade 3 diarrhea with complicating features (dehydration and or hospitalization) 
Dietetic measures: 
Same as above 
 
Pharmacological treatment: 
 Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first bout of 
diarrhea followed by 2 mg (1 tablet/capsule) 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). 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 to 8 hours may be added (or equivalent as approved by PI).  
 Administer octreotide (150 μg SC tid if dehydration is severe or at the treating 
physician’s discretion, with dose escalation up to 500 μg SC TID).  
 Use IV 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 using the appropriate CRF. 
7.6.2 Permitted Concomitant Treatment 
 Any palliative and/or supportive care for cancer-related symptoms, which are not 
otherwise specified in the list of prohibited medication, is permitted at the Investigator’s 
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 Standard therapies for preexisting medical conditions, medical and/or surgical 
complications and palliation. All medication(s) as well as previous hormonal therapy, 
dose and length of therapy should be recorded in the CRF. 
7.6.3 Concomitant Treatment Prohibited in Combination with Neratinib 
The following treatments are prohibited throughout the duration of the active (treatment) phase 
of the study:  
 Any concurrent chemotherapy, radiotherapy (including palliative radiotherapy), surgery 
related to cancer, anticancer immunotherapy, or other anticancer treatments including 
other investigational agents, megestrol and hormonal agents.  
 Concurrent use of strong CYP3A4 inducers/inhibitors (Appendix F) should be cautiously 
monitored. 
7.6.4 Other concomitant medications with potential for interaction 
Concomitant administration of neratinib and P glycoprotein (P-gp) substrates with a narrow 
therapeutic window should be monitored closely with the exception of loperamide. Co-
administration of neratinib with digoxin could result in increased digoxin levels and associated 
digoxin toxicity. Co-administration of digoxin while patient is on neratinib is prohibited. Refer to 
Appendix D for a list of substrates and inhibitors of P-gp. 
Patients using drugs known to cause QT/QTc prolongation should be monitored closely with 
serial electrocardiograms (ECG) at the Investigator’s discretion. Refer to Appendix E for a 
summary of drugs known to have a risk of causing QT/QTc prolongation, potentially causing 
Torsade de Pointes (TdP). 
Patients should avoid agents known to be strong cytochrome P450 (CYP) 3A4 inducers or 
inhibitors (e.g., ketoconazole) for the duration of the active stage/phase of the study. Patients 
should also avoid grapefruit/grapefruit juice and herbal remedies, including St John's Wort. 
Refer to Appendix F for a list of inhibitors and inducers of CYP isoenzymes.  
Chronic immunosuppressive therapies should be avoided, including systemic corticosteroids. If 
unavoidable, patients taking such agents should be monitored closely. Steroids given for 
physiological replacement, as anti-emetics, or inhaled, as well as short course of oral/topical 
steroids given for allergic reactions or asthma flares, are allowed. 
Patients taking oral coumarin-derivative anticoagulants (i.e., warfarin) should be monitored 
closely and their anticoagulant dose adjusted as needed. 
The solubility of neratinib is pH dependent and treatments that alter gastrointestinal pH such as 
proton pump inhibitors (PPIs), H2-receptor antagonists, and antacids may lower the solubility of 
neratinib. It has been observed that a single 240-mg dose of neratinib combined with 
lansoprazole may decrease neratinib AUC by up to 70%. It is unknown whether separating PPI 
and a neratinib dose reduces the interaction. If an H2-receptor antagonist such as ranitidine is 
required, neratinib should be taken 10 hours after the H2-receptor antagonist dosing and at least 
2 hours before the next dose of the H2-receptor antagonist. If antacids are necessary, the antacid 
dose and the neratinib dose should be separated by 2 to 4 hours. 
 


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7.6.4.1 Additional Studies 
Geriatric assessment(GA):  
The comprehensive geriatric assessment questionnaires are listed in Appendix H (Self Geriatric 
Assessment Measure – Patient Questionnaire) and Appendix I (Healthcare Professional 
Questionnaire). As part of the study initiation, the study team (including PI, nurses, and CRAs) 
will be trained on the use of geriatric assessment questionnaires as well as potential interventions 
based on the results. The GA results will be made available to treating physicians and nurse. The 
individual treating physician will follow up on the GA results using their best clinical judgment. 
Furthermore, if a patient scores 11 or greater (a potential indicator of cognitive impairment) on 
the Blessed Orientation Memory and Concentration Test, the results will be reported to the 
treating physician so that further work-up and treatment can be performed as they deemed 
medically appropriate. Furthermore, if the patient endorses depression or anxiety (score great 
than or equal to 5), the doctor will be notified.  
If patient’s native language was not covered by the current language forms, Geriatric assessment form can 
be omitted with clear documentation. 
 
PK and peripheral blood biomarkers: 
Please refer to Section 11 for PK and peripheral blood biomarkers correlative studies to be 
conducted under this protocol.   
7.7 Laboratory Studies/Monitoring Studies  
7.7.1 Required Clinical, Laboratory and Disease Evaluation at Baseline 
Complete blood count and differential, comprehensive metabolic panel (including sodium, 
potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, ALT, AST, 
alkaline phosphatase, total bilirubin, total protein, and albumin), must be performed within 14 
days of enrolling on trial.  
A full history and physical exam including demographics, medical history, concurrent 
medications, vital signs, height measurement, weight measurement, and performance status 
analysis must be done within one week of enrolling on trial. 
Radiologic evaluation including computed tomography (CT) of the chest, abdomen, and pelvis; 
or combined PET-CT with a diagnostic CT component, must have been performed within 30 
days of study enrollment. If measurable disease is present, tumor measurements must be 
performed and reported from this scan. Central review is not required for treatment decisions in 
individual subjects. 
The patient must complete a Geriatric Assessment prior to starting therapy (see Appendix I). If 
patient’s native language was not covered by the current language forms, Geriatric assessment form can 
be omitted with clear documentation. 
Cardiac imaging (either by echocardiogram or MUGA scan) with a reported left ventricular 
ejection fraction must be obtained within 30 days of study enrollment. Regardless of where the 
baseline evaluation is performed, future cardiac evaluation must be performed using only the 


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same modality as the baseline evaluation. A baseline EKG before starting treatment is also 
required. 
 
7.7.2 Studies Obtained During the Trial 
7.7.2.1 Disease evaluation 
CT scans of the chest, abdomen, and pelvis; or PET-CT with a diagnostic CT component must be 
performed every 12 weeks (±1 week) in the absence of symptoms to document disease response 
or progression. In the presence of symptoms, these tests may be performed at the discretion of 
the treating physician. 
7.7.2.2 Cardiac evaluation 
Echocardiogram or MUGA scan must also be performed every 12 weeks (±1 week) in the 
absence of symptoms. The modality must be the same as the modality used in the baseline 
cardiac evaluation. In the presence of symptoms, or in the setting in which a prior study shows 
an abnormality requiring confirmation, echocardiogram or MUGA will be done at the discretion 
of the treating physician. 
Complete blood count with differential and complete metabolic panel must be performed every 
four weeks (+/- 1 wk). If screening laboratories are performed within 14 days of the first study 
treatment, repeat laboratory tests will not be required before Week 1, Day 1. 
7.7.2.3 Pharmacokinetics 
Please refer to section 11.1 for details of sample collection, labeling, storage. Shipping, 
and analysis of PK samples. 
 
7.7.2.4 Peripheral Blood Biomarkers Predicting Chemotherapy Tolerability 
Please refer to section 11.2 for details of sample collection, labeling, storage and analysis of 
peripheral blood biomarker samples . 
 
7.7.3 Monitoring Studies 
7.7.3.1 Toxicity Evaluation 
Because early toxicity is common during cycles 1 and 2 with neratinib, patients will have a 
focused visit with a study nurse to evaluate for new toxicities (Week 2, Week 3). A complete 
case report form is not required for these short visits, which are designed to ensure that 
interventions may occur should toxicity be apparent. 
7.7.3.2 Adherence Evaluation 
Adherence to neratinib will be measured by pill count every 4 weeks during the first five cycles 
during the investigator assessment, and every twelve weeks thereafter, as well as by patient self-
report in dedicated patient diaries evaluated at the same time as pill count. In the event of 
discrepancy in these two measures of adherence, we will follow whichever indicates the lower 
measure of adherence (i.e. if patient states they took 26 of 28 doses, but only 20 doses are 


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missing, we will count the patient as having taken only 20 days. Alternatively, if 26 doses are 
missing, but the patient stated she only took 20 doses, we will count the patient as having taken 
only 20 doses.) All toxicity related dose interruptions or reductions, hospitalizations, and adverse 
events will be noted.  Subjects will be followed for toxicity outcomes for an additional 30 days 
after stopping the drug, and until resolution of all grade >3 toxicities. 
7.7.3.3 Geriatric Assessment 
Geriatric assessment surveys will be administered at baseline(+/- 7 days), after every four cycles, 
cycle 4 day 1(+/- 7 days), cycle 7 day 1(+/- 7 days) and at the end of the study (+/- 7 days) if not 
performed in the previous  month (see Appendix I for Geriatric Assessment Survey). If patient’s 
native language was not covered by the current language forms, Geriatric assessment form can be omitted 
with clear documentation. 
7.7.3.4 Survival Status 
Patients will be followed indefinitely to establish overall survival. All participants enrolled on 
the study will be informed that their medical condition will be followed indefinitely. In order to 
obtain survival status on the enrolled patients we will need the patient's first and last name, 
middle initial, social security number, date of birth, and gender. This information will be 
securely transferred to the primary coordinating institution (City of Hope) and will be kept in a 
separate password protected file, which will only be linked for the purpose of establishing 
survivor status. The investigators will utilize the Social Security Death Index and the National 
Death Index to establish survival status. Survival analysis will be conducted once a year. 
8.0 Dose Delays/Modifications for Adverse Events 
Patients will be treated per protocol or until disease progression or withdrawal from treatment 
due to unacceptable adverse events or treatment consent withdrawal. At each study assessment, 
subjects are to be evaluated for evidence of drug-related adverse events. 
In all cases where the subject is withdrawn due to unusual or unusually severe adverse event 
considered related to neratinib, the Investigator must report the withdrawal as a Serious Adverse 
Event. 
Treatment may be delayed for up to 4 weeks, to allow for resolution of toxicity except in the 
event of those toxicities described below in which cases treatment must be discontinued 
permanently (see Table 7). 
Recommended dose reductions for the -1 and -2 dose levels of Neratinib are listed as following:   
Dose level  
 
Neratinib 
Starting dose  
 
240mg 
-1  
 
 
160mg 
-2  
 
 
120mg 
If a dose of neratinib is held, study procedures for that cycle will proceed on schedule as 
planned, without any delay. This also applies to tumor assessments, which should continue to be 
done every 12 weeks, starting from the first dose of neratinib until the first planned tumor 
assessment at 12 weeks (±1wk), and then after every subsequent 12 weeks (±1week) of treatment 
regardless of any changes in dose or occurrence of AEs. Missed dose(s) of neratinib (i.e., any 


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dose that is not administered within the protocol-defined administration window) will not be 
made up. The dose adjustment guidelines represent the minimum set of measures that 
investigators must follow. However, additional measures may be taken as necessary, for certain 
patients per the Investigator’s medical judgment. All dose modifications/adjustments should be 
documented in the patient’s source file. 
Once neratinib dose has been reduced for a patient, all subsequent cycles must be administered at 
that dose, unless further dose reduction is required. Dose re-escalation is not permitted. 
If a patient developed AE requiring dose reduction while on neratinib dose level of 120mg, 
neratinib will be discontinued.  
8.1 General Toxicities 
Detailed guidelines for dose adjustments of neratinib for general toxicities (exclude alopecia) are 
shown in Table 7. Grade 2 or 3 toxicities that are unrelated to neratinib will be excluded from 
the dose adjustment. 
8.2 Gastrointestinal Toxicity 
Neratinib dose adjustment guideline is listed in Table 8.  
8.3 Pulmonary Toxicity 
Guidelines for adjusting doses of neratinib in the event of pulmonary toxicity are shown in Table 
9. 
Interstitial lung disease, which can sometimes be fatal, has been reported with other oral tyrosine 
kinase inhibitors that target HER1 ± HER2, including lapatinib, gefitinib and erlotinib. Rare 
cases of pneumonitis (0.6%) and lung infiltration (0.4%) have been reported in patients treated 
with neratinib monotherapy, and were considered drug-related. Patients receiving neratinib 
should be monitored for acute onset or worsening of pulmonary symptoms such as dyspnea, 
cough and fever and treated appropriately. 
 
Table 7: General Toxicities Requiring Dose Adjustment of Neratinib* 
NCI CTCAE v.4.0 
Action 
Grade 3 adverse reaction 
1st appearance 
Hold neratinib until event resolves to Grade ≤1; then resume neratinib at one dose level 
lower, lowest dose of neratinib is 120mg.  
2nd appearance 
Hold neratinib until event resolves to Grade ≤1; then resume neratinib at one dose level 
lower, lowest dose of neratinib is 120 mg   
3rd appearance 
Discontinue neratinib permanently. 
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Any 
Discontinue neratinib permanently.   
Based on NCI CTCAE v.4.0: National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. 
* Grade 2 or 3 toxicities that are unrelated to neratinib will be excluded from the dose adjustment. 
 
 
Table 8: Gastrointestinal Toxicities Requiring Dose Adjustment of Neratinib 
NCI CTCAE v.4.0 
Actions 
Grade 1 Diarrhea: Increase of ≤3 stools per 
day over baseline. 
OR 
Grade 2 Diarrhea: Increase of 4-6 stools 
per day over baseline. Lasting ≤5 days 
Adjust antidiarrheal treatment per the guidelines for management 
of diarrhea at the first onset of diarrhea (refer to Section7.6.1.1). 
Instruct patient to follow dietetic recommendations in the 
guidelines for management of diarrhea 
Fluid intake of ~2 L/day should be maintained to avoid 
dehydration. 
 
 
Grade 3 Diarrhea: Increase of ≥7 stools per 
day over baseline; incontinence; 
hospitalization indicated; limiting self-care 
and activities of daily living. Lasting ≤2 
days 
Adjust antidiarrheal treatment per the guidelines for management 
of diarrhea at the first onset of diarrhea (refer to Section 7.6.1.1). 
Hold neratinib until recovery to Grade ≤1 or baseline 
Instruct patient to follow dietetic recommendations of the 
guidelines for management of diarrhea. Fluid intake of ~2 L/day 
should be maintained by IV, if needed. 
If recovery occurs: 
 
≤1 week after withholding treatment, resume neratinib at 
the next reduced dose level 
 
Within 2-4 weeks after withholding treatment, reduce 
neratinib dose at the next lower dose. 
If event occurs a second time and the neratinib dose has not 
already been decreased, reduce neratinib dose to next lower dose 
level.  
If subsequent events occur, reduce the dose of neratinib to the next 
lower dose level. 
Once the event resolved to Grade ≤1 or baseline, start loperamide 
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Grade 3 Diarrhea: lasting >2 days despite 
treatment with optimal medical therapy, or 
associated with fever, dehydration 
OR Any Grade 4 Diarrhea: Life-
threatening consequences: urgent 
intervention indicated. (would recommend 
d/c) 
Recommend permanently discontinue neratinib OR if Investigator 
deems it to be in the patient’s best interest to continue, hold 
neratinib until AE resolved to Grade ≤1; then resume neratinib at 
120 mg.  
Based on NCI CTCAE v.4.0: National Cancer Institute Common Terminology Criteria for Adverse Events Version 
4.0. 
 
 
Table 9: Pulmonary Toxicities Requiring Dose Adjustment of Neratinib 
NCI CTCAE v.4.0 
Actions 
Grade 2 Pneumonitis/Interstitial Lung Disease: 
Symptomatic; medical intervention indicated; 
limiting instrumental activities of daily living. 
Hold neratinib until recovery to Grade ≤1 or baseline.  
Reduce neratinib by one dose level or discontinue neratinib 
per investigator’s best medical judgment. 
Grade 3 Pneumonitis/Interstitial Lung Disease: 
Severe symptoms; limiting self-care activities of 
daily living; oxygen indicated. 
Discontinue neratinib permanently. 
8.4 Liver Toxicity 
Guidelines for dose adjustment of neratinib in the event of liver toxicity are shown in Table 10. 
Abnormal values in alanine transaminase (ALT) concurrent with abnormal elevations in total 
bilirubin that meet the criteria outlined below in the absence of other causes of liver injury are 
considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and should 
always be considered important medical events.  
Patients who experience Grade ≥3 diarrhea requiring IV fluid treatment or any signs or 
symptoms of hepatotoxicity such as worsening of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia should be evaluated for changes in liver function 
tests. Fractionated bilirubin and PT must also be collected during hepatotoxicity evaluation. 
8.5 Left Ventricular Ejection Fraction Toxicity 
Guidelines for dose adjustments of neratinib in the event of abnormalities in LVEF are shown in 
Table 11. LVEF assessments will be performed according to the Schedule of Procedures (refer 
to study calendar). It is strongly recommended to use the same method of cardiac evaluation 
(ECHO or MUGA) at each time point for each patient. 
If a patient has a second episode of asymptomatic decline in LVEF that meets either of the above 
criteria, permanently discontinue neratinib, repeat LVEF in 4 weeks and follow up cardiology 
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Note that, for AEs other than asymptomatic LVEF decline, if neratinib is held for >28 days, the 
patient should be withdrawn from the active treatment phase of the study. In case of 
asymptomatic LVEF decline, patients may resume neratinib within 1 week after LVEF recovery 
is documented as above, even if the timeframe exceeds 3 weeks. 
 
 


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Table 10: Liver Function Test Abnormalities Requiring Dose Adjustment of Neratinib 
NCI CTCAE v.4.0 
Actions 
Grade 3 ALT (>5-20 x ULN) 
or 
Grade 3 bilirubin (>3-10 x ULN) 
Hold neratinib until recovery to Grade ≤1 for patients with ALT Grade ≤1 
at baseline.  
Evaluate alternative causes.  
For patients with ALT ≤ Grade 1 at baseline: Resume neratinib at the next 
lower dose level if recovery to ≤Grade 1 occurs within 4 weeks. 
If Grade 3 ALT or bilirubin occurs again despite one dose reduction, 
permanently discontinue neratinib.  
 
Grade 4 ALT (>20 x ULN) 
or Grade 4 Bilirubin (>10 x ULN) 
Permanently discontinue neratinib. 
Evaluate alternative causes. 
ALT >3 x ULN 
and 
Total bilirubin >2 x ULN 
and 
Alkaline phosphatase <2 x ULN 
(potential Hy’s law indicators of 
drug-induced liver damage) 
Hold neratinib. 
The patient should be evaluated as soon as possible, preferably within 48 
hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical assessment and for 
oncology studies, the possibility of hepatic neoplasm (primary or secondary) 
should be 
considered. In addition to repeating AST and ALT, laboratory tests should 
include albumin, total bilirubin, direct bilirubin, PT and alkaline 
phosphatase. A detailed history, including relevant information, such as 
review of ethanol, concomitant medications, recreational drug and 
supplement consumption, family history, sexual history, travel history, 
history of contact with a jaundiced patient, surgery, blood transfusion, 
history of liver or allergic disease, and work exposure, should be collected. 
Further testing for acute hepatitis A, B, or C infection and liver imaging 
(e.g., biliary tract) may be warranted. All cases confirmed on repeat testing 
as meeting the criteria mentioned above (i.e., ALT >3 x ULN associated with 
bilirubin >2 x ULN and alkaline phosphatase <2 x ULN), with no other 
cause for liver function test abnormalities identified at the time should be 
considered potential Hy’s Law cases, irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal 
liver function tests. Such potential Hy’s Law cases should be reported as 
SAEs.  
Contact the investigator/sponsor immediately to discuss next steps, including 
evaluation of alternative causes, and management of investigational product. 
These events must be reported as SAEs. 
NOTE: During evaluation of hepatotoxicity, bilirubin must be fractionated, PT must be measured, and liver 
imaging should be considered 
 
 


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Table 11: Left Ventricular Ejection Fraction (LVEF) Results Requiring Dose Adjustment of Neratinib for 
NYHA Level 1 (asymptomatic) or Level 2 (symptomatic) drop of LVEF. 
Event on day of scheduled 
Actions 
Asymptomatic absolute decline of 
LVEF ≥10% from baseline OR 
LVEF<50% 
A) If LVEF < 50%: Hold neratinib and seek 
Cardiology consult   
Recheck LVEF in a month,  
- If LVEF remains <50% or confirmed LVEF drop ≥ 10%, stop neratinib 
permanently; 
- If LVEF ≥ 50% and confirmed LVEF drop <10%, resume treatment and 
monitor LVEF every 12 weeks; 
B) If LVEF is ≥ 50%, but LVEF drop ≥10%, Hold neratinib     and repeat 
LVEF in 4 weeks and follow step A 
C) If LVEF ≥ 50%, and  LVEF drop <10%, continue neratinib 
Symptomatic cardiac failure 
Neratinib should be discontinued. 
9.0 Data and Safety Monitoring Plan 
Definition of Risk Level  
This is a Risk Level 4 study as defined in the City of Hope Institutional Data and Safety 
Monitoring Plan [policy dated 07/09/2014].  This determination was made because the study 
involves a City of Hope held IND. 
Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) is responsible for monitoring the data and safety of this 
study.  The PMT consists of the Principal Investigator (PI), Collaborating Investigator, 
CRA/protocol nurse, and Biostatistician.  The PMT is responsible for monitoring the data and 
safety of this study, including implementation of the stopping rules for safety and efficacy. 
 
The PMT is required to submit periodic status reports (i.e., the PMT Report) according to the 
frequency prescribed in the City of Hope Institutional Data and Safety Monitoring Plan [policy 
dated 07/09/2014].  Important decisions made during PMT meetings only need to be noted in the 
PMT Report submitted to the Data and Safety Monitoring Committee (DSMC).   
 
Protocol specific data collection will include the following items: 
After 20 patients have completed one full cycle of therapy, the study team will review the data 
and assess the toxicity profile and rates of dose reduction, delays, interruptions and 
hospitalization related to the agent. Within this interim analysis, a specific review will be made 
of the data for the patients over 75 years of age. Additional guidelines will be used to flag an 
unexpected number of patients that experience symptomatic cardiac toxicity (NYHA Class III or 


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IV if cardiac failure, or Grade 3 or higher by NCI NCTAE v4.0 for other cardiac events), safety 
of neratinib in older adults (using CRFs based on CTCAE v.4.0), efficacy of neratinib in older 
adults (based on imaging using RECIST 1.1 criteria), geriatric assessment of older adults, 
adherence of the population to the oral medication, or cardiac safety in the study population 
(using cardiac imaging).  
 
Adverse Events and Serious Adverse Events 
The PI will be responsible for determining the event name, assessing the severity (i.e., grade), 
expectedness, and attribution of all adverse events. 
 
Adverse Event (AE) - An adverse event is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
 
Reporting Non-serious Adverse Events – Adverse events will be collected after the patient is 
given the study treatment or any study related procedures.  Adverse events will be monitored by 
the PMT.  Adverse events that do not meet the criteria of serious OR are not unanticipated 
problems will be reported only in the PMT Report. 
Serious Adverse Event (SAE) [Modified from the definition of unexpected adverse drug 
experience in 21 CFR 312.32] - defined as any expected or unexpected adverse events that result 
in any of the following outcomes: 
 Death 
 Is life-threatening experience (places the subject at immediate risk of death 
from the event as it occurred) 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation 
of existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the outcomes listed above (examples of such 
events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias of convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or 
drug abuse). 
 
Reporting Serious Adverse Events - begins after study treatment or any study related 
procedures.  All SAEs occurring during this study, whether observed by the physician, nurse, or 
reported by the patient, will be reported according to the approved City of Hope’s Institutional 


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policy [policy effective date:  05/14/14].  Serious Adverse Events that require expedited 
reporting will be submitted electronically using iRIS. 
 
Adverse Event Name and Severity 
The PI will determine the adverse event name and severity (grade) by using the CTCAE version 
4.0.  In addition, New York Heart Association (NYHA) Class III and IV heart failure will be 
captured.  
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event, 
OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event. 
 
Unexpected Adverse Event [21 CFR 312.32 (a)] – An adverse event is unexpected if it is not 
listed in the investigator’s brochure and/or package insert; is not listed at the specificity or 
severity that has been observed; is not consistent with the risk information described in the 
protocol and/or consent; is not an expected natural progression of any underlying disease, 
disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
 
Adverse Event Attribution 
The following definitions will be used to determine the causality (attribution) of the event 
to the study agent or study procedure. 
 
 Definite - The AE is clearly related to the investigational agent or study procedure 
and unrelated to any other cause. 
 
 Probable - The AE is likely related to the investigational agent or study procedure 
and unlikely related to other cause(s). 
 
 Possible -The AE may be related to the investigational agent or study procedure and 
may be related to another cause(s). 
 
 Unlikely -The AE is doubtfully related to the investigational agent or study procedure 
and likely related to another cause(s). 
 
 Unrelated -The AE is clearly not related to the investigational agent or study 
procedure and is attributable to another cause(s). 
COH Held IND 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report 
using the MedWatch Form FDA 3500A for Mandatory Reporting. 


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The criteria that require reporting using the Medwatch 3500A are: 
 Any unexpected fatal or life threatening adverse experience associated with use of the 
drug must be reported to the FDA no later than 7 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(2)] 
 Any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(1)] 
 Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
 
The PI or designee will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  
OIDRA will assist the PI with the preparation of the report and submit the report to the FDA in 
accordance with the approved City of Hope’s Institutional policy [policy effective date:  
05/14/14]. 
 
Deviations and Unanticipated Problems 
Deviation - A deviation is a divergence from a specific element of a protocol that occurred 
without prior IRB approval.  Investigators may deviate from the protocol to eliminate immediate 
hazard(s) for the protection, safety, and well-being of the study subjects without prior IRB 
approval.  For any such deviation, the PI will notify the COH DSMC and IRB within 5 calendar 
days of its occurrence via iRIS in accordance with the Clinical Research Protocol Deviation 
policy [policy effective date:  11/07/11].   
 
It is not a deviation if the participants receive 80% of their assigned dose each cycle unless they 
have had a toxicity or the dose is modified.  
 
Single Subject Exception (SSE) 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific 
procedures called for in a protocol are not in the best interests of a specific patient.  It is a 
deviation that is anticipated and receives prior approval by the PI and the IRB.  The SSE must be 
submitted as a “Single Subject Exception Amendment Request” via iRIS in accordance with IRB 
guidelines and the Clinical Research Protocol Deviation policy [policy effective date:  11/07/11].  
An IRB approved SSE does not need to be submitted as a deviation to the DSMC. 
 
Unanticipated Problem (UP) – Any incident, experience, or outcome that meets all three of 
the following criteria: 
 


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1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure (IB); 
and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcomes may have been 
caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or 
recognized. 
 
Any UP that occurs during study conduct will be reported to the DSMC and IRB in accordance 
with the City of Hope’s Institutional policy [policy effective date:  05/14/14] using iRIS.   
COH Held IND  
The Office of IND Development and Regulatory Affairs (OIDRA) will assist the PI in reporting 
the event to the Food and Drug Administration (FDA). 
Reporting to Puma by the Principal Investigator 
1. Principal Investigator (PI) or designee will inform Puma Pharmacovigilance of all SAEs 
that occur from the time of informed consent through 30 calendar days post last dose of 
neratinib, regardless of attribution/ causality. 
 
A completed MEDWATCH report will be emailed to Puma (PumaSAE@parexel.com) 
on or before the specified timelines listed below: 
 
 All expedited reports sent to the FDA will forwarded to Puma 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), from the time of receipt of the SAE by Institution-
Sponsor.   
 
 Any SAE that do not meet FDA’s criteria for expedited reporting will be 
reported to Puma no later than thirty (30) days from the time of receipt of the 
SAE by Institution-Sponsor. 
 
 Should an Investigator be made aware of any SAEs occurring any time after 
the reporting period that may be causally related to the administration of 
neratinib, it should be promptly reported.  
 
2. The PI or designee will report to Puma aggregate safety information every 3 months at 
the time of the COH PMT report. 
 
Reporting to COH by Puma 


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During the Study and for a period of at least two (2) years following completion or early 
termination of the Study, Puma will report to Institution-Sponsor any new or unexpected 
information about the Study Drug that, in Puma’s sole judgment, may pose a significant health or 
safety risk to Study Subjects or may influence the conduct of the Study. 
 
10.0 Agent Information and Risks 
10.1 Neratinib 
10.1.1 Description 
Generic Name/United States Adopted Name (USAN): Neratinib 
Code Names: PB-272, HKI-272, HKI-272 maleate 
Chemical Abstracts Service Indexed Name: 2-Butenamide, 
N-[4-[[3-chloro-4-(2-pyridinylmethoxy) phenyl] amino]-3-cyano-7-ethoxy-6-quinolinyl]-4- 
(dimethylamino)-, (2E)-, (2Z)-2-butenedioate (1:1). 
The molecular structure of neratinib maleate is shown below: 
The physical, chemical, and pharmaceutical properties of neratinib maleate are listed in Table 
12. 
 
Table 12: Physical, Chemical, and Pharmaceutical Properties of Neratinib 
Molecular Formula  
C30H29ClN6O3∙C4H4O4  
Molecular weight  
673.11  
Appearance  
Off-white to yellow powder  
Solubility in water (room temperature) 
0.4-0.5 mg/mL at pH 5.1  
Dosage form 
Capsules and tablets 
 
Neratinib maleate has been provided as 40 mg immediate release tablets using common 
compendial excipients. Neratinib should be stored at 25°C (77°F) or below; do not freeze. 


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Excursions are permitted to 30°C (86°F). Neratinib should be stored with desiccant. Keep 
containers closed tightly. 
10.2 Adverse Drug Reactions 
Safety results from the completed and ongoing studies show that neratinib is generally well 
tolerated and has a consistent safety profile for subjects with breast cancer or other solid tumors. 
GI disorders accounted for the most frequently reported treatment related adverse effects (AEs). 
Diarrhea was the primary dose limiting toxicity (DLT) in the first in humans Phase 1 study. A 
pooled analysis of 476 subjects with advanced solid tumors who received neratinib monotherapy 
at dosages of 240 mg/day was performed, and the most common AEs were diarrhea (88.2%), 
nausea (46.2%), and vomiting (35.5%). The most commonly reported Grade 3 TEAEs were 
diarrhea (27.1%) and dyspnea (4.2%). Rash, which is associated with the use of other EGFR 
inhibitors, has been reported 17.4% of subjects treated with neratinib monotherapy. 
10.2.1 Diarrhea and Other Gastrointestinal Toxicities 
Diarrhea is the most frequent AE reported with neratinib, both as monotherapy and in 
combination with other drugs. In subjects with cancer, it is the most frequently reported AE 
leading to treatment discontinuation. Treatment-emergent diarrhea of all grades affected 88.2% 
of monotherapy subjects, and was Grade 3 or greater in 27.7%. There were 3 subjects (0.6%) 
who reported Grade 4 diarrhea events and there were no Grade 5 events (Table 3). The Grade 4 
events occurred prior to the implementation of the intensive diarrhea management plan. Other 
specific event terms reported included gastroenteritis (1.1%), colitis (0.2%), enteritis (0.2%), and 
fecal incontinence (0.2%). 
Diarrhea generally occurs early in the course of neratinib treatment. An intensive diarrhea 
management plan with prophylactic use of loperamide is being implemented for all ongoing and 
future neratinib clinical studies to reduce the frequency and severity of diarrhea within the first 
cycle of neratinib treatment. Among subjects receiving loperamide prophylactic antidiarrheal 
medication, 12-16% of subjects experienced Grade 3 diarrhea; no Grade 4 diarrhea were 
reported. In contrast, in studies without diarrhea prophylaxis, 28-32% of subjects experienced 
Grade 3 or Grade 4 diarrhea.  
An updated prophylactic diarrhea management plan has shown promise in reducing the incidence 
and severity of diarrhea resulting from neratinib treatment. Preliminary results suggest that this 
plan, which has been implemented on all Puma-initiated clinical trials of neratinib, reduces the 
frequency of neratinib-related severe diarrhea events. In some cases, treatment interruption, dose 
reduction, antidiarrheal therapy, and, less frequently, treatment discontinuation may be 
necessary. Subjects with diarrhea complicated with vomiting, nausea, or anorexia need closer 
monitoring to ensure adequate hydration and the ability to ingest neratinib. 
The intensive diarrhea management with prophylactic use of loperamide (Section 7.6.1) is 
anticipated to reduce or mitigate the occurrence of diarrhea complications, such as dehydration, 
and to markedly reduce the frequency of dose reduction or drug discontinuation episodes, 
thereby maximizing the likelihood that neratinib-treated subjects will remain on study-directed 
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Other frequent treatment-emergent GI disorders of all grades reported in monotherapy subjects 
include nausea (46.2%), vomiting (35.5%), and abdominal pain (21.8%) ( Table 4). The toxicity 
grades of the vast majority of these events were ≤Grade 2 (61.2%). 
Stomatitis is a general term that includes inflammation and ulceration of the mucosal lining of 
the mouth resulting from any cause. Oral mucositis is the more specific term that is used to 
describe oral mucosal inflammation and ulceration induced by cancer therapies. In general, 
stomatitis events have been reported in 10.7% of subjects who received neratinib as 
monotherapy. The toxicity grades of the vast majority of the events are Grade 1 (9.2%) and 
Grade 2 (1.3%). One (1) subject had a Grade 3 mucosal inflammation that resolved with 
treatment. There were no Grades 4 or 5 and none were reported as serious adverse events. About 
84% resolved without neratinib dose interruption or discontinuation and about 6% resolved with 
treatment interruption. Specific event terms reported included stomatitis (4.6%), mucosal 
inflammation (3.8%), mouth ulceration (1.3%), aphthuous stomatitis (0.8%), mucosal ulceration 
(0.2%), and oral mucosal blistering (0.2%). 
10.2.2 Dermatologic Toxicities 
Dermatologic toxicities associated with EGFR inhibitors include rash, dryness of the skin and 
mucus membranes, hair changes and alopecia, nail changes, and hand and foot reactions. EGFRs 
are expressed in epidermis, the sweat glands, and hair follicles of the skin. EGFR inhibitor-
induced toxicity is believed to be caused by an increase in keratinocyte production that occludes 
skin follicles and impairs their differentiation which causes the outer layers of the skin to shed, 
decreasing skin thickness [84] . Dry skin (xerosis) occurs as a consequence of abnormal 
keratinocyte differentiation, which disrupts thestratum corneum and sebaceous production 
impairing the ability of the epidermis to retain water [85]. Extreme dryness and erythema causes 
fissuring or ulceration of the skin [86]. 
Skin and subcutaneous tissue disorders have been reported in 43.7% of subjects who received 
neratinib as monotherapy. Rash in general has been reported in 19.3% of subjects including 
14.5% reported as Grade 1; there were no events ≥ Grade 3. Specific event terms reported 
included rash (17.4%), rash pustular (0.8%), rash erythematous (0.6%), rash maculo-papular 
(0.4%), rash follicular (0.2%), rash generalized (0.2%), and rash pruritic (0.2%). 
Additional dermatologic toxicity event terms reported included dry skin (8.6%), pruritus (6.3%), 
dermatitis acneiform (5.3%), erythema (4%), palmar-plantar erythrodysesthesia (PPES, i.e. hand-
foot syndrome, 3.2%), alopecia (3.2%), skin fissures (2.3%), acne (1.5%), eczema (1.3%), skin 
ulcer (1.3%), hyperhidrosis (1.3%), night sweats (1.1%), skin exfoliation (1.3%), skin lesion 
(1.1%), and dermatitis (0.8%). Among subjects who received neratinib monotherapy at 240 
mg/day (N=476), PPES has been reported in 3.2% of subjects; the majority of PPES events were 
Grade 1 (1.5%) and Grade 2 (1.7%). 
Alopecia has been reported in 3.2% of subjects who received neratinib as monotherapy, the 
majority of which were Grade 1 (2.5%). 
Paronychia has been reported in 4% of subjects who received neratinib as monotherapy, the 
majority of which were Grade 1 (2.9%), and none were reported as serious. 


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10.2.3 General Disorders (Fatigue and Asthenia) 
Fatigue has been reported in 33.6% of subjects who received neratinib as monotherapy. The 
majority of fatigue AEs was reported as Grade 1 (19.1%), Grade 2 (11.6%), and Grade 3 (2.9%); 
none were Grade 4 or 5. 
Asthenia has been reported in 14.3% of subjects who received neratinib as monotherapy, and the 
majority of those AEs were reported as Grade 1 (7.4%) and Grade 2 (4.8%). 
10.2.4 Metabolic and Nutritional Disorders (Decreased Appetite and Dehydration) 
Many forms of cancer present with a complex metabolic profile characterized by loss of lean 
body mass known as cancer cachexia. Decreased appetite characteristic of cancer cachexia is 
common in subjects with cancer. Approximately half of all subjects with cancer experience 
cachexia with prevalence as high as 86% [87]. 
Decreased appetite has been reported in 30.3% of subjects who received neratinib as 
monotherapy. Dehydration as a complication of diarrhea has been reported in 10.9% of subjects 
on neratinib monotherapy, in particular, when diarrhea is associated with nausea and vomiting. 
The vast majority of these events were ≤Grade 2 (7.1%). 
10.2.5 Nervous System Disorders (Headache) 
Headache is one of the more common side effects of TKIs reported in as much as 37% of 
subjects treated with imatinib and nilotinib[88] [89]. Headache has been reported in 17.9% of 
subjects who received neratinib as monotherapy. The majority of headache AEs was Grade 1 
(14.3%), and the majority was reported as non-serious. 
10.2.6 Hematologic Toxicities  
Overall, hematologic toxicities have been reported in 20.6% of subjects who received neratinib 
as monotherapy. It is subdivided into 3 categories: anemia, leukopenia and neutropenia, and 
thrombocytopenia.  Leukopenic and neutropenic events have been reported in 10.3% of subjects 
who received neratinib as monotherapy. The vast majority of the reports were ≤Grade 2 (8.8%). 
Specific event terms reported included lymphopenia (4.6%), leukopenia (3.2%), neutropenia 
(3.2), WBC count decreased (1.5%), febrile neutropenia (0.2%), and neutrophil count decreased 
(0.2%). Thrombocytopenia has been reported in 1.7% of subjects who received neratinib as 
monotherapy. 
Neratinib preclinical data from a 1-month and a 6-month toxicity study in rats showed decreases 
in parameters of red cell mass (RBCs, hemoglobin, and hematocrit, 4% to 9%). In the clinical 
setting, 19.1% of subjects on neratinib monotherapy presented treatment-emergent blood and 
lymphatic disorders, of which, 3.3% comprised Grade 3 and 4 events (there were no Grade 5 
events). The most frequently reported event was anemia (10.9%), the majority of which were 
Grade 1 (5.7%) and Grade 2 (4%), with 1.3% of subjects reporting Grade 3/4. In addition, 
decreased hemoglobin has been reported in 3.8% of subjects who received neratinib 
monotherapy, the majority of which were Grade 1 (2.3%) and Grade 2 (1.3%). 
 


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10.2.7 Hepatotoxicity 
In general, hepatotoxicity events have been reported in 18.1% of subjects who received neratinib 
as monotherapy. Specific event terms reported included ALT increased (8%), AST increased 
(8%), blood alkaline phosphatase increased (6.9%), gamma-glutamyl transferase (GGT) 
increased (3.4%), hypoalbuminaemia (2.3%), hyperbilirubinaemia (1.7%), ascites (0.8%), 
transaminases increased (0.8%), blood bilirubin increased (0.4%), hepatic failure (0.2%), hepatic 
function abnormal (0.2%), hepatic pain (0.2%), jaundice (0.2%), and varices oesophageal 
(0.2%). The vast majority of these events were ≤Grade 2 (12.8%) with a few Grade 3 (4.8%) and 
1 subject (0.2%) who had Grade 4 events. 
10.2.8 Pulmonary Toxicity 
Dyspnea has been reported in 16.8% of subjects who received neratinib as monotherapy, the 
majority of which were Grade 1 (6.1%) and Grade 2 (4.4%). Uncommon reports of lung 
infiltration (0.2%) and pneumonitis (0.2%) have been received in subjects treated with neratinib 
as monotherapy. Both events were reported as Grade 1. Patients receiving neratinib should be 
monitored for acute onset or worsening of pulmonary symptoms such as dyspnea, cough, and 
fever, and treated appropriately. 
10.2.9 Cardiac Toxicities 
Overall, cardiac toxicities have been reported in 12.6% of subjects who received neratinib 
monotherapy. Cardiac toxicities are divided into 3 categories: cardiac arrhythmia, cardiac failure, 
and ischemic heart diseases. 
Cardiac Arrhythmia events have been reported in 3.6% of subjects who received neratinib 
monotherapy. The majority of the events were ≤Grade 2 (3.1%). Specific event terms reported 
included palpitations (1.1%), tachycardia (0.8%), arrhythmia (0.6%), syncope (0.6%), loss of 
consciousness (0.4%), bradycardia (0.2%), and electrocardiogram abnormal (0.2%) (Data 
provided thorough Neratinib IB). 
Cardiac Failure events have been reported in 6.9% of subjects who received neratinib as 
monotherapy. Specific events reported included oedema peripheral (4.6%), oedema (1.1%), 
ejection fraction decreased (0.6%), left ventricular dysfunction (0.4%), cardiac failure (0.2%), 
and cardiopulmonary failure (0.2%). The majority of the reports were ≤Grade 2 (6.6%) (Table 
13). Guidelines for dose adjustments of neratinib in the event of abnormalities in LVEF are 
provided in study protocols, which include withholding treatment if LVEF is below 50% and 
discontinuation of treatment for symptomatic cardiac failure. Subjects receiving neratinib should 
be monitored for the development of signs and symptoms of congestive heart failure and 
evaluated appropriately. 
Ischemic Heart Disease events have been reported in 3.8% of subjects who received neratinib 
as monotherapy. Specific event terms reported included blood creatine phosphokinase increased 
(1.9%), electrocardiogram T wave abnormal (0.4%), coronary artery stenosis (0.2%), 
electrocardiogram T wave inversion (0.2%), troponin I increased (0.2%), and troponin increased 
(0.2%). The majority of these events are ≤Grade 2. Four (4) cases of angina pectoris (0.8%) have 
been observed in subjects on neratinib monotherapy; all cases were ≤Grade 2 and were non-
serious. In addition, 1 non-serious Grade 2 subendocardial ischemia and 1 serious Grade 4 acute 
myocardial ischaemia have also been reported (Neratinib IB). 


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Table 13. Summary of LVEF Abnormalities, Shift from Baseline in % by Worst On-study Value, Occurring 
in Subjects With Advanced Solid Malignancies Receiving Single-agent Neratinib (240 mg, All Subjects, Safety 
Population, Pooled Studies) 
Baseline LVEF  
Number of Subjects (N =476) 
Worst LVEF% On-Study 
<45% n (%) 
45%-50% n (%) 
50–55% n (%) 
≥55% n (%) 
<45% 
0 
0 
0 
0 
45-50% 
0 
0 
3 (0.6) 
0 
50-55% 
1 (0.2) 
4 (0.8) 
14 (2.9) 
9 (1.9) 
>=55% 
5 (1.1) 
3 (0.6) 
35 (7.4) 
299 (62.8) 
  
11.0 Correlative/Special Studies 
11.1 11.1 PK Analysis 
A population pharmacokinetic-pharmacodynamic analysis of neratinib efficacy and tolerability 
endpoints will be performed in this patient population to assess the variability of neratinib 
concentrations among individuals in the target patient population. Blood samples will be 
collected, processed and stored until analysis.  
PK samples will be collected at the following time points:  Cycle 1 Day 15 pre-dose (± 
20minutes), 6 hours post-dose (60 minutes) and Day 1 Cycle 3 and Day 1 Cycle 4 pre-dose (± 20 
minute) (Table 14). All pre-dose samples should be collected within 30 minutes before the daily 
dose. Patients will be instructed to record the exact time to the minute that the dose was taken on 
these days. In the event that the neratinib dose is held or the dose level is changed, 
pharmacokinetic sample will be rescheduled accordingly.  
Table 14. PK Sample Collection Time Points 
PK sample 
collection 
Cycle 1 Day 15 (±1day) 
 
Cycle 3 Day 1 (±3days) 
 
Cycle 4 Day 1 (±3days) 
 
Collection time Pre-dose  (± 20 minutes); 
6 hours post-dose 
(±60 minutes)  
pre-dose 
(± 20 minutes). 
Pre-dose 
(± 20 minutes). 
At each of the required time points, 10 mL venous blood will be collected into a tube containing 
K2EDTA. Samples will be inverted several times and kept on ice until processing can begin. 
Plasma will be separated from whole blood by centrifugation at 1,500 x g for 10 minutes at 4° C 
and ten approximately equal aliquots (300 uL minimum) will be transferred to appropriately-
labeled polypropylene tubes and maintained on wet ice until frozen at ≤ -70°C until shipping. 
Specimens will be batched at each participating site and stored in freezers at each site. At City of 
Hope, the specimens will be stored in a freezer accessible only to members of the City of Hope 
pharmacokinetic staff working under the auspices of Tim Synold, PharmD. Each tube will be 
labeled with the study number, patient registration number, time point, and the date and time the 
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At end of study, a shipment of frozen serum samples at each site will be packed in the shipping 
container in sufficient dry ice to last at least 3 days (typically 6-8 kg). The container will be 
sealed and shipped along with the packing worksheet via courier to: 
 
Covance Bioanalytical 
3301 Kinsman Blvd. 
Madison, Wisconsin 53704-2523;  
Phone: (608) 230-1691 
Concentrations of neratinib will be measured in plasma with a validated assay method. 
NONMEM, a statistical software program that uses non-linear, mixed effects models to 
determine PK parameters (clearance and volume of distribution), the inter- and intra-patient 
variability and the population variability in the parameter estimates will be used for this analysis. 
Random sources of error, intrinsic factors (e.g., age, sex, race, body weight, liver function and 
renal function) and extrinsic factors (e.g., concomitant medications such as proton pump 
inhibitors, digoxin, or anti-infectives) will be evaluated to identify factors that contribute to the 
observed variability in the PK parameter estimates. 
A population pharmacokinetic-pharmacodynamic analysis of neratinib efficacy and tolerability 
endpoints will be performed in this patient population. The final PK data will be used to generate 
post-hoc neratinib patient-level plasma PK profiles, from which patient-level neratinib area 
under the curve (AUC) and maximum plasma concentration (Cmax) exposure metrics will be 
estimated. Neratinib dose and estimated AUC and Cmax exposure metrics will then be used to 
complete an exploratory data analysis of potential exposure-response relationships for efficacy 
and safety endpoints. 
11.2 Peripheral Blood Biomarkers Predicting Chemotherapy Tolerability 
Peripheral blood biomarkers (IL-6, CRP, D-dimer) analysis will be performed on samples 
collected at baseline after 3 cycles, and at end of study when patient receives geriatric 
assessment. At each of the required time points, two tubes of venous blood (10 mL) will be 
collected into a K2EDTA tube (purple top) and will be transported on ice to Dr. Timothy 
Synold’s laboratory in the 1st floor of the Shapiro Clinical Research Bldg., Room 1042., one for 
peripheral blood biomarkers and one for ctDNA. A medical log will be kept in each laboratory, 
to be filled out by the deliverer of the samples, and signed off by a member of Dr. Synold’s lab. 
A receipt will be made and stored in the patient’s chart for future record keeping. This will 
ensure safety and proper identification of the sample. Plasma will be separated from whole blood 
by centrifugation at 1,500 x g for 10 minutes at 4° C and transferred to appropriately-labeled 
polypropylene tubes and frozen at ≤ -20°C.  Specimens will be batched at each participating site 
and stored in freezers at each site. At City of Hope, the specimens will be stored in a freezer 
accessible only to members of Dr. Synold’s laboratory.  Each tube will be labeled with the study 
number, patient registration number, time point, and the date and time the sample was drawn.  
Peripheral blood biomarkers (IL-6, CRP, D-dimer) analysis will be performed on samples 
collected at baseline after 3 cycles, and at end of study when patient receives geriatric 
assessment. Methods for measuring the three biomarkers are well established with enzyme-
linked immunosorbent assays. For plasma biomarker measurement, 7.5 ml peripheral blood is 


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collected prior to initiation of chemotherapy. Plasma is stored at -80 ºC until assays are run. 
Quantitative IL-6 and CRP levels will be obtained using NOVEX® immunoassay (Invitrogen) 
and D-dimer levels will be measured with Nanopia® D-dimer (Sekisui). 
Circulating DNA fragments carrying tumor-specific sequence alterations (ctDNA) are found in 
the cell-free fraction of blood, representing a variable and generally small fraction of the total 
circulating DNA. Advances in sequencing technologies have enabled the rapid identification of 
somatic genomic alterations in individual tumors, and these can be used to design personalized 
assays for the monitoring of ctDNA. Studies have shown the feasibility of using ct DNA to 
monitor tumor dynamics in a limited number of patients with various solid cancers, but few cases 
of breast cancer have been analyzed [65]. 
 
11.3 Specimen Labeling and Shipping 
Tubes containing plasma samples must be clearly labeled, preferably with a printed label 
containing the following information:  
1) 
An anonymized number that clearly indicates the site at which the sample was accrued 
and processed. For example, samples from City of Hope could be labeled COH001, 
COH002 etc. The Synold lab wishes to remain blinded throughout the duration of this 
study. Therefore, it is the responsibility of each site to maintain a record of the 
anonymized sample numbers sent to the Synold Lab and the patient ID#’s linked to them. 
2) 
Date and time when the patient’s blood draw was performed. 
3) 
The IRB Protocol # associated with the collection of the sample. 
Every 4 months, frozen plasma will be shipped from participating sites to Dr. Synold’s 
laboratory at City of Hope. The specimens will be shipped via FedEx Priority Overnight® 
on dry ice to ensure the specimens remain frozen during transportation. 
 
Dr. Timothy Synold  
Clinical Immunobiology Correlative Studies Laboratory (CICSL) 
Shapiro Building Room 10-12-1044 
City of Hope Comprehensive Cancer Center 
1500 East Duarte Rd. 
Duarte, CA 91010 
 
11.4 Bacteriomic Profiling  
11.4.1 16S Gut Microbiome rRNA analysis 
Fecal samples are relatively easy to collect and non-invasive. They provide an indication of the 
gut microbiome which may be an indicator of general health, impact drug availability, and 
indicate the presence of communities associated with inflammation, digestive inefficiencies, and 
pathogens. Monitoring the gut microbiome may allow us to predict the risk of possible side 
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The exploratory objective to monitor the gut microbiota at baseline, on treatment and end of 
treatment using fecal samples.  The differences in gut microbiota within and between fecal 
samples will be compared using alpha and beta diversity metrics based on 16S rRNA 
sequencing.  
11.4.2 Stool Specimen Collection 
Fecal material will be collected in a Zymo Research DNA/RNA Shield Fecal Collection Tube by 
patients as instructed.  A standard operating procedure (SOP) has been generated for stool 
collection, as outlined in Appendix O. Stool collection kit contents are listed in Appendix Q. A 
copy of this SOP will be provided to the patient and their understanding of the SOP will be 
documented by the PI.   
Samples will be collected pre-treatment (within 7 days prior to start of Neratinib), C1Day 15 (+/-
3 days), C2Day1 (+/-3 days), C2Day15 (+/-3 days), C3Day1 (+/-3 days). Patient will bring 
samples on the scheduled study visits. 
All samples will be collected by participants at home or during study visit. Study team will 
collect the samples and transport to Biospecimen Coordinator in COH Biorepository. 


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12.0 Experimental Design Schema 
 
Pre-Study 
(up to  
28 days 
prior to 
enrolling)i 
Cycle 1 
Day 1 
(28 day  
cycle) 
Cycle 1 
Day 8  
(± 1 day) 
Cycle 1 
Day 15 
(± 1 day) 
Cycle 2  
Day 1  
(± 3 days) 
Cycle 2 
Day 15 
(± 3 days) 
Cycle 3 
Day 1 
(± 3 days) 
Cycle 4 
Day 1 
(± 3 days) 
Cycle 5 
Day 1 
(±3 days) 
Cycle 6  
Day 1 
(±3 days) 
Every 
Cycle  
Thereafter 
(± 3 days) 
Every 3 
cycles 
(±7 
days) 
Off  
Treatm
enth 
Neratinib  
(day 1-7 of each wk) a,b 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Physical exam  (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Vital signs (± 1 wk)  
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (± 1 wk) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Performance Status (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
CBC w/diff, plts (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Complete Metabolic Panelc  
(± 1 wk) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diarrhea Checklist  
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
Nurse brief toxicity 
evaluation 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic samples j 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Adherence evaluation (pill 
count, diaries) (± 1 wk) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event evaluation 
(± 1wk) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Tumor measurements using 
CT or PET-CT (± 1 wk) 
Xd 
 
 
 
 
 
 
X 
 
 
 
Xe 
Xf 
LVEF Assessment 
Xd 
 
 
 
 
 
 
Xe 
 
 
 
Xe 
Xf 
Geriatric Assessment 
Survey(±1 wk) k 
X 
 
 
 
 
 
 
X 
 
 
 
 
Xg 
Peripheral Blood 
Correlativesk 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Bacteriomic profiling 
Xm 
 
 
X 
X 
X 
X 
 
 
 
 
 
 


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a: Dose as assigned; neratinib 240mg orally daily; Doses held due to toxicity will not be made up. 
b: If baseline laboratory tests are done within 14 days of start of treatment, these labs do not need to be repeated prior to Day 1. 
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
d: Baseline assessment may be done up to 30 days prior to study enrollment. 
e: Tumor measurements and LVEF assessment are repeated every 3 months ± 1 wk until patient comes off study. Documentation (radiologic or clinical) must be provided 
for patients removed from study for progressive disease. 
f: Off-study radiologic evaluation will only be done if clinically indicated. 
g: Geriatric assessment will be performed at baseline prior to study, after 3 cycles (±7 days) and at end of study (±7 days). Geriatric assessment will be repeated off study 
ONLY if it had not been administered within the previous month. If patient’s native language was not covered by the current language forms, Geriatric assessment form can 
be omitted with clear documentation. 
h: Patients will be followed for 30 days following discontinuation of therapy in order to capture toxicity attributable to therapy. 
i. Chart review data must be within 28 days to determine if patient meets study criteria. Once patient meets study criteria, then all criteria must be within window specified in 
protocol from Day 1 as indicated in column one in the schema above. 
j: Pharmacokinetics samples will be collected at the following time points:  Cycle 1 Day 15 pre-dose (± 20 minutes) and  6 hours post-dose (± 60 minutes); pre-dose (± 20 
minutes) on Cycle 3 Day 1 and Cycle 4 Day 1.All pre-dose samples should be collected within 30 minutes before the daily dose in 10 ml purple-top tube. 
k: Peripheral blood correlatives for inflammatory marker measurement (IL-6, CRP and D-dimer) and ctDNA will be collected in 10 ml purple-top tube at baseline, after 3 
cycles (Cycle 4 Day 1 ± 7days), and at end of study (±7days) when patient receives geriatric assessment.  
L: An “Optimal Management of Diarrhea Checklist” will be reviewed and signed by study investigator or study nurse on Cycle 1 Day1. The study team will call patients at 
1day, 2 days and 3 days after first dose of neratinib to assess tolerance. 
m. Stool samples must be collected within 7 days prior to start of neratinib, C1Day 15 (+/-3 days), C2Day1 (+/-3 days), C2Day15 (+/-3 days), C3Day1 (+/-3 days). 


 
 
 
 
 
 
 
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13.0 Endpoint Evaluation Criteria/Measurement of Effect 
13.1 Response Criteria  
For the purposes of this study, patients should be reevaluated for response every 12 
weeks. Response and progression will be evaluated in this study using the new updated 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee version 1.1. Per the RECIST criteria, as disease response is not the 
primary endpoint of this trial, confirmatory scans following documentation of 
progression or response will not be required. Rather, progression/response will be 
determined based on results of the single scan. 
Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their 
first treatment with Neratinib. 
Evaluable for objective response: Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
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 >10mm with 
conventional techniques (CT, MRI, or caliper measurement) and as >20mm by chest X-
ray (if clearly defined and surrounded by aerated lung.) Lymph nodes greater than 10mm 
on short axis are considered measureable as well. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <20 mm by chest X-ray or <10 mm using CT, MRI or caliper 
measurement), are considered non-measurable disease. Organomegaly, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI) are all non-
measurable. 
Target lesions: All measurable lesions up to a maximum of two lesions per organ and five 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Lymph nodes less than 15mm in the short 
axis cannot be used as target lesions. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest diameter 


 
 
 
 
 
 
 
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(LD) for all target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference by which to characterize the objective tumor 
response. 
Non-target lesions: All other lesions (or sites of disease) including any measurable 
lesions over and above the 10 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 or absence 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 30 days 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 when both methods have 
been used to assess the antitumor effect of a treatment. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). 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: These techniques should be performed with cuts of 10 mm or 
less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and 
pelvis. Head and neck tumors and those of extremities usually require specific protocols. 
Ultrasound (US): When the primary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated. Their uses in this specific context 
require sophisticated equipment and a high level of expertise that may only be available 
in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in reference centers. However, such 
techniques may be useful to confirm complete pathological response when biopsies are 
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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. 
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. 
13.4 Response Criteria 
13.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Lymph node CR is when 
the lymph node has decreased to less than 10mm in the short axis. 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) 
of target lesions, taking as reference the baseline sum LD. 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started (including 
the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of 
new lesions. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started. 
13.5 Evaluation of Non-Target Lesions (see Table 15) 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level 
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
Incomplete Response (SD): 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. However, unequivocal progression should not 
normally trump target disease status. It must be representative of overall disease status 
change, not a single lesion increase.  
Although a clear progression of non-target lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances. 


 
 
 
 
 
 
 
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13.5.1 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 the smallest measurements recorded since the 
treatment started as reference for progressive disease). The patient's best response 
assignment will depend on the achievement of measurement criteria, but confirmation is 
not necessary. 
 
 


 
 
 
 
 
 
 
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Table 15: Assessment of Best Overall Response Using Target and Non-Target Lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 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. 
13.6 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). 
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. 
13.7 Progression-free Survival 
Progression-free survival is determined programmatically from adjudicated PD, defined 
as the interval from the start of treatment  until the first date on which recurrence, 
progression (per RECIST v1.1) or death due to any cause, is documented, censored at the 
last assessable evaluation, or at the initiation of new anticancer therapy. It is not 
necessary to confirm disease progression. 
13.8 Overall Survival 
Overall survival is defined as the time from the start of treatment to death due to any 
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13.9 Clinical Benefit Rate 
The CBR is defined as the proportion of patients who achieved overall tumor response 
(CR or PR) or SD for at least 24 weeks. Stable disease is measured from enrollment until 
the criteria for disease progression or response are met, per RECIST v1.1  
14.0 Data Reporting/Protocol Deviations 
14.1 Data Reporting 
14.1.1 Confidentiality and Storage of Records 
Electronic Data Collection will be used for this protocol. The data will be stored in 
encrypted, password protected, secure computers that meet all HIPAA requirements. When 
results of this study are reported in medical journals or at meetings, identification of those 
taking part will not be disclosed. Medical records of subjects will be securely maintained 
in the strictest confidence, according to current legal requirements. They will be made 
available for review, as required by the FDA, HHS, or other authorized users such as the 
NCI, under the guidelines established by the Federal Privacy Act and rules for the 
protection of human subjects. 
14.1.2 Subject Consent Form 
At the time of registration, the original signed and dated Informed Consent form, HIPAA 
research authorization form, and the California Experimental Subject’s Bill of Rights (for 
the medical record) and three copies (for the subject, the research record, and the 
Coordinating Center) must be available.  All Institutional, NCI, Federal, and State of 
California requirements will be fulfilled. 
14.1.3 Data Collection Forms and Submission Schedule  
All data will be collected using electronic data collection, stored as indicated in Section 
12.1.1, and submitted according to the timelines indicated in Table 16. 
Table 16: Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 10 calendar days of treatment administration 
Adverse Event Report Forms 
For Cycle 1 only, within 7 calendar days of AE 
assessment/notification; for all other cycles, within 10 
calendar days of AE assessment/notification  
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other 
Assessment 
Forms 
(as 
applicable) 
Within 10 calendar days of the assessment 


 
 
 
 
 
 
 
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Off Treatment/Off Study Forms 
Within 10 calendar days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Forms 
Within 14 calendar days of the protocol defined follow up 
visit date or call 
14.1.3.1 Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research 
associate and signed by an authorized investigator prior to registering the subject.  See 
Section 4.3 for the registration procedure. 
14.2 Protocol Deviations 
14.2.1 Deviation Policy 
This protocol will be conducted in accordance with COH’s “Clinical Research Protocol 
Deviation Policy” located at 
http://www.coh.org/dsmc/Documents/Institutional%20Deviation%20Policy.pdf. 
Deviations from the written protocol that could increase patient risk or alter protocol 
integrity require prior IRB approval of a single subject exception (SSE) request.  In 
addition, if contractually obligated, the sponsor must also approve the deviation.  IRB 
pre-approved SSE protocol modifications are considered an amendment to the protocol 
and not a deviation.  The submission of a deviation report is not required. 
Brief interruptions and delays may occasionally be required due to travel delays, airport 
closure, inclement weather, family responsibilities, security alerts, government holidays, 
etc.  This can also extend to complications of disease or unrelated medical illnesses not 
related to disease progression.  The PI has the discretion to deviate from the protocol 
when necessary so long as such deviation does not threaten patient safety or protocol 
scientific integrity.  Examples include, but are not limited to:  a) dose adjustments based 
on excessive patient weight; b) alteration in treatment schedule due to non-availability of 
the research participant for treatment; c) laboratory test results which are slightly outside 
the protocol requirements but at levels that do not affect participant safety.  These 
instances are considered to be deviations from the protocol.  A deviation report will be 
submitted to the DSMC/IRB within five days. 
14.2.2 Reporting of Deviations 
All deviations will be reported to the COH DSMC within five days.  The DSMC will 
forward to report to the IRB following review. 
14.2.3 Resolving Disputes 
The COH Investigational Drug Service (IDS) cannot release a research agent that would 
cause a protocol deviation without approval by the PI.  Whenever the protocol is 
ambiguous on a key point, the IDS should rely on the PI to clarify the issue. 


 
 
 
 
 
 
 
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In situations where there is misperception or dispute regarding a protocol deviation 
among the persons involved in implementing the protocol, it is the responsibility of the PI 
to resolve the dispute and the PI may consult with the DSMC chair (or designee) to arrive 
at resolution. 
 
15.0 Statistical Considerations 
The study will be an open label, single arm, phase II safety and tolerability study of 
neratinib (240 mg orally daily) in patients age 60 or older with HER2 positive breast 
cancer. As diarrhea has been seen with neratinib, we have established additional 
guidelines and criteria which will be used to flag an unexpected number of patients that 
experience grade 3 diarrhea within the 2 cycles on neratinib treatment in the presence of 
aggressive mandatory anti-diarrhea management which will lead to a careful data review.  
There will also be one interim analysis of the toxicity profile after 20 subjects have been 
on drug for one cycle.  
15.1 Sample Size and Accrual Rate 
Given a sample size of 40 subjects the widest half-width of the 95% confidence limits for 
the rate of grade 2 or higher toxicities will be less than or equal to 0.16. For example if 
we saw a toxicity rate of 0.2 (8 subjects/40) the 95% lower and upper confidence limits 
would be .09 and .36, respectively. With a sample size of 40, we would expect to see 
toxicity that has a true rate of occurrence of 0.05 in 87% of trials.  We expect an accrual 
rate of 3 subjects every 2 months, for a total accrual rate of 18 subjects per year. With this 
rate, the full complement of 40 subjects will be accrued over a 30 month period.  The 
median number of cycles for this patient population is approximately 9, so we would 
expect to complete this study in 42 to 48 months. 
15.2 Interim Analyses and Stopping rules 
15.2.1 Interim Analyses 
After 20 patients have completed one full cycle of therapy, the study team will review the 
data, determine the rate of grade 2 and above toxicities attributed (level possibly and 
above) to neratinib, and assess the toxicity profile in general and specifically look at all 
grades of GI toxicities. We will also estimate the rates of dose reduction, holds, and 
hospitalization related to the neratinib. Within this interim analysis we will include a 
specific review the data from the participants over 75 years of age. 
15.2.2 Stopping Rules (see Table 17) 
As diarrhea has been seen with neratinib, we have established additional guidelines and 
criteria which will be used to flag an unexpected number of patients that experience grade 
3 diarrhea within the 2 cycles on neratinib treatment in the presence of aggressive 
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The risk set to be used in the safety monitoring decision (to trigger a review of the 
protocol) will include all patients that have received the neratinib in the presence of 
aggressive mandatory anti-diarrhea management. 
Every time a patient experience ≥ grade 3 diarrhea within the first 2 cycles on treatment 
in the presence of aggressive mandatory anti-diarrhea management we will look at the 
column for the total number of patients that have experienced this toxicity (X), and 
compare the total number of patients, N, who are in the risk set to NX. If the total number 
of patients, N, is greater than NX, the number given in the bottom row of the table below, 
then accrual will continue.   If N is less than or equal to NX, then the monitoring 
boundary will have been crossed and a careful review of the trial data will be mandated. 
 
Table 17: Criteria for Suspending Accrual to Evaluate Safety 
X: # pts who experience ≥ grade 
3 diarrhea within the first 2 
cycles on neratinib treatment in 
the presence of aggressive 
mandatory anti-diarrhea 
management. 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Nx: safety boundary crossed if # 
patients in risk set  (N) is less 
than or equal to Nx  (if N  Nx) 
≤6 
≤ 11 
≤ 16 
≤20 
≤25 
≤29 
≤34 
≤38 
≤40 
These rules were selected to ensure a low probability that the safety boundary would be 
crossed, indicating excessive ≥grade 3 diarrhea, if the true chance of   ≥grade 3 diarrhea 
were less than 15% and a high probability that the boundary would be crossed if the true 
chance of  ≥grade 3 diarrhea reached 30%. Criteria for flagging an excessive number of 
patients that have toxicity are based on the sequential probability ratio test with a=0.10, 
b=0.10, po=0.15 and pa=0.30. The table below summarizes these probabilities.  The 
values in Table 18 below are based on 10,000 simulations. 
Table 18: Probability of Crossing the Safety Boundary (i.e. too many patients have TOX) 
True Chance of Experiencing  
experience ≥ grade 3 diarrhea within the first 2 cycles on 
neratinib treatment in the presence of aggressive mandatory anti-
diarrhea management. 
5% 
15% 
30% 
50% 
Probability of Crossing the Safety Boundary 
<0.001 
0.07 
0.71 
>.99 
15.3 Data Analysis 
Tables will be created to summarize the toxicities and side effects by organ system, 
attribution and severity for all participants that receive at least one dose of neratinib. 


 
 
 
 
 
 
 
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Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be 
estimated for 1) grade 2 or higher toxicities attributed to neratinib, 2) all grade GI 
toxicities (diarrhea, nausea and vomiting),  3) dose reductions, holds  and 
hospitalizations,  and 4) the objective response  (CR+PR) and clinical benefit  
(CR+PR+SD) and 5) 16 week progression free survival(PFS). EFS, PFS and OS will be 
estimated using the product limit method of Kaplan and Meier. Descriptive statistics will 
be provided for drug adherence and participant demographics.  Serum samples from this 
study will be integrated into a population PK analysis dataset to explore the effects of age 
on PK parameters (clearance and volume of distribution) and exposure-response 
relationships on efficacy and safety of neratinib. Generalized linear models and graphical 
methods will be used to explore factors as identified by a cancer-specific geriatric 
assessment and serum biomarkers that may be predictive of toxicity dose reductions, dose 
holds or hospitalizations. We will use generalized linear models to determine if any of 
these factors independently predict toxicity, response, and/or pharmacokinetic parameters 
of interest. 
16.0 Human Subject Issues 
16.1 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that 
complies with the federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of 
California Health and Safety code, Title 17,  must review and approve this protocol and 
the informed consent form prior to initiation of the study.  All institutional, NCI, Federal, 
and State of California regulations must be fulfilled. 
16.2 Recruitment of Subjects 
Potential research subjects will be identified by a member of the patient’s treatment team, 
the protocol investigator, or research team, from the pool of patients seen by the study 
center with locally advanced or metastatic breast cancer. Potential subjects will be 
contacted by their treating physician and will be referred to the investigator/research staff 
of the study at their institution.  
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of their medical records at the participating institution, provided that the 
investigator/research team is only reviewing records at their home institution, in order to 
further assess eligibility. They will use the information provided by the patient and/or 
medical record to confirm that the patient is eligible and to contact the patients regarding 
study enrollment. If the patient turns out to be ineligible for the research study, the 
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conversation and medical records review, except for any information that must be 
maintained for screening log purposes. 
In most cases, the initial contact with the prospective subject will be conducted by the 
treatment team, investigator, or the research staff working in conjunction with the 
treatment team. The recruitment process outlined presents no more than minimal risk to 
the privacy of the patients who are screened, and minimal PHI will be maintained as part 
of a screening log. For these reasons we seek a limited waiver of authorization for the 
purposes of (1) reviewing medical records to identify potential research subjects and 
obtain information relevant to the enrollment process; (2) conversing with patients 
regarding possible enrollment; (3) handling of PHI contained within those records and 
provided by the potential subjects; and (4) maintaining information in a screening log of 
patients approached (if applicable). Treating physicians will be contacted regarding 
potentially eligible patients, and may then choose whether to offer eligible patients the 
opportunity to participate in the study. The goals of the study will be described and the 
patient will be given a copy of the informed consent to review. The interested patient will 
sign the consent form and retain a copy. 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this 
trial will be done only after obtaining written informed consent. Blood tests that were 
performed within 14 days and radiologic tests performed within 28 days for clinical 
indications (not exclusively to determine study eligibility) may be used for baseline 
values, even if the studies were done before informed consent was obtained.  
16.3 Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, 
lay summary to be posted on City of Hope’s public Clinical Trials On-LineSM website, 
etc., will be reviewed and approved by the IRB prior to their use to recruit potential study 
subjects. 
16.4  Study location and Performance Sites 
This study will be performed at COH including the main campus, South Pasadena and 
Antelope Valley. Other sites may enroll patients onto the research protocol provided that 
this protocol, with site-specific changes only, is approved by each site IRB. All data 
analysis will be performed at City of Hope. 
16.5 Confidentiality  
This research will be conducted in compliance with federal and state of California 
requirements relating to protected health information (PHI). The study will record 
individual response to the study drugs and any side effects, and this will be linked to the 
subject’s identity using a coded study number. The principal investigator, co-
investigators, and laboratory technicians will have access to this information, but all 


 
 
 
 
 
 
 
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information will be treated confidentially. No identifiers will be used in any subsequent 
publication of these results. 
16.6 Financial Obligations and Compensation 
The study drug neratinib will be provided by the manufacturer free of charge to patients 
on this study. Pharmacokinetic lab draws, processing, and results will also be free of 
charge as a part of research. Routine standard of care clinic visits, laboratory tests, and 
tumor imaging will be billed to the patient and/or the patient’s insurance. Cardiac 
imaging will be provided free of charge. Medication and/or treatment needed for side 
effects of study drug will be billed to the patient and/or the patient’s insurance.  
If there is a serious medical complication of the research, treatment will be available at 
City of Hope, but there will be no compensation to the subject for this injury. 
16.7 Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, 
duration, purpose of the study, potential risks, alternatives and potential benefits, and all 
other information contained in the informed consent document. In addition, they will 
review the experimental subject’s bill of rights and the HIPAA research authorization 
form.  Research subjects will be informed that they may withdraw from the study at any 
time and for any reason without prejudice, including as applicable, their current or future 
care or employment at City of Hope or any relationship they have with City of Hope. 
Research subjects will be afforded sufficient time to consider whether or not to 
participate in the research. 
Should sufficient doubt be raised regarding the adequacy of comprehension, further 
clarifications will be made and the questionnaire repeated until a satisfactory result is 
obtained.  Prospective research subjects who cannot adequately comprehend the 
fundamental aspects of the research study with a reasonable amount of discussion, 
education and proctoring will be ineligible for enrollment.  For those subjects who do 
comprehend the fundamental aspects of the study, consent will be obtained and 
documented, followed by eligibility testing.  The research team will review the results of 
eligibility testing and determine if the subject is a candidate for study enrollment.  
17.0 References 
1. 
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the treatment of patients with ErbB2-positive metastatic breast cancer pretreated 
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2. 
Jankowitz, R.C., et al., Safety and efficacy of neratinib in combination with 
weekly paclitaxel and trastuzumab in women with metastatic HER2positive breast 
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Chow, L.W., et al., Combination neratinib (HKI-272) and paclitaxel therapy in 
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Burstein, H.J., et al., Neratinib, an irreversible ErbB receptor tyrosine kinase 
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Wong, K.K., et al., A phase I study with neratinib (HKI-272), an irreversible pan 
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Martin, M., et al., A phase two randomised trial of neratinib monotherapy versus 
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for the treatment of advanced breast cancer: A phase I/II study Journal of Clinical 
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Gandhi, L., et al., Phase I study of neratinib in combination with temsirolimus in 
patients with human epidermal growth factor receptor 2-dependent and other 
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Hurria, A., et al., Developing a cancer-specific geriatric assessment. Cancer, 
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Yancik, R. and L.A. Ries, Aging and cancer in America. Demographic and 
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Horner, M., et al., (eds). SEER Cancer Statistics Review, 1975-2006, National 
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Smith, B.D., et al., Future of cancer incidence in the United States: burdens upon 
an aging, changing nation. J Clin Oncol, 2009. 27(17): p. 2758-65. 
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Talarico, L., G. Chen, and R. Pazdur, Enrollment of Elderly Patients in Clinical 
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Gianni, L., et al., Neoadjuvant chemotherapy with trastuzumab followed by 
adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with 
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controlled superiority trial with a parallel HER2-negative cohort. Lancet, 2010. 
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Gebhart, G., et al., 18F-FDG PET/CT for early prediction of response to 
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de Azambuja, E., et al., Lapatinib with trastuzumab for HER2-positive early 
breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, 
multicentre, phase 3 trial and their association with pathological complete 
response. The Lancet Oncology. 15(10): p. 1137-1146. 
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Geyer, C.E., et al., Lapatinib plus capecitabine for HER2-positive advanced 
breast cancer. N Engl J Med, 2006. 355(26): p. 2733-43. 
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Hurria, A. and S.M. Lichtman, Pharmacokinetics of chemotherapy in the older 
patient. Cancer Control, 2007. 14(1): p. 32-43. 
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Baker, S.D. and L.B. Grochow, Pharmacology of cancer chemotherapy in the 
older person. Clin Geriatr Med, 1997. 13(1): p. 169-83. 
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Vestal, R.E., Aging and pharmacology. Cancer, 1997. 80(7): p. 1302-10. 
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Pharmacokinetics and Pharmacodynamics: Influence of Chronological versus 
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Related Changes in the Pharmacokinetics (pK), Response, and Toxicity of Weekly 
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O'Reilly, S., et al., Malignant lymphomas in the elderly. Clin Geriatr Med, 1997. 
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Johnston, S., et al., Lapatinib combined with letrozole versus letrozole and 
placebo as first-line therapy for postmenopausal hormone receptor-positive 
metastatic breast cancer. J Clin Oncol, 2009. 27(33): p. 5538-46. 
28. 
Morrison, V.A., et al., Approach to therapy of diffuse large B-cell lymphoma in 
the elderly: the International Society of Geriatric Oncology (SIOG) expert 
position commentary. Ann Oncol, 2015. 
29. 
Morrison, V.A., et al., Diffuse large B-cell lymphoma in the elderly: Impact of 
prognosis, comorbidities, geriatric assessment, and supportive care on clinical 
practice. An International Society of Geriatric Oncology (SIOG) Expert Position 
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30. 
Wildiers, H., et al., End points and trial design in geriatric oncology research: a 
joint European organisation for research and treatment of cancer--Alliance for 
Clinical Trials in Oncology--International Society Of Geriatric Oncology position 
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31. 
Launay-Vacher, V., et al., Renal insufficiency in elderly cancer patients: 
International Society of Geriatric Oncology clinical practice recommendations. 
Ann Oncol, 2007. 18(8): p. 1314-21. 
32. 
Lichtman, S.M., et al., International Society of Geriatric Oncology Chemotherapy 
Taskforce: evaluation of chemotherapy in older patients--an analysis of the 
medical literature. J Clin Oncol, 2007. 25(14): p. 1832-43. 
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Extermann, M., et al., Use of comprehensive geriatric assessment in older cancer 
patients: recommendations from the task force on CGA of the International 
Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol, 2005. 55(3): p. 
241-52. 
34. 
Mazzola, R., et al., Capecitabine in combination with oxaliplatin as first-line 
therapy for advanced gastric cancer: a case report. Tumori, 2011. 97(1): p. 115-
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35. 
Bajetta, E., et al., Safety and efficacy of two different doses of capecitabine in the 
treatment of advanced breast cancer in older women. J Clin Oncol, 2005. 23(10): 
p. 2155-61. 
36. 
Yuen, G.J., Altered pharmacokinetics in the elderly. Clin Geriatr Med, 1990. 6(2): 
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Valero, V., et al., Multicenter phase III randomized trial comparing docetaxel and 
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Piccart, M., et al., Everolimus plus exemestane for hormone-receptor–positive, 
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Gajewski, T.F., M.B. Fuertes, and S.R. Woo, Innate immune sensing of cancer: 
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breast cancer. Cancer Discov, 2013. 3(2): p. 224-37. 
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With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase 
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Allen, A., The cardiotoxicity of chemotherapeutic drugs. Semin Oncol, 1992. 19: 
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Hurria, A., et al., Predicting Chemotherapy Toxicity in Older Adults With Cancer: 
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Zhang, G.J. and I. Adachi, Serum interleukin-6 levels correlate to tumor 
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Deangelo, D.J., Managing chronic myeloid leukemia patients intolerant to 
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APPENDIX A: ECOG Performance Status Criteria 
ECOG Performance Status Scale  
Grade 
Criteria 
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: Karnofsky Performance Status Criteria 
Karnofsky Performance Scale  
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
 


 
 
 
 
 
 
 
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APPENDIX C: Multicenter Guidelines 
Responsibility of the Protocol Chair 
 The Protocol Chair will be the single liaison with sponsoring organization. The 
Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments. The protocol must 
not be rewritten or modified by anyone other than the Protocol Chair. There will 
be only one version of the protocol, and each participating institution will use that 
document. The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
 The Protocol Chair is responsible for the overall conduct of the study at all 
participating institutions and for monitoring its progress. All reporting 
requirements to the FDA and Puma Biotechnology Inc. (Puma) are the 
responsibility of the Protocol Chair. 
 The Protocol Chair is responsible for the timely review of Adverse Events (AE) to 
assure safety of the patients. 
 The Protocol Chair will be responsible for the review of and timely submission of 
data for study analysis. 
Responsibilities of the Data Coordinating Center 
 Each participating institution will have an appropriate assurance on file with the 
Office for Human Research Protection (OHRP), NIH. The Data Coordinating 
Center is responsible for assuring that each participating institution has an OHRP 
assurance and must maintain copies of IRB approvals from each participating site. 
 The Data Coordinating Center is responsible for central patient registration of 
patients from participating institutions. The Data Coordinating Center is 
responsible for assuring that IRB approval has been obtained at each participating 
site prior to the first patient registration from that site. 
 The Data Coordinating Center is responsible for the preparation of all submitted 
data for review by the Protocol Chair that has been received by the participating 
institutions. 
 The Data Coordinating Center will maintain documentation of AE reports. There 
are two options for AE reporting: (1) participating institutions may report directly 
to the FDA and Puma with a copy to the Coordinating Center, or (2) participating 
institutions report to the Coordinating Center who in turn report to Puma and the 
FDA. The Data Coordinating Center will submit AE reports to the Protocol Chair 
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 Routine monitoring of data quality will take place for all data received from 
participating institutions. The participating institution will be asked to provide the 
Data Coordinating Center source documentation pertaining to the data collected. 
This information should be de-identified by the participating institution prior to 
faxing to the Data Coordinating Center. 
 Audits may be accomplished in one of two ways: (1) source documents and 
research records for selected patients are sent from participating sites to the Data 
Coordinating Center for audit, or (2) selected patient records may be audited on-
site at participating sites. If the study sponsor chooses to have an audit at the Data 
Coordinating Center, then the Data Coordinating Center is responsible for having 
all source documents, research records, all IRB approval documents, NCI Drug 
Accountability Record forms, patient registration lists, response assessments 
scans, x-rays, etc. available for the audit. 
Inclusion of Multicenter Guidelines in the Protocol 
The protocol must include the following minimum information: 
 The title page must include the name and address of each participating institution 
and the name, telephone number and e-mail address of the responsible 
investigator at each participating institution. 
 The Data Coordinating Center must be designated on the title page. 
 Central registration of patients is required. The procedures for registration must be 
stated in the protocol. 
 Data collection forms should be of a common format. Sample forms should be 
submitted with the protocol. The frequency and timing of data submission forms 
to the Data Coordinating Center should be stated. 
 Describe how AEs will be reported from the participating institutions through the 
Data Coordinating Center. 
Agent Ordering 
 Except in very unusual circumstances, each participating institution will order 
neratinib directly from Puma Biotechnology Inc. 


 
 
 
 
 
 
 
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APPENDIX D: Substrates and Inhibitors of P-glycoprotein (P-gp) a 
P-glycoprotein Substrates 
Amiodarone (eg, Cordarone) 
Fluphenazine (eg, Prolixin) 
Progesterone (eg, Prometrium) 
Chlorpromazine (eg, Thorazine) 
Hydrocortisone (eg, Cortef) 
Promethazine (eg, Phenergan) 
Clarithromycin (eg, Biaxin) 
Indinavir (Crixivan 
Quinidine 
Cyclosporine (eg, Neoral) 
Itraconazole (eg, Sporanox) 
Reserpine 
Dactinomycin (Cosmegen) 
Ketoconazole (eg, Nizoral) 
Ritonavir (Norvir) 
Daunorubicin (eg, Cerubidine) 
Lidocaine (eg, Xylocaine) 
Saquinavir (eg, Fortovase) 
Dexamethasone (eg, Decadron) 
Loperamide (eg, Imodium) 
Sirolimus (Rapamune) 
Digoxin (eg, Lanoxin) 
Lovastatin (eg, Mevacor) 
Tacrolimus (Prograf) 
Diltiazem (eg, Cardizem) 
Mifepristone (Mifeprex) 
Tamoxifen (eg, Nolvadex) 
Doxorubicin (eg, Adriamycin) 
Mitoxantrone (Novantrone) 
Teniposide (Vumon) 
Erythromycin (eg, Ery-Tab) 
Nelfinavir (Viracept) 
Testosterone Delatestryl) 
Estradiol (eg, Estrace) 
Nicardapine (eg, Cardene) 
Trifluoperazine 
Etoposide (eg, Vepesid) 
Nifedipine (eg, Procardia) 
Verapamil (eg, Calan) 
Felodipine (Plendil) 
Ondansetron (Zofran) 
Vinblastine (eg, Velban) 
Fexofenadine (Allegra) 
Paclitaxel (eg, Taxol) 
Vincristine (eg, Vincasar PFS) 
P-glycoprotein Inhibitors 
Amiodarone (eg, Cordarone) 
Indinavir (Crixivan) 
Quinidine 
Atorvastatin (Lipitor) 
Itraconazole (eg, Sporanox) 
Reserpine 
Chlorpromazine (eg, Thorazine) 
Ketoconazole (eg, Nizoral) 
Ritonavir (Norvir) 
Clarithromycin (eg, Biaxin) 
Lidocaine (eg, Xylocaine) 
Saquinavir (eg, Fortovase) 
Cyclosporine (eg, Neoral) 
Mifepristone (Mifeprex) 
Tacrolimus (Prograf) 
Diltiazem (eg, Cardizem) 
Nelfinavir (Viracept) 
Tamoxifen (eg, Nolvadex) 
Erythromycin (eg, Ery-Tab) 
Nicardipine (eg, Cardene) 
Testosterone (Delatestryl) 
Felodipine (Plendil) 
Nifedipine (eg, Procardia) 
Trifluoperazine 
Fluphenazine (eg, Prolixin) 
Progesterone (eg, Prometrium) 
Verapamil (eg, Calan 
Hydrocortisone (eg, Cortef) 
Propranolol (eg, Inderal) 
 
a. 
This list is not all inclusive and may change. 


 
 
 
 
 
 
 
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APPENDIX E: Drugs Associated with Risk of QT/QTc Prolongation 
Leading to Torsade de Pointesc 
Drugs Reported to Prolong QT Interval 
Analgesics 
Celecoxib (Celebrex) 
Methadone (e.g., Dolophine, Methadose) 
Anesthetic agents 
Enflurane (e.g., Ethrane) 
Halothane 
Isoflurane (e.g., Forane) 
 
Antiarrhythmic agents 
Class IA 
Class III 
Disopyramide (e.g., Norpace)* 
Amiodarone (e.g., Cordarone)*b 
Procainamide (e.g., Procanbid)* 
Bretylium* 
Quinidine* 
Dofetilide (Tikosyn)*b 
Class IC 
Ibutilide (Corvert)*b 
Flecainide (e.g., Tambocor)*a 
Sotalol (e.g., Betapace)*b 
Propafenone (e.g., Rythmol)*b 
 
Anticonvulsants 
Felbamate (Felbatol)* 
Fosphenytoin (Cerebyx) 
Antiemetics 
Dolasetron (Anzemet)b 
Droperidol (e.g., Inapsine)*b 
Ondansetron (Zofran) 
Antihistamines 
Desloratadine (Clarinex) (overdose)b 
Fexofenadine (Allegra) 
Diphenhydramine (e.g., Benadryl) 
Hydroxyzine (Atarax) 
Anti-infectives 
Amantadine (e.g., Symmetrel)* 
Macrolides and related antibiotics 
Antimalarials 
Azithromycin (e.g., Zithromax) 
Mefloquine (e.g., Lariam)b 
Clarithromycin (e.g., Biaxin)*b 
Quinine* 
Erythromycin (e.g., Ery-Tab, EES)*b 
Antivirals 
Telithromycin (Ketek)b 
Efavirenz (Sustiva)* 
Troleandomycin 
Azole antifungal agents 
Pentamidine (e.g., Pentam 300, Nebupent)* 
Fluconazole (e.g., Diflucan)*b 
Quinolones 
Itraconazole (e.g., Sporanox) 
Gatifloxacin (e.g., Tequin)*b 
Ketoconazole (e.g., Nizoral) 
Levofloxacin (e.g., Levaquin)*a.b 
Voriconazole (Vfend)b 
Moxifloxacin (e.g., Avelox)b 
Chloroquine (e.g., Aralen)* 
Ofloxacin (e.g., Floxin)*b 
Clindamycin (e.g., Cleocin) 
Sparfloxacin (Zagam)b 


 
 
 
 
 
 
 
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Foscarnet (Foscavir) 
Trimethoprim/sulfamethoxazole (e.g., Bactrim)* 
Antineoplastics 
Arsenic trioxide (Trixenox)*b 
Doxorubicin (e.g., Adriamycin) 
Tamoxifen (e.g., Nolvadex) 
Bronchodilators 
Albuterol (e.g., Proventil)b 
Salmeterol (Serevent) b 
Formoterol (Foradil) b 
Terbutaline (e.g., Brethine) b 
Isoproterenol (e.g., Isuprel) 
 
Calcium channel blockers 
Isradipine (DynaCirc) 
Nicardipine (e.g., Cardene) 
Contrast media 
Ionic contrast media* 
Non-ionic contrast media: Iohexol (Omnipaque) 
Corticosteroids 
Prednisolone (e.g., Prelone) 
Prednisone (e.g., Deltasone)* 
Diuretics 
Furosemide (e.g., Lasix) 
Indapamide (e.g., Lozol) 
Gastrointestinal agents 
Cisapride (Propulsid)*b,c 
Famotidine (e.g., Pepcid)* 
Immunosuppressants 
Tacrolimus (Protopic)* (postmarketing)b 
Miscellaneous 
Levomethadyl 
Papaverine (e.g., Pavaden three times daily [TID])* 
Moexipril/Hydrochlorothiazide (Uniretic) 
Probucol (Lorelco)*c 
Octreotide (Sandostatin)b 
Vasopressin (e.g., Pitressin)* 
Oxytocin (e.g., Pitocin; intravenous bolus) 
 
Psychotropics 
Droperidol (e.g., Inapsine)* 
Primozide (Orap)*b,d 
Trazodone (e.g., Desyrel) 
Haloperidol (e.g., Haldol)* 
Quetiapine (Seroquel)b 
Tricyclic antidepressants 
Lithium (e.g., Eskalith)* 
Risperidone (Risperdal) (overdose)b 
Amitriptyline* 
Maprotiline* 
Serotonin Reuptake Inhibitors (SRIs) 
Clomipramine (e.g., Anafranil) 
Phenothiazines 
Citalopram (e.g., Celexa)* 
Desipramine (e.g., Norpramin)* 
Chrlorpromazine (e.g., Thorazine)* 
Fluoxetine (e.g., Prozac)*a 
Doxepin (e.g., Sinequan)* 
Fluphenazine (e.g., Prolixin)* 
Paroxetine (e.g., Paxil)* 
Imipramine (e.g., Tofranil)* 
Perphenazine 
Sertraline (Zoloft)* (postmarketing)a,b 
Nortriptyline (e.g., Pamelor) 


 
 
 
 
 
 
 
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Thioridazine (Mellaril)* b 
Venlafaxine (Effexor)  b 
 
Trifluopherazine 
Serotonin 5-HT agonists 
Naratriptan (Amerge) 
Sumatriptan (Imitrex) b 
Zolmitriptan (Zomig) b 
Skeletal muscle relaxants 
Tizanidine (e.g., Zanaflex) (animals) b 
*Drug for which Torsades de Pointes has also been reported 
a, Association unclear 
b, QT, QTc and/or Torsades de Pointes association listed in FDA approved product labeling 
Source: Tatro, DS. Drug-induced Prolongation of the QT Interval and Torsades de Pointes. Drug 
Interaction Facts. The Authority on Drug Interactions. Wolters Kluwer Health 2012 
c. This list is not all inclusive and may change. 


 
 
 
 
 
 
 
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APPENDIX F: Inhibitor and Inducers of the Cytochrome A P450 
Isoenzymesa 
CYP3A4 Inhibitors  
Amprenavir 
Grapefruit juice 
Paroxetine 
Anastrozole 
Indinavir 
Propranolol 
Cimetidine 
Itraconazole 
Quinidine 
Clarithromycin 
Ketoconazole 
Quinine 
Clotrimazole 
Mibefradil 
Ranitidine 
Danazol 
Miconazole 
Ritonavir 
Delavirdine 
Mirtazapine (weak) 
Saquinavir 
Diethyldithiocarbamate 
Nefazodone 
Sertraline 
Diltiazem 
Nelfinavir 
Sildenafil (weak) 
Erythromycin 
Nevirapine 
Troglitazone 
Fluconazole 
Norfloxacin 
Troleandomycin 
Fluoxetine 
Norfluoxetine 
Zafirlukast 
Fluvoxamine 
 
 
CYP3A4 Inducers 
Carbamazepine 
Macrolide antibiotics 
Rifabutin 
Efavirenz 
Phenobarbital 
Rifampin 
Glucocorticoids: 
Phenylbutazone 
Rifapentine 
Dexamethasone 
Phenytoin 
St. John’s Wort 
Prednisone 
Primidone 
Sulfinpyrazone 
CyP3A5-7 Inducers 
Phenobarbital 
Primidone 
Rifampin 
Phenytoin 
 
 
Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health 
2012. 
a This list is not all inclusive and may change. 


 
 
 
 
 
 
 
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APPENDIX G: Eligibility Checklist 
Inclusion Criteria 
Yes 
No 
Is this patient age 60 or older? 
 
 
Is this patient’s ECOG performance 0-2? 
 
 
Does the patient have a life expectancy of >12 weeks?  
 
 
Does the patient have histologically or cytologically proven metastatic breast 
cancer? 
 
 
Does this patient have documented HER2 positive disease per ASCO CAP 
guidelines? 
IHC: 
 
FISH:  
 
Does this patient have stage IV Her2/Neu positive breast cancer and failed 
previous anti-HER2 targeted therapies? There is no limitation on the number of 
prior lines of systemic therapy or HER2-targeted therapies. 
 
 
If HER2 negative, does the tumor have documented HER2 gene mutations 
through CLIA certified laboratory test? (Missense substitutions ( G309A, 
G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P,  
E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, 
R849W, L869R, R896C ); Insertions/deletions (A775_G776insYVMA aka 
Y772_A755dup, 
G776VinsC, 
G776AinsVGC,G776 
insertions, 
G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del).  
 
 
Does the patient have adequate organ and bone marrow functions within 4 wk 
of pre-registration:  
o Hemoglobin:  ≥ 9g/dL (after transfusion, if necessary) 
o Total bilirubin: within normal institutional limits 
o AST (SGOT)/ALT (SGPT): ≤ 2.5 X institutional upper limit of normal 
o Creatinine clearance ≥ 30 mL/minas calculated by Cockroft-Gault 
formula 
 
 


 
 
 
 
 
 
 
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Does the patient have baseline LVEF > 50% as evaluated by echocardiogram 
(ECHO) or multiple-gated acquisition scan (MUGA)? 
 
 
Have all Grade >2 toxicities other than alopecia from prior therapy been 
resolved? 
 
 
Has the patient completed radiation therapy with adequate recovery of bone 
marrow and organ functions? 
 
 
Does the patient have stable or treated brain metastases? Asymptomatic patients 
with metastatic brain disease who have been on a stable dose of corticosteroids 
for treatment of brain metastases for at least 14 days are eligible to participate in 
the study. 
 
 
Has the patient been provided written, informed consent to participate in the 
study and follow the study procedures? 
 
 
Exclusion Criteria: 
No 
Yes 
Has the patient previously been treated with neratinib? 
 
 
Is the patient currently using other investigational agents, chemotherapy, or 
hormone therapy? Prior chemotherapy, hormonal therapy, targeted therapy, 
and investigational agents are allowed but all toxicities grade ≥2 must have 
resolved by the time of study commencement (except alopecia). 
 
 
Has the patient had any major surgery ≤ 28 days prior to the initiation of 
investigational products, or received anti-cancer therapy (including 
chemotherapy, biological therapy, hormonal therapy, investigational agents, or 
other anti-cancer therapy) administered ≤ 14 days prior to initiation of 
investigational products? 
 
 
Has the patient had active uncontrolled cardiac disease, including 
cardiomyopathy, congestive heart failure (New York Heart Association 
functional classification of  ≥2, including individuals who currently use 
digitalis specifically for congestive heart failure ),  unstable angina, myocardial 
infarction within 12 month of enrollment or ventricular arrhythmia? 
 
 
 
Is the patient concurrently using digoxin due to cardiac disease? 
 
 


 
 
 
 
 
 
 
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Does the patient have QTc interval ≥450 milliseconds (men) and ≥ 470 
milliseconds (women) within 2 weeks of registration or known history of QTc 
prolongation or Torsades de Pointes? 
 
 
 
Is the patient unable to take oral medication? 
 
 
 
Does the patient have any known hypersensitivity to any component of the 
investigational product? 
 
 
 
Does the patient have other malignancy within the past 3 years with the 
exception of: a) adequately treated basal cell carcinoma, squamous cell skin 
cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer 
considered cured by surgical resection or unlikely to impact survival during the 
duration of the study, such as localized transitional cell carcinoma of the 
bladder, or benign tumors of the adrenal or pancreas? 
 
 
 
Does the patient have significant chronic gastrointestinal disorder with 
diarrhea as a major symptom (e.g., Crohn’s disease, malabsorption, or Grade 
≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse 
Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at baseline)? 
 
 
 
Does the patient have known clinically active infection with hepatitis B or 
hepatitis C virus? 
 
 
 
Does the patient have evidence of significant medical illness, abnormal 
laboratory finding or psychiatric illness/social situations that would, in the 
Investigator’s judgment, makes the patient inappropriate for this study? 
 
 
 
 


 
 
 
 
 
 
 
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APPENDIX H: Self Geriatric Assessment Measure – Patient 
Questionnaire 
Responsible person name (Physician, Nurse, or CRA) __________________________________ 
Assessment Period (as applicable to this study): 
 
 Timepoint 1 (Baseline);   
  Timepoint 2 ( At cycle #4);  
 Timepoint 3 (End of study) 
 
 
Patient Instructions:  If you are unable to complete the questionnaire, a member of your health 
care team will assist you. Please do not have a family member complete the questionnaire for 
you. 
 
A. BACKGROUND INFORMATION 
1. What is the highest grade you finished in school? (Mark one with an X. 
 8th or less 
 
 
 
 
 Vocational/technical school 
 9-11th grade  
 
 
 Bachelor’s degree 
 High school graduate/GED  
 Advanced degree 
 
 Associate degree/some college 
 
 I prefer not to answer 
 
2. What is your marital status? (Mark one with an X.) 
 
 
 Married 
 
 
 Separated 
 
 
 Domestic partnership 
 Never married 
 
 
 Widowed 
 
 
 I prefer not to answer 
 
 
 Divorced 
 
3. With whom do you live? (Mark all that apply with an X.) 
 
 Spouse / partner 
 
 
 
 Parent(s)/ parent(s)-in-law 
 
 Girlfriend / boyfriend 
 
 
 Live alone 
 
 Children aged 18 years or younger 
 Other specify ________________ 
 
 Children aged 19 years or older 
 
 Other relative specify 
________________ 
 


 
 
 
 
 
 
 
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4. What is your current employment status?  (Mark one with an X.) 
 
 Employed 32 hours or more per week 
 Unemployed 
 
 Employed less than 32 hours per week 
 Retired 
 
 Homemaker  
 
 
 Full-time student 
 
 Disabled 
 
 
 
 
 Part-time student 
 
 On medical leave 
 
 
 
 Other specify ________________ 
 
5. How old are you? _____ years old 
 
6. What is your race? (Mark one with an X) 
 
 
 White 
 
 
 
 
 Asian 
 
 
 Black or African American  
 
 Native Hawaiian or Other Pacific 
Islander 
 
 
 Native Indian or Alaskan Native 
 
 Unknown 
 
7. What is your ethnicity? (Mark one with an X) 
 
 
 Hispanic or Latino  
 
 
 
 
 
 Non-Hispanic 
 
 
 
 
 Unknown 
 
 
 
B. DAILY ACTIVITIES* 
 
PATIENT INSTRUCTIONS: Indicate your response by marking an X in one box per question. 
 
1. Can you use the telephone… 
 without help, including looking up and dialing; 
 with some help (can answer phone or dial operator in an emergency, but need a special 
phone or help in getting the phone number or dialing); or 
 are you completely unable to use the telephone? 
 


 
 
 
 
 
 
 
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2. Can you get to places out of walking distance… 
 without help (can travel alone on busses, taxis, or drive your own car); 
 with some help (need someone to help you or go with you when traveling) ; or 
 are you unable to travel unless emergency arrangements are made for a specialized 
vehicle like an ambulance? 
 
3. Can you go shopping for groceries or clothes (assuming you have transportation) … 
 without help (taking care of all shopping needs yourself, assuming you have 
transportation); 
 with some help (need someone to go with you on all shopping trips); or 
 are you completely unable to do any shopping? 
 
4. Can you prepare your own meals… 
 without help (plan and cook full meals yourself); 
 with some help (can prepare some things but unable to cook full meals yourself) ; or 
 are you completely unable to prepare any meals? 
 
5. Can you do your housework… 
 without help (can clean floors, etc); 
 with some help (can do light housework but need help with heavy work); or 
 are you completely unable to do any housework? 
 
6. Can you take your own medicines… 
 without help (in the right doses at the right time); 
 with some help (able to take medicine if someone prepares it for you and/or reminds 
you to take it); or 
 are you completely unable to take your medicines? 
 
7. Can you handle your own money… 
 without help (write checks, pay bills, etc.); 


 
 
 
 
 
 
 
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 with some help (manage day-to-day buying but need help with managing your 
checkbook and paying your bills); or 
 are you completely unable to handle money? 
 
* OARS IADL – Fillenbaum, G.G. and Smyer, M.A., 1981 
 
C. PHYSICAL ACTIVITIES*  
1. The following items are activities you might do during a typical day. Does your health limit 
you in these activities?  (Mark an X in the box on each line that best reflects your 
situation.) 
Activities 
Limited  
a lot 
Limited  
a little 
Not limited  
at all 
a. Vigorous activities, such as running, lifting heavy objects, 
participating in strenuous sports 
 
 
 
b. Moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf 
 
 
 
c. Lifting or carrying groceries 
 
 
 
d. Climbing several flights of stairs 
 
 
 
e. Climbing one flight of stairs 
 
 
 
f. Bending, kneeling, or stooping 
 
 
 
g. Walking more than a mile 
 
 
 
h. Walking several blocks 
 
 
 
i. Walking one block 
 
 
 
j. Bathing or dressing yourself 
 
 
 
 
* MOS, Physical Functioning Scale – Stewart, A.L. and Ware, J.E., 1992 
 
 
D. CURRENT HEALTH RATING* 
 
Which one of the following phrases best describes you at this time? (Mark one with an X.) 
 
 Normal, no complaints, no symptoms of disease 


 
 
 
 
 
 
 
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 Able to carry on normal activity, minor symptoms of disease 
 
 Normal activity with effort, some symptoms of disease 
 
 Care for self, unable to carry on normal activity or do active work 
 
 Require occasional assistance but able to care for most of personal needs 
 
 Require considerable assistance for personal care 
 
 Disabled, require special care and assistance 
 
 Severely disabled, require continuous nursing care 
 
* Patient KPS – Loprinzi, C.L., et al., 1994 
 
E. FALLS 
How many times have you fallen in the last 6 months?  __ __ __ 
 
F. YOUR MEDICATIONS  
Are your taking medications?  
 Yes  
 No 
How many prescribed medications are you taking? ___ medications 
How many over-the-counter medications are you taking? ___ medications 
How many herbs and vitamins are you taking? ___ herbs and vitamins 
 
G. YOUR HEALTH  
1. Your General Health* 
Patient Instructions: Do you have any of the following illnesses at the present time, and if so, 
how much does it interfere with your activities: Not at All, A Little or A Great Deal? (Mark an 
X in the box that best reflects your answer.) 
 


 
 
 
 
 
 
 
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If you have this illness:  
How much does it interfere with your 
activities? 
Illness 
No 
Yes 
 
Not  
at all 
A little 
A great 
deal 
a. Other cancers or leukemia 
 
 
→ 
 
 
 
b. Arthritis or rheumatism 
 
 
→ 
 
 
 
c. Glaucoma 
 
 
→ 
 
 
 
d. Emphysema or chronic bronchitis 
 
 
→ 
 
 
 
e. High blood pressure 
 
 
→ 
 
 
 
f. Heart trouble 
 
 
→ 
 
 
 
g. Circulation trouble in arms or legs 
 
 
→ 
 
 
 
h. Diabetes 
 
 
→ 
 
 
 
i. Stomach or intestinal disorders 
 
 
→ 
 
 
 
j. Osteoporosis 
 
 
→ 
 
 
 
k. Liver disease 
 
 
→ 
 
 
 
l. Kidney disease 
 
 
→ 
 
 
 
m. Stroke 
 
 
→ 
 
 
 
n. Depression 
 
 
→ 
 
 
 
* OARS IADL – Fillenbaum, G.G. and Smyer, M.A., 1981 
 
2. How is your eyesight (with glasses or contacts)?  (Mark one with an X.) 
 Excellent 
 
 Good  
 Fair 
 
 
 Poor  
 


 
 
 
 
 
 
 
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 Totally blind 
 
3. How is your hearing (with a hearing aid, if needed)? (Mark one with an X.) 
 Excellent 
 
 Good  
 Fair 
 
 
 Poor  
 
 Totally deaf 
 
4. Do you have any other physical problems or illnesses (other than listed in questions 1-4) at 
the present time that seriously affect your health? 
 No 
 
 Yes   (If yes), specify _________________________________________________ 
 
(If yes), how much does this interfere with your activities?  (Mark one with an X.) 
 
 
 Not at all 
 
 Somewhat  
 A great deal 
 * OARS IADL – Fillenbaum, G.G. and Smyer, M.A., 1981 
 
H. NUTRITIONAL STATUS 
1.  Have you lost weight involuntarily over the past 6 months?   
 
 No 
 
 Yes 
 
 
 
If yes, how much? 
 
 
 
_____ pounds 
 
2.  What is your weight now?   
 
 _____  pounds 
 
3. What was your weight 6 months ago? 
 
 _____  pounds 


 
 
 
 
 
 
 
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I. HEALTH QUESTIONNAIRE* 
 
INSTRUCTIONS: These questions are about how you have been feeling within the past 
month. Please mark an “X” in the box on each line that best reflects your situation.  
 
How much of the time during the past 
month: 
All  
of the 
Time 
Most 
of the 
Time 
A Good 
Bit of the 
Time 
Some  
of the 
Time 
A Little 
of the 
Time 
None 
of the 
Time 
1. has your daily life been full of things 
that were interesting to you? 
 
 
 
 
 
 
2. did you feel depressed? 
 
 
 
 
 
 
3. have you felt loved and wanted? 
 
 
 
 
 
 
4. have you been a very nervous 
person? 
 
 
 
 
 
 
5. have you been in firm control of your 
behavior, thoughts, emotions, 
feelings? 
 
 
 
 
 
 
6. have you felt tense or high-strung? 
 
 
 
 
 
 
7. have you felt calm and peaceful? 
 
 
 
 
 
 
8. have you felt emotionally stable? 
 
 
 
 
 
 
9. have you felt downhearted and blue? 
 
 
 
 
 
 
10. have you felt restless, fidgety, or 
impatient? 
 
 
 
 
 
 
11. have you been moody, or brooded 
about things? 
 
 
 
 
 
 
12. have you felt cheerful, light-hearted? 
 
 
 
 
 
 
13. have you been in low or very low 
spirits? 
 
 
 
 
 
 
14. were you a happy person? 
 
 
 
 
 
 
15. did you feel you had nothing to look 
forward to? 
 
 
 
 
 
 


 
 
 
 
 
 
 
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16. have you felt so down in the dumps 
that nothing could cheer you up? 
 
 
 
 
 
 
17. have you been anxious or worried? 
 
 
 
 
 
 
 
 
 
 
 
* MHI-17 – Stewart, A.L. and Ware, J.E., 1992 
 
J. SOCIAL ACTIVITIES* 
 
1. During the past 4 weeks, how much time has your physical health or emotional problems 
interfered with your social activities (like visiting with friends, relatives, etc.)?  
(Mark one with an X.) 
 
 All of the time 
 Most of the time 
 Some of the time 
 A little of the time 
 None of the time 
 
 
2. Compared to your usual level of social activity, has your social activity during the past 6 
months decreased, stayed the same, or increased because of a change in your physical or 
emotional condition?  (Mark one with an X.) 
 
 Much less socially active than before 
 Somewhat less socially active than before 
 About as socially active as before 
 Somewhat more socially active as before 
 Much more socially active than before 
 
 
3. Compared to others your age, are your social activities more or less limited because of your 
physical health or emotional problems? (Mark one with an X.) 
 


 
 
 
 
 
 
 
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 Much more limited than others 
 Somewhat more limited than others 
 About the same as others 
 Somewhat less limited than others 
 Much less limited than others 
 
* MOS, Social Activities – Stewart, A.L. and Ware, J.E., 1992 
 
K. SOCIAL SUPPORT* 
INSTRUCTIONS: People sometimes look to others for companionship, assistance or other 
types of support. How often is each of the following kinds of support available to you if you 
need it? (Mark an X in the box on each line that best reflects your situation.) 
 
 
None  
of the 
Time 
A 
Little 
of the 
Time 
Some  
of the 
Time 
Most  
of the 
Time 
All  
of the 
Time 
1. Someone to help you if you were confined to 
bed. 
 
 
 
 
 
2. Someone you can count on to listen to you 
when you need to talk. 
 
 
 
 
 
3. Someone to give you good advice about a 
crisis. 
 
 
 
 
 
4. Someone to take you to the doctor if you 
needed it. 
 
 
 
 
 
5. Someone to give you information to help you 
understand a situation. 
 
 
 
 
 
6. Someone to confide in or talk to about 
yourself or your problem. 
 
 
 
 
 
7. Someone to prepare your meals if you were 
unable to do it yourself. 
 
 
 
 
 
8. Someone whose advice you really want. 
 
 
 
 
 
9. Someone to help you with daily chores if you 
were sick. 
 
 
 
 
 
10. Someone to share your most private worries 
 
 
 
 
 


 
 
 
 
 
 
 
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and fears with. 
11. Someone to turn to for suggestions about how 
to deal with a personal problem. 
 
 
 
 
 
12. Someone who understands your problems. 
 
 
 
 
 
* MOS Social Support Survey – Sherbourne, C.D. and Stewart, A.L., 1991 
 
 
L. SPIRITUALITY/RELIGION* 
 
Directions: Please answer the following questions about your religious beliefs and/or 
involvement. (Please mark an “X” in the box on each line that best reflects your situation.)  
 
1. How often do you attend church, synagogue, or other religious meetings? (Mark one with an 
X.) 
 More than once per week 
 Once a week 
 A few times a month 
 A few times a year 
 Once a year or less 
 Never 
 
2. How often do you spend time in private religious activities, such as prayer, meditation or 
Bible study?  (Mark one with an X.) 
 More than once a day 
 Daily 
 Two or more times per week 
 Once a week 
 A few times a month 
 Rarely or never 
 
 


 
 
 
 
 
 
 
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The following section contains 3 statements about religious belief or experience.  Please mark the 
extent to which each statement is true or not true for you. 
 
3. In my life, I experience the presence of the Divine (i.e., God). (Mark one with an X.) 
 Definitely true of me 
 Tends to be true 
 Unsure 
 Tends not to be true 
 Definitely not true 
 
4. My religious beliefs are what really lie behind my whole approach to life. (Mark one with an 
X.) 
 Definitely true of me 
 Tends to be true 
 Unsure 
 Tends not to be true 
 Definitely not true 
 
5. I tried hard to carry my religion over into all other dealings in my life. (Mark one with an X.) 
 Definitely true of me 
 Tends to be true 
 Unsure 
 Tends not to be true 
 Definitely not true 
* DUREL: Duke University Religion Index – Koenig et al., 1997 
 
M. YOUR FEELINGS* 
1. Do you often feel sad or depressed? (Mark one with an X.) 
 
 No     
 Yes 
 


 
 
 
 
 
 
 
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2. How would you describe your level of anxiety, on the average? Please circle the number (0-10) 
best reflecting your response to the following that describes your feelings during the past week, 
including today.  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No anxiety  
 
 
 
 
 
 
                   Anxiety as bad as it 
can be 
 
* Mahoney et al., 1994; LASA – Locke et al., 2007 
 
 
 
 
N. FACT-B 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
PHYSICAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of 
energy
 ................................................................. 
0 
1 
2 
3 
4 
GP2 
I have 
nausea
 ................................................................. 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have 
trouble meeting the needs of my 
family
 ................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 


 
 
 
 
 
 
 
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GP4 
I have 
pain
 ................................................................. 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment
 ................................................................. 
0 
1 
2 
3 
4 
GP6 
I feel 
ill
 ................................................................. 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in 
b d
0 
1 
2 
3 
4 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GS1 
I feel close to my 
friends
 ................................................................. 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my 
family
 ................................................................. 
0 
1 
2 
3 
4 
GS3 
I get support from my 
friends
 ................................................................. 
0 
1 
2 
3 
4 
GS4 
My family has accepted my 
illness
 ................................................................. 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family 
communication about my 
 
0 
 
1 
 
2 
 
3 
 
4 


 
 
 
 
 
 
 
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Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GE1 
I feel 
sad
 ................................................................ 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping 
with my 
illness
 ................................................................ 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my 
illness
 ................................................................ 
0 
1 
2 
3 
4 
illness
 ................................................................. 
GS6 
I feel close to my partner (or the person 
who is my main 
support)
 ................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of 
sexual activity, please answer the 
following question. If you prefer not to 
 
 
 
 
 
GS7 
I am satisfied with my sex 
life
 ................................................................. 
0 
1 
2 
3 
4 


 
 
 
 
 
 
 
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GE4 
I feel 
nervous
 ................................................................ 
0 
1 
2 
3 
4 
GE5 
I worry about 
dying
 ................................................................ 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
0 
1 
2 
3 
4 
 
FUNCTIONAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
GF1 
I am able to work (include work at 
home)
 ................................................................ 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is 
fulfilling
 ................................................................ 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy 
life
 ................................................................ 
0 
1 
2 
3 
4 
GF4 
I have accepted my 
illness
 ................................................................ 
0 
1 
2 
3 
4 
GF5 
I am sleeping 
well
 ................................................................ 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for 
fun
 ................................................................ 
0 
1 
2 
3 
4 


 
 
 
 
 
 
 
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GF7 
I am content with the quality of my life 
0 
1 
2 
3 
4 
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
B1 
I have been short of 
breath
 .................................................................. 
0 
1 
2 
3 
4 
B2 
I am self-conscious about the way I 
dress
 .................................................................. 
0 
1 
2 
3 
4 
B3 
One or both of my arms are swollen or 
tender
 .................................................................. 
0 
1 
2 
3 
4 
B4 
I feel sexually 
attractive
 .................................................................. 
0 
1 
2 
3 
4 
B5 
I am bothered by hair 
loss
 .................................................................. 
0 
1 
2 
3 
4 
B6 
I worry that other members of my family 
might someday get the same illness I 
have
 .................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
B7 
I worry about the effect of stress on my 
illness
 .................................................................. 
0 
1 
2 
3 
4 


 
 
 
 
 
 
 
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B8 
I am bothered by a change in 
weight
 .................................................................. 
0 
1 
2 
3 
4 
B9 
I am able to feel like a 
0 
1 
2 
3 
4 
P2 
I have certain parts of my body where I 
experience 
pain
 .................................................................. 
0 
1 
2 
3 
4 
 
O. QUESTIONS CONCERNING THE QUESTIONNAIRE 
1. Were there any questions difficult to understand?  
 No     
 Yes 
(If yes), which questions were they? 
 
 
 
 
2. Was the time it took to answer all the questions too long, just right or too short? 
 Too short  →  How long would you have liked the questionnaire to be?   __ __ minutes 
 Just right 
 Too long →  How long would you have liked the questionnaire to be?   __ __ minutes 
 
 
Which items would you remove? 
 
 
 
 
 
3. Did you find any of the questions upsetting?  
 No     
 Yes 
(If yes), which questions were they? 


 
 
 
 
 
 
 
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Could you tell me why they were upsetting? 
 
 
 
 
 
 
4. Do you think the questionnaire left out any questions that were important to ask? 
 
 
 
 
 
 
 
Thank you for your participation. 
 
 
 


 
 
 
 
 
 
 
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APPENDIX I: Geriatric Assessment Healthcare Professional 
Questionnaire 
I. This form completed by: (Mark all that apply with an X.) Assessment Period (as 
applicable to this study) 
□ Physician 
    □ Nurse 
   □ CRA 
□ Pre-treatment   □ Cycle #4   □ End of 
Treatment 
 
□ Mark box with an “X”, if form was not completed at specified timepoint and 
specify reason:  
   (Mark one with an X.) 
□ Patient refused  
□ Patient withdrew consent □ Not 
done 
□ Other, specify ______________________________________________________ 
(For assessment date, record approximate date form was to be completed.) 
 
II.  Karnofsky Performance Status: _____________% 
Please rate your assessment of patient’s Karnofsky Performance Status as of date this 
form is completed. (Scale is listed below.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
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DEFINITION 
% 
CRITERIA 
Able to carry on normal activity 
and able to work. No special care is 
needed. 
100 
Normal: no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
 
80 
Normal Activity with effort; some signs or 
symptoms of disease. 
Unable to work. Able to live at home, and 
for most personal needs. A varying amount 
of assistance is needed 
70 
Cares for self. Unable to carry on normal 
activity or to do active work. 
 
60 
Requires occasional assistance, but is able to 
care for most of his needs 
 
50 
Requires considerable assistance and frequent 
medical care 
Unable to care for self. Requires equivalent 
of institutional or hospital care. Disease 
may be progressing rapidly 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated 
although death not imminent. 
 
20 
Very sick; hospitalization necessary; active 
supportive treatment necessary. 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead. 
 
* Physician KPS – Karnofsky, D.A. and Burchenal, J.H., 1949 
Geriatric Assessment Healthcare Professional Questionnaire 
III. Timed “Up and Go”* 
INSTRUCTIONS: The timed “Up and Go” measures, in seconds, the time it takes for an 
individual to  stand up from a standard arm chair (approximate seat height of 46 cm 
[approximately 1.5 ft]), walk a distance of 3 meters (approximately 10 feet), turn, walk 
back to the chair, and sit down again. The subject wears his/her regular footwear and uses 
their customary walking aid (none, cane, walker, etc.) No physical assistance is given. 


 
 
 
 
 
 
 
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The subject starts with his back against the chair, his arm resting on the chair’s arm, and 
his walking aid in hand.  He is instructed that on the word “go”, he is to get up and walk 
at a comfortable and safe pace to a line on the floor three meters (approximately ten feet) 
away, turn, and return to the chair and sit down again. The subject walks through the test 
once before being timed in order to become familiar with the test. Either a wrist watch 
with a second hand or a stop-watch can be used to time the performance. 
 
 
Time to perform “Up and Go” seconds :_______________________ 
IV. COGNITION : Orientation-Memory-Concentration Test 
 
 
Patient’s 
Maximum 
 
 
Final 
Response 
  
Errors 
Score 
Weight 
Score 
 
1. What year is it now?  
 
1 
 
 x 
4 
= 
 
 
[without looking at 
 
a calendar] 
 
2. What month is it now? 
 
1 
 
 x 
3 
= 
 
 
[without looking at 
 
a calendar] 
 
Memory Phrase 
Repeat this phrase after me: ‘John Brown, 42 Market Street, Chicago’. 
 
3. About what time is it  
: 
1 
 
 x 
3 
= 
 
[within 1 hour – without 
looking at your watch] 
 
4. Count backwards from  
2 
 
 
x 
2 = 
 
 
20 to 1. 


 
 
 
 
 
 
 
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5. Say the months in reverse 
2 
 
 
x 
2 = 
 
 
order. 
 
6. Repeat the memory phrase 
5 
 
 
x 
2 = 
 
 
 
 
 
  
Total 
Score: 
 
 
 
Scoring:  For items 1 to 3, the response is either correct (score 0) or incorrect (score 1). For items 
4 to 6, subtract one point for each error (item 4 and 5 maximum error is 2; for item 6, maximum 
error is 5); total all scores in “Final Score” column. Total score of 11 or greater indicates 
cognitive impairment; please notify MD and assist patient in completing questionnaires. 
Maximum score = 28 
 
 
V. Nutrition  
a) What is the patient’s height? ________________ 
b) What is the patient’s current weight? __________ 
c) What is the patient’s weight approximately 6 months ago? ___________ 
d) Calculated Body Mass Index: _______________________ 
 
Body Mass Index=Weight/(Height)2 
 
e) Percent Unintentional Weight Loss: __________________ 
 
% unintentional weight loss =  


 
 
 
 
 
 
 
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(unintentional weight lost in last 6 months/baseline body weight) x 100 
 
 
 
VI. Labs: (performed within 4 weeks of this assessment) 
a) Creatinine:______________ 
b) Hemoglobin:____________  
c) Albumin:_______________ 
d) Liver Function Tests: Normal or Not normal_________________ 
e) WBC: __________________ 
f)  CA125 (Gynecological patients ONLY): ____________________      
g) Blood Urea Nitrogen: __________________   
 
 
 
VII.  Scoring 
a) Did the patient score > 11 on the Blessed Orientation-Memory-Concentration Test (see 
previous page)? 
 No 
 Yes (if yes, notify the patient’s treating physician) 
 
VIII. Was the patient able to complete “Geriatric Assessment – Patient Questionnaire” on his/her 
own? 
 
□Yes     □No 
 
If no, why? (Mark all that apply with an X.) 
□ Not literate (does not read or write) 
□ Visual problem 
□ Fatigue 
□ Questions too difficult (above the patient’s reading ability) 


 
 
 
 
 
 
 
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□ Other: specify_________________________________________________ 
 
 
IX. Time to complete 
 
a) Appendix H  (Questionnaires to be completed by the study participant) 
 
 
 
Start Time:________ 
 
End Time: ________ 
 
b) Appendix I (Data to be gathered by the healthcare team) 
 
Start Time:_________ 
 
End Time: _________ 
 
Total time to complete Appendix H and I: ______________ 
 
 
Name of person completing this document: _________________________ 
Signature: ___________________________________________________ 
Date: _______________________________________________________ 
 
 
 


 
 
 
 
 
 
 
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APPENDIX J: SAE/UP Reporting Coversheet 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT 
For Use by Participating Institutions Only 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500A FORM MUST BE EMAILED TO DCC@COH.ORG 
WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE EVENT OR UNANCTICIPATED 
PROBLEM  
COH IRB # (insert once IRB number known)     - Participating Site IRB # ___________ 
Staff Submitting Form:   
Date: 
Phone No.: 
Email: 
 
Reporting Investigator: 
Event:  
Participant ID: 
Institution: 
Date Event Met Reporting Criteria (as defined in protocol):   
Type of Report:  Initial    Follow-up 
CTCAE Grade:   G1/mild    G2/moderate     G3/severe    G4/life threatening   
 G5 
Attribution to Neratinib:   Unrelated   Unlikely   Possible    Probable   
Definite 
Meets Definition of Serious AE:      Serious      Non-serious 
Meets Definition of Unanticipated Problem:      UP      Not a UP 
Has the event been reported to the participating institution’s IRB?  __ No    __ Yes    
Date: __ __ / __ __  / __ __  (If yes, please attach report to this submission) 


 
 
 
 
 
 
 
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APPENDIX K: 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. Use of anti-diarrheal medication is required 
for all enrolled subjects to help reduce or prevent diarrhea. 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 nurse/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 4 or more 
stools per day over usual, call your study nurse /team at phone number 
_______________________ to let them know so they can work with you to control the diarrhea.  
If you are dizzy or weak because of diarrhea, call your study nurse/team immediately. If you are 
unable to reach assistance, please seek medical attention immediately. 
Please record the number of stools and any anti-diarrheal medication taken during all Cycles of 
the study 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   


 
 
 
 
 
 
 
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 
When I took my last study drug 
 
Any other information that could explain my diarrhea (food, recent travel, contact with 
other people with diarrhea). 
 
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 initially take 2 tablets/capsules (4 mg) with the first dose of neratinib  
 
Thereafter, I will take 2 tablet/capsule (4 mg) three times a day for the next two weeks; 
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 two weeks, I will take 2 tablet (4 mg) twice a day onwards through the 
first 1cycle of therapy (28days) from the start of neratinib regardless of whether I have 
diarrhea or not. 
 
If I continue to have diarrhea while taking loperamide, I should contact my study 
doctor/team for additional anti-diarrheal medication and consult.  
 
If I have diarrhea with increase of up to 6 stools per day over usual any time after 
completing the two cycles of therapy and I am not taking any anti-diarrheal medication, I 
will take 2 tablets/capsules (4 mg) immediately after the first loose stool and then 1 
tablet (2 mg) every 4 hours or after each loose stool to a maximum dose of 8 
tablets/capsules (16 mg) in any 24 hour period until I haven’t had any loose stool for at 
least 12 hours. 
□ 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 


 
 
 
 
 
 
 
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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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1.2.1 
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, and I cannot reach my study doctor/team, 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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 APPENDIX L: Optimal Management of Diarrhea Checklist  
This checklist must be completed for each patient by study team (invesetigator or 
study nurse) during the Day 1 visit before the patient leaves the site with study 
medication. 
 
Patient Number: |_____|_____|_____|_____|_____|         
 
Day 1 Visit Date: |___|___| / |___|___|___| / |___|___| 
 
 I have communicated the risk and the timing of diarrhea occurrence to my patient 
while discussing the informed consent form and patient diarrhea instruction sheet. 
 I have ensured that my patient takes home loperamide along with study 
medication.  
 I have instructed my patient to take loperamide concomitantly with the first dose 
of neratinib and to take the prophylactic dose of loperamide 4mg three times a 
day for the next 14 days to minimize the occurrence and severity of diarrhea. 
Thereafter, continue to take loperamide 4mg twice a day as indicated in the 
protocol for first cycle (28 days). 
 I have reviewed with my patient dietetic measures (e.g., hydration, low lactose, 
low fat diet enriched with bananas, rice, applesauce and toast) recommended in 
case he/she experiences loose stools or diarrhea. 
 I have instructed my patient to record the number of daily stools, the occurrence 
of diarrhea and any anti-diarrheal treatment along with the daily dose of study 
medication in his/her diary daily for all cycles of study medication. 
 I have informed my patient that he/she will receive a call at 1 day, 2 days and 3 
days after first dose of study medication to assess his/her tolerance to the study 
medication and to document the date the first dose of study medication was taken. 
 I will follow-up with my patient on severe diarrhea and other adverse events until 
resolution. 


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 I checked with my patient that he/she can be reached at 
_______________________.  
 My patient has received my number and knows to call me as soon as he/she 
experiences loose stool or diarrhea (COH medical oncology call center: 626-471-
9200). 
 
Study CRA or Study Nurse’s Name and Signature:  
 
______________________________________________________________________
________________________ 
Loperamide is the recommended standard therapy for diarrhea in this study. Additional 
treatment may be required.  Refer to the protocol for other therapy and literature.  
 


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APPENDIX M: Patient Diary 
Date 
dd/mm
/yy 
Name of 
Drug 
Time 
Taken 
Dose 
Taken 
# of 
Tablets per  
Day 
# of 
Stools 
per Day 
 
Comments on missed or 
reduced doses for Study 
Medication(s), any 
additional anti-diarrheal 
medication, and any 
symptoms (i.e. Diarrhea, 
Vomiting, Pain)  
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 


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Date 
dd/mm
/yy 
Name of 
Drug 
Time 
Taken 
Dose 
Taken 
# of 
Tablets per  
Day 
# of 
Stools 
per Day 
 
Comments on missed or 
reduced doses for Study 
Medication(s), any 
additional anti-diarrheal 
medication, and any 
symptoms (i.e. Diarrhea, 
Vomiting, Pain)  
 
 
Loperamide 
 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
Neratinib 
 
 
 
 
 
 
Loperamide 
 
 
 
 
 
Patient Diary  
Patient Number: I__I__I__I__I__I__I__I__I__I  
 


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Record from: ______________ to: ______________  
 
 
Date of your next visit: ____________________________  
 
 
 
EMERGENCY CONTACT:  
 
 
_____________________________________________________________________  
Call your study team immediately if you are experiencing any new symptoms (diarrhea, 
vomiting, etc.).  
 
 
TAKE TABLETS AS PRESCRIBED BY YOUR STUDY DOCTOR. PLEASE BRING 
ORIGINAL STUDY MEDICATION BOTTLES WITH YOU TO EACH STUDY VISIT  
 
Please complete the diary every day and bring it with you to the next scheduled visit as 
instructed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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COMPLETION GUIDELINES  
 
1. Enter the study drug that you are taking each day under the column “Name of Drug” and 
complete corresponding dose and # of tablets taken.  
 
2. Make sure to enter the amount of loperamide you are taking as well (see example on table below).  
 
3. If you experience diarrhea, enter # of stools per day. 
 
Date 
dd/mm/y
y 
Name of 
Drug 
Time 
Taken 
Dose 
Taken 
# of 
Tablets 
per  
Day 
# of Stools 
per Day 
 
Comments on missed 
or reduced doses for 
Study Medication(s), 
any additional anti-
diarrheal medication, 
and any symptoms 
(i.e. Diarrhea, 
Vomiting, Pain)  
 
05/Sep/12 
(Day 1) 
 Neratinib  
 
 240 mg  
 6  
 
 
 
 
05/Sep/12  
 Loperamide   
 4 mg  
2  
 0  
 
 
06/Sep/12  
 Neratinib  
 
 240 mg  
 6  
 3  
(+) diarrhea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix N: Registration Coversheet 
COH IRB (Insert Please):  PHASE II STUDY OF NERATINIB IN PATIENTS 60 AND 
OLDER WITH HER2 POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER 
For use by participating instiution’s staff only (not COH) 
 
Data Coordinating Center:  City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  626-256-4673 x 83968  
Email:  DCC@coh.org (use #secure# in subject line) 
 
 
Participating Site’s CRA/Study Coordinator:  _________________________   
Contact Number:  ______________________________ 
 
Patient’s Initials (F M L): 
Institution: 
Medical Record No:  N/A 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Race: 
___ 
Black 
___ 
Caucasian 
___ 
Asian 
___ 
American Indian 
___ 
Native Hawaiian/Pacific Islander 
___ 
Other ____________ 
Ethnicity: 
___ Hispanic 
 
___ Non-Hispanic 
 
___ Other 
______________ 
 
Projected start date of treatment: 
 
Method of payment: ________________ 
Codes: 
01 Private 
 06 Military or Veterans Adm. sponsored 
02 Medicare 
 07 Self-pay (no insurance) 
03 Medicare & private ins. 08 No means of payment  (no insurance) 
04 Medicaid 
09 Unknown 
05 Medicaid & Medicare 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix O: Stool Collection Procedure 
STOOL COLLECTION KIT GENERAL INSTRUCTIONS 
As a part of your participation in the current study, we have some specific instructions related to 
collection of stool.  Please abide by these instructions, as they are essential for the proper 
conduct of the study. 
You are being asked to collect samples at the following times: 
 7 days prior to start of neratinib  
 C1Day 15 (+/- 3 days), C2Day1 (+/- 3 days), C2Day15 (+/-3 days), 
C3Day1 (+/- 3 days). 
 
If you have any questions about sample collection, please call this number: 
______________________ 
USING THE STOOL COLLECTION KIT 
Before you begin, review the following: 
a. Make sure you have a collection hat and collection tube. 
b. Make sure you are able to deliver the sample to City of Hope within 1 week. 
 
STEP ONE: Please place the collection hat 
around the rim of your toilet seat for stool 
collection.  
 
 
STEP TWO: Unscrew the collection tube 
cap and use the spoon to scoop one 
spoonful of feces (about the size of a 
quarter) from a sample. Place the sample 
in the collection tube. Tighten the cap and 
shake to mix the contents thoroughly (invert 
10 times) to create a suspension.  
Note: Some fecal material may be difficult to re-
suspend. As long as the material is suspended, the 
sample is stabilized. Foaming/frothing during 
shaking is normal.  
 


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STEP THREE: Wash hands well, and write 
today’s date on the label. 
 
STEP FOUR: Place the plastic tube in the 
bag, and seal the back using the adhesive 
tape already present on the bag.  
 
 
STEP FIVE: Bring the sample to your City 
of Hope appointment.   
THANK YOU FOR YOUR 
PARTICIPATION! 
 
 


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Appendix P:    Diet and Stool Frequency Log  
DIET and STOOL FREQUENCY LOG - GENERAL INSTRUCTIONS 
As a part of your participation in the current study, we are requesting that you complete a study log every day. 
General pointers: 
 When you come to the clinic, bring your logs with you. 
 Each page has room for seven days – one row should be completed for each day. 
 Please avoid any intake of yogurt, yogurt-containing foods, or other bacteria-fortified foods.  
Example of how the top part of the log will look: 
 A study team member will complete the information in this box before you leave the clinic. 
 
Example of how the information you enter might look:   
 You or someone close to can complete the log for you, so long as the information is correct.  
 List all prescription and non-prescription medications. 
 The person who completes that day’s entry should write his or her initials in the last column. 
 
Example of the signature line: 
 When you hand over the document to the study team, they will ask to sign and date at the bottom of each log if you agree that 
the information is complete and correct. 
 
COMPLETED BY STUDY TEAM                       Participant Initials:                                Participant Research Number:                            


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Day 
and 
Date 
General description of food I ate: 
Did I eat 
yogurt or take 
probiotics? 
How was my stool frequency? 
Was a stool 
sample 
collected? 
Medications taken 
Initials of 
person filling 
information 
 
Eggs, toast, juice 
Ham sandwich, coke, potato chips 
Steak, mashed potatoes, wine 
⃝ Yes 
⃝ No 
⃝Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
Vitamin C, 
Lipitor 
 
JBC 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
 
 
⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
X 
X 
X 


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⃝ Yes 
⃝ No 
⃝ Seems like baseline 
⃝1-3 stools more than baseline 
⃝4-6 stools more than normal 
⃝7 or more than baseline, or incontinence 
⃝ Yes 
⃝ No 
 
 
  
At the time of handing over the document   --   Participant Signature: __________________________________________ Date -
_____________________________


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Appendix Q: At Home Sample Collection Kit Contents 
 
Contents of each kit to be provided to participants for at home collection: 
[] Copy of Appendix O: Instructions for Stool Specimen Collection 
[] Stool collection hat 
[] Specimen tube with label attached 
 Label should have participant identifier added; the participant will be asked to 
add the date himself/herself. 
[] Plastic sealable bag 
 
 
 


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Appendix R: Checklist for study nurses, including documentation of patient’s primary language for 
Geriatric Assessment 
 
Patient’s name and MRN______________________________ 
Patient’s primary language_____________________________ 
 
 
Pre-study (up 
to 28 days 
prior to 
enrolling)i 
C1D1 
(28 day 
cycle)  
C1D8 
(± 1 
day) 
C1D15 
(± 1 
day) 
C2D1 (± 
3 days) 
C2D15 
(±3 days)  
C3D1 
(± 3 
days) 
C4D1 
(± 3 
days) 
C5D1 
(± 3 
days) 
C6D1 
(± 3 
days) 
Every 
cycle 
thereafter 
(± 3 days)  
Every 3 
cycles (± 
7 days) 
Off 
treatmenth 
Diarrhea 
Checklist 
 
□l 
 
 
 
 
 
 
 
 
 
 
 
Nurse brief 
toxicity 
evaluation  
 
□ 
□ □ 
□ 
□ 
□ 
 
 
 
 
 
 
Adherence 
evaluation (pill 
count, diaries) (± 
1 week) 
 
□ 
□ □ 
□ 
□ 
□ 
□ 
□ □ 
□ 
 
 
Tumor 
measurements 
using CT or PET-
CT (± 1 week)  
□d
 
 
 
 
 
 
 
□ 
 
 
 
□e
 
□f
 
Geriatric 
Assessment 
Survey (±1 week) 
□ 
 
 
 
 
 
 
□ 
 
 
 
 
□g
 
d: Baseline assessment may be done up to 30 days prior to study enrollment. 


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e: Tumor measurements are repeated every 3 cycles ± 1 wk until patient comes off study. Documentation (radiologic or clinical) must be provided for patients removed from 
study for progressive disease. 
f: Off-study radiologic evaluation will only be done if clinically indicated.  
g: Geriatric assessment will be performed at baseline prior to study, after 3 cycles and at the end of study. Geriatric assessment will be repeated off study ONLY if it had not 
been administered within the previous month. If patient’s native language is not covered by the current language forms, geriatric assessment form can 
be omitted with clear documentation. 
h: Patients will be followed for 30 days following discontinuation of therapy in order to capture toxicity attributable to therapy.  
i: Chart review data must be within 28 days to determine if patient meets study criteria. Once patient meets study criteria, then all criteria must be within window specified in 
protocol from Day 1 as indicated in column one in the schema above.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX S: SAMPLE GUIDELINES 
 
SAMPLES MUST BE DE-IDENTIFIED WITH NO PHI. AIM TO DELIVER SAMPLES ON A 
MONDAY THROUGH THURSDAY.  
1. Peripheral Blood Samples: 
Dr. Tim Synold 
Cc: Lesley Smith-Powell 
Analytical Pharmacology Core Facility (APCF) 
Shapiro 1042 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Tel: 626-218-2954 
tsynold@coh.org; Lsmith-Powell@coh.org 
 
2. Microbiome specimens:  
Dr. Cui Ke  
CC: Biospecimen Coordinator  
COH Biorepository Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
626-218-1848; 626-218-0462 
kcui@coh.org; spathan@coh.org 
Approximately 30-50 samples stool samples will be temporarily stored at -80oC in the Analytical 
Pharmacology Core Facility (APCF) in Shapiro 1042 (Dr. Tim Synold/Leslie Smith-Powell) 
until batch shipping to TGen: 
 
 
Sarah Highlander, PhD, Director 
TGen Clinical Microbiome Services Center 
Pathogen and Microbiome Division 
Translational Genomics Research Institute 
3051 W. Shamrell Blvd., Suite 106 
Flagstaff, AZ 86005 
shighlander@tgen.org | 928-213-6996