Conditions: Breast Cancer
Keywords: NSABP Trastuzumab Emtansine T DM1 Neratinib Metastatic Breast Cancer HER2 positive Dose Escalation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 49
Healthy volunteers: no

Brief summary:
This study is being done for the following reasons:

* The study has two parts. The purpose of the first part (Phase I) of the study is to find out the highest dose of neratinib that can be given safely with T-DM1.
* The purpose of the second part of the study (Phase II) is to find out whether the dose of neratinib with T-DM1 determined in Phase I will keep breast cancer from getting worse for a period of time.
* In order to learn more about study therapy levels in blood and discover genetic and protein changes associated with cancer, the study includes special research tests using samples from blood and from breast tumor. Blood samples will be collected before study treatment, once during treatment, and after study treatment stops.
* In the optional part of this study, three biopsies will be performed to obtain fresh tumor samples from an area where your cancer has spread.

Detailed description:
The FB-10 study is designed as an open label, single arm, Phase Ib/II study with a dose-escalation phase and an expanded cohort (phase II) to evaluate the combination of trastuzumab emtansine (T-DM1) with neratinib in women with metastatic, HER2-positive breast cancer. The primary aim of the phase Ib portion of this study is to determine the safety and tolerability of the two-drug combination. The primary aim of the phase II portion is to demonstrate efficacy.

Patients will receive concurrent therapy with T-DM1 (3.6 mg/kg IV) on Day 1 of a 3-week (21 day) cycle and neratinib as a continuous daily oral dose. The neratinib dose-escalation will include 4 dose levels (120 mg, 160 mg, 200 mg, and 240 mg). At the recommended phase II dose (RP2D) of the T-DM1 and neratinib combination, up to 39 additional patients will be treated.

The sample size of the phase I portion of the study was 27 patients. The sample size of the Phase II portion will be 22 evaluable patients (and 4 replacement patients). The total study enrollment, phase Ib and II, will be a maximum of 50 patients.

Submission of diagnostic tumor samples and blood samples for FB-10 correlative science studies will be a study requirement for all patients. Blood samples for pharmacokinetics (PKs) and for future study will be collected prior to administration of study therapy on Cycle 1/Day 1, Cycle 1/Day 8, and Cycle 2/Day1.

A tumor biopsy will be procured from an accessible site of metastasis before study therapy is initiated (after the patient has signed the consent and has been screened for eligibility).

Arms:
arm 1: None

Interventions: intervention 1: Neratinib intervention 2: T-DM1
Intervention descriptions: intervention 1: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day.

Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day

Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy intervention 2: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.

Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.

Protocol document:
Prot_SAP_000.pdf: 
Confidential 
NSABP FB-10 
Page 1 
 
NSABP PROTOCOL FB-10 
 
 
A Phase Ib/II Dose-Escalation Study Evaluating the Combination of  
Trastuzumab Emtansine (T-DM1) with Neratinib in Women with  
Metastatic HER2-Positive Breast Cancer 
 
 
 
 
 
NSABP Foundation, Inc. 
 
 
 
 
TELEPHONE: 
 
E-MAIL: 
 
CLINICAL QUESTIONS: 
 
 
 
 
KEY STUDY PERSONNEL 
NSABP Chair: Norman Wolmark, MD 
Protocol Chair: Jame Abraham, MD 
Protocol Officer: Samuel Jacobs, MD 
Protocol Statistician: Marc Buyse, ScD 
 
 
Protocol FB-10 IND #107366 (neratinib), 
sponsored by the NSABP Foundation, Inc. 
 
Puma Biotechnology, Inc. – Protocol [FB-10] 
 
 
 
 
 
Version Date:  January 3, 2018 (Replaces all other versions) 
 
 
 
 
CONFIDENTIAL 
 
 


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PROTOCOL REVISION RECORD 
 
Original Version: 
June 6, 2014 
Amendment #1: 
June 26, 2014 
NSABP FB-10 Protocol and consent amended prior to activation of the study. 
Amendment #2: 
February 5, 2015 
Sections Changed/Added 
Cover Page 
Glossary of Abbreviations and Acronyms 
Section 3.0: 
3.3.1, 3.3.4 
Section 7.0: 
7.4 
Section 12.0: 
12.3.3 
Amendment #3: 
March 1, 2016 
Sections Changed/Added 
Cover Page 
Section 4.0: 
4.2.7 
Section 6.0: 
Table 2 (footnote e added; subsequent footnotes relettered) 
Section 9.0: 
9.1 (Tables 5, 6, 7, and 8); 9.3.5 
Section 10.0: 
10.7.3 (Table 11) 
Section 11.0: 
11.2.3 
Appendix C 
FB-10 Consents: 
 
Study Consent: Cover page, pages 1, 5, 6, 9, 10; Addendum #1 has been added. 
 
Optional Tumor Collection Consent: Cover page, and page 1. 
 
Amendment #4:       
October 11, 2016 
Sections Changes/Added 
Cover Page 
Table of Contents 
Glossary of Abbreviations and Acronyms  
Section 1.0: 
1.1 
Section 2.0: 
2.5 
Section 6.0: 
Table 1 
Section 7.0: 
7.1 (Table 3), 7.3, 7.4.1, 7.4.2, 7.5, 7.5.1, 7.5.2, 7.6 
Section 10.0: 
10.5.4 
References: 
References 40-45 were added; subsequent references were renumbered 
FB-10 Consents: 
 
Study Consent: Cover page, pages 1, 15-20 


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Amendment #5:       
August 8, 2017 
Sections Changes/Added 
Cover Page 
Information Resources 
Section 1.0: 
1.1, 1.2; figure 1 schema revised 
Section 2.0: 
2.1, 2.2, 2.4, 2.5 
Section 3.0: 
3.3, 3.3.2, 3.4 
Section 4.0: 
4.2.7, 4.2.8 
Section 6.0: 
Table 1, Table 2  
Section 7.0: 
7.1, Table 3, 7.3.1, 7.4.1, 7.4.2, 7.4.3, 7.4.4, 7.5.1, 7.6.1, 7.7 
Section 8.0: 
8.0, 8.3 
Section 9.0: 
9.0, 9.1 Table 5 revised; Tables, 6, 7 deleted; subsequent Tables were renumbered.  9.3.4, 
9.4.4 
Section 10.0: 
10.1, 10.2, 10.2.1, 10.2.2; 10.5 added, subsequent sections renumbered; 10.6, 10.6.1, 
10.6.2,  10.6.3, 10.6.4, 10.7, 10.8.1 Table 6, 10.8.2 Table 7, and 10.9 Table 8 
Section 11.0: 
11.2.4, 11.2.5, 11.2.9 
Section 12.0: 
12.2 added, subsequent sections renumbered; 12.3.2 deleted, subsequent sections 
renumbered; 12.7.2 
Section 13:0 
13.1.1, 13.3 
Section 14.0 
14.3 
Section 16.0: 
16.1, 16.2, 16.3, 16.4, and 16.5 
Section 18.0: 
References were added and reformatted 
Appendix C 
FB-10 Consents have been revised. 
 
Amendment #6:       
January 3, 2018 
Sections Changes/Added 
Cover Page 
Section 1.0 
1,2 
Section 6.0 
Table 1, Table 2 
Section 7.0 
Section 7.1 (Table 3); 7.4.2 
Section 9.0 
9.3.5, 9.3.6 added 
Section 11.0 
11.2.3 
FB-10 Consents have been revised. 
 
 
 


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TABLE OF CONTENTS 
 
NSABP PROTOCOL FB-10 ........................................................................................................... 1 
INFORMATION RESOURCES ..................................................................................................... 7 
GLOSSARY OF ABBREVIATIONS AND ACRONYMS ............................................................ 8 
 
1.0 
OVERVIEW OF STUDY DESIGN .............................................................................................. 11 
1.1 
Summary ........................................................................................................................... 11 
1.2 
Addendum ......................................................................................................................... 11 
2.0 
BACKGROUND ........................................................................................................................... 14 
2.1 
Overview of HER2 targeted therapy ................................................................................. 14 
2.2 
Background for T-DM1 .................................................................................................... 15 
2.3 
Background for neratinib .................................................................................................. 16 
2.4 
Phase Ib results (FB-10) of T-DM1 plus neratinib ........................................................... 17 
2.5 
Rationale for incorporation of patient-derived xenografts as co-clinical trial .................. 18 
3.0 
STUDY AIMS AND ENDPOINTS .............................................................................................. 20 
3.1 
Primary aim and endpoint for the Phase I part of the study .............................................. 20 
3.2 
Primary aim and endpoint for the Phase II part of the study ............................................ 20 
3.3 
Secondary aims and endpoints (Phase I and Phase II) ...................................................... 20 
3.4 
Exploratory translational science ...................................................................................... 20 
4.0 
PATIENT ELIGIBILITY AND INELIGIBILITY ........................................................................ 21 
4.1 
Patient selection guidelines ............................................................................................... 21 
4.2 
Conditions for patient eligibility ....................................................................................... 21 
4.3 
Conditions for patient ineligibility .................................................................................... 22 
5.0 
CARDIAC SAFETY MONITORING ........................................................................................... 24 
5.1 
LVEF assessments ............................................................................................................ 24 
5.2 
Protocol-defined cardiac events ........................................................................................ 24 
6.0 
REQUIREMENTS FOR STUDY ENTRY DURING TREATMENT, AND FOLLOW-UP ....... 25 
7.0 
PATHOLOGY AND CORRELATIVE SCIENCE STUDIES ...................................................... 28 
7.1 
Overview of requirements................................................................................................. 28 
7.2 
Use of specimens .............................................................................................................. 29 
7.3 
Tumor and blood sample submission procedures ............................................................. 29 
7.4 
Required tissue and blood samples ................................................................................... 30 
7.5 
Patient derived xenografts (PDX) ..................................................................................... 31 
7.6 
PDX Model Development................................................................................................. 31 
7.7 
Rationale for correlative science studies ........................................................................... 32 
8.0 
DOSE ESCALATION ................................................................................................................... 34 
8.1 
Dose escalation design ...................................................................................................... 34 
8.2 
Definition of dose-limiting toxicity (DLT) ....................................................................... 34 
8.3 
Dose escalation rules ........................................................................................................ 35 
9.0 
STUDY TREATMENT ................................................................................................................. 36 
9.1 
Treatment regimen ............................................................................................................ 36 
9.2 
Dose determinations ......................................................................................................... 37 
9.3 
Supportive therapy ............................................................................................................ 37 
9.4 
Prohibited therapies .......................................................................................................... 38 
9.5 
Participation in other clinical trials ................................................................................... 38 
10.0 
TREATMENT MANAGEMENT ................................................................................................. 39 
10.1 
General instructions .......................................................................................................... 39 
10.2 
Treatment management for T-DM1 and neratinib ............................................................ 39 


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10.3 
Study therapy following tumor progression...................................................................... 39 
10.4 
Management of anemia ..................................................................................................... 39 
10.5 
Infusion reactions/allergic reaction - T-DM-1 .................................................................. 39 
10.6 
Management of diarrhea ................................................................................................... 40 
10.7 
Management of dermatologic toxicities ............................................................................ 42 
10.8 
Dose modifications for T-DM1 and neratinib................................................................... 43 
10.9 
Management of toxicities during T-DM1 and neratinib ................................................... 43 
10.10 Cardiac left ventricular dysfunction .................................................................................. 48 
10.11 Liver dysfunction (Hy's Law) ........................................................................................... 48 
11.0 
DRUG INFORMATION ............................................................................................................... 50 
11.1 
T-DM1 .............................................................................................................................. 50 
11.2 
Neratinib (HKI-272) ......................................................................................................... 50 
12.0 
ADVERSE EVENT REPORTING ................................................................................................ 52 
12.1 
Definition of an AE ........................................................................................................... 52 
12.2 
Definition of adverse events of special interest (AESI) .................................................... 52 
12.3 
Definition of an SAE ........................................................................................................ 53 
12.4 
Events requiring expedited reporting ................................................................................ 53 
12.5 
Pregnancy.......................................................................................................................... 54 
12.6 
Protocol-defined AE reporting exceptions ........................................................................ 54 
12.7 
Grading the severity of the AE ......................................................................................... 54 
12.8 
Expedited reporting instructions ....................................................................................... 55 
12.9 
Time period and frequency for routine reporting of AEs ................................................. 55 
12.10 Documentation requested following death ....................................................................... 56 
13.0 
ASSESSMENT OF EFFECT ........................................................................................................ 57 
13.1 
Definitions ........................................................................................................................ 57 
13.2 
Response criteria ............................................................................................................... 58 
13.3 
Evaluation of best overall response .................................................................................. 58 
13.4 
Symptomatic deterioration ................................................................................................ 58 
14.0 
PATIENT ENTRY PROCEDURES .............................................................................................. 59 
14.1 
Patient consent form ......................................................................................................... 59 
14.2 
Study entry ........................................................................................................................ 59 
14.3 
Patient study number and treatment assignment ............................................................... 59 
14.4 
Investigator-initiated discontinuation of study therapy .................................................... 59 
14.5 
Patient-initiated discontinuation of study therapy ............................................................ 59 
14.6 
Patient-initiated withdrawal from the study ...................................................................... 59 
15.0 
DATA HANDLING AND RECORDKEEPING .......................................................................... 60 
16.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 61 
16.1 
Statistical considerations for the Phase I part of the study ............................................... 61 
16.2 
Statistical considerations for the Phase II part of the study .............................................. 62 
16.3 
Sample size ....................................................................................................................... 62 
16.4 
Accrual time and study duration ....................................................................................... 63 
16.5 
Medical Oversight ............................................................................................................. 63 
17.0 
PUBLICATION INFORMATION ................................................................................................ 64 
18.0 
REFERENCES .............................................................................................................................. 65 
APPENDIX A  ASSESSMENT OF PERFORMANCE STATUS AND ACTIVITIES OF DAILY 
LIVING ....................................................................................................................................................... 71 
APPENDIX B  CONCOMITANT MEDICATIONS AND OTHER SUBSTANCES PROHIBITED 
DURING STUDY THERAPY ................................................................................................................... 72 
APPENDIX C   NSABP FB-10 SAMPLE PATIENT INSTRUCTIONS FOR THE MANAGEMENT OF 
DIARRHEA ................................................................................................................................................ 73 
APPENDIX D   MANAGEMENT OF PARONYCHIA ............................................................................ 76 


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Figure 1 
NSABP FB-10 Schema ..................................................................................................... 13 
Figure 2 
PDX accuracy and clinical response correlation............................................................... 19 
Figure 3 
Management of paronychia............................................................................................... 76 
Table 1 
Tests, exams, and other requirements prior to study entry ............................................... 25 
Table 2 
Tests, exams, and other requirements following study entry ............................................ 27 
Table 3 
Summary of FB-10 patient sample submission requirements .......................................... 28 
Table 4 
Dose escalation design ...................................................................................................... 34 
Table 5 
Treatment regimen – Phase II ........................................................................................... 36 
Table 6 
Dose levels for T-DM1 (Phase II) .................................................................................... 43 
Table 7 
Dose levels for neratinib (Phase II) .................................................................................. 43 
Table 8 
Treatment management for T-DM1 and neratinib (Phase II) ........................................... 43 
Table 9 
T-DM1 and neratinib management based on LVEF assessments ..................................... 48 
Table 10 
Determination of response ................................................................................................ 58 
Table 11 
Dose escalation design ...................................................................................................... 61 
Table 12 
Response criteria for study continuance ........................................................................... 62 
 
 
 


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INFORMATION RESOURCES 
NSABP Department of Site and Study Management  
 
 
 
 
Phone: 
  E-mail: 
 
For questions regarding: 
• 
IRB review & informed consent 
• 
Submission of IRB approval 
• 
Study entry information 
• 
Eligibility 
• 
Treatment regimen 
• 
Dose modifications/delays 
• 
Other clinical aspects of the trial 
• 
Adverse event reporting including 
SAE reporting 
• 
eCRF completion 
• 
Neratinib shipments 
NSABP Department of Site and 
Study Management (DSSM) 
Phone: 
 
E-mail: 
 
For questions regarding data 
management 
DSSM 
Phone: 
 
E-mail: 
 
Submission of data forms 
(including expedited AE reports) 
DSSM 
E-mail: 
 
Requests for study drug (neratinib) 
DSSM 
E-mail: 
 
Questions and submission of tumor 
and blood samples for correlative 
science studies (excluding PDX 
samples) 
NSABP Division of Pathology 
1307 Federal Street, Suite 303 
Pittsburgh, PA  15212 
E-mail: 
 
Phone: 
 
Refer to FB-10 Pathology and 
Correlative Science Instructions and 
to the Champions Oncology 
Overview-Tumor Collection Logistics 
PDX Model Development 
Questions and submission of tumor 
and blood samples for PDX 
correlative science studies 
Champions Oncology 
E-mail: 
 
 
 
 
 
 
 


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GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
ADCC 
antibody dependent cytotoxicity 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ARDS 
acute respiratory distress syndrome 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the curve 
BCIRG 
Breast Cancer International Research Group 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CISH 
chromogenic in situ hybridization 
CNS 
central nervous system 
Cmax 
maximum concentration 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCs 
circulating tumor cells 
CTCAE v4.0 
Common Terminology Criteria for Adverse Events Version 4.0 
CTEP 
Cancer Therapy Evaluation Program 
CYP 
cytochrome P450 
dbGaP 
database of Genotypes and Phenotypes 
DLT 
dose-limiting toxicity 
DSSM 
NSABP Department of Site and Study Management 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 1 
EMILIA 
An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine plus 
Lapatinib in Patients with HER2-positive Locally Advance or Metastatic Breast 
Cancer 
ER 
estrogen receptor 
ErbB 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
FISH 
fluorescence in situ hybridization 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma-glutamyl transferase 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
H&P 
history and physical 
HER2 
human epidermal growth factor receptor 2 


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GLOSSARY OF ABBREVIATIONS AND ACRONYMS (continued) 
HERA 
A study of Intravenous Herceptin (Trastuzumab) in Women with HER2-positive 
Primary Breast Cancer 
HR 
hazard ratio 
IB 
Investigator's Brochure 
IHC 
immunohistochemistry 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
LD 
longest diameter 
LLN 
lower limit of normal 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
MAPK 
mitogen-activated protein kinase 
MARIANNE 
A study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab 
Placebo versus Trastuzumab (Herceptin) Plus a Taxane in Patients with 
Metastatic Breast Cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCCTG 
North Central Cancer Treatment Group 
NeoALTTO 
Neo adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Study 
NCI 
National Cancer Institute 
NK 
natural killer cells 
NOD/SCID                   nonobese diabetic/severe combined immunodeficiency 
NSABP 
NSABP Foundation, Inc. 
ORR 
overall response rate 
p 
probability 
PBMC 
peripheral blood mononuclear cells 
pCR 
pathologic complete response 
PD 
progressive disease 
PDX 
patient derived xenograft 
PET 
positron emission tomography 
PFS 
progression-free survival 
PgR 
progesterone receptor 
PK 
pharmacokinetics 
PO 
by mouth 
PR 
partial response 
PTEN 
phosphatidylinositol phosphate 3'-phosphatase 
q 
every 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase II dose 
RT 
radiation therapy 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SD 
stable disease 
TDM 
therapeutic drug monitoring 
T-DM1 
trastuzumab emtansine 


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GLOSSARY OF ABBREVIATIONS AND ACRONYMS (continued) 
TKI 
tyrosine kinase inhibitor 
tpCR 
total pathological complete response 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
 
 


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1.0 
OVERVIEW OF STUDY DESIGN 
1.1 
Summary 
Note:  On May 3, 2017, accrual to the Phase 1b portion of FB-10 was completed. See Addendum 
below for the rationale for Amendment #5, the Phase II portion of the study. 
The FB-10 study is designed as an open label, single arm, Phase Ib/II study with a dose-escalation 
phase and an expanded cohort (phase II) to evaluate the combination of trastuzumab emtansine  
(T-DM1) with neratinib in women with metastatic, HER2-positive breast cancer.  The primary 
aim of the phase Ib portion of this study is to determine the safety and tolerability of the two-drug 
combination.  The primary aim of the phase II portion is to demonstrate efficacy. 
Patients will receive concurrent therapy with T-DM1 (3.6 mg/kg IV) on Day 1 of a 3-week  
(21 day) cycle and neratinib as a continuous daily oral dose.  The neratinib dose-escalation will 
include 4 dose levels (120 mg, 160 mg, 200 mg, and 240 mg).  At the recommended phase II dose 
(RP2D) of the T-DM1 and neratinib combination, up to 39 additional patients will be treated. 
The neratinib dose-escalation for the study will proceed using a 3+3 design on the basis of  
dose-limiting toxicity (DLT) during cycle 1.  DLT will be defined as the occurrence of 1 or more 
of the following events during cycle 1: any grade diarrhea that is associated with fever or 
dehydration requiring IV fluids; grade 3 diarrhea lasting more than 2 days on optimal medical 
therapy; grade 4 diarrhea of any duration; grade 3 or 4 neutropenia associated with fever; grade 4 
neutropenia lasting more than 7 days; grade 4 thrombocytopenia; grade 3 or 4 non-hematological 
toxicity (excluding grade 3 rash or allergic reaction/hypersensitivity); or any toxicity-related 
delay of more than 2 weeks to initiate cycle 2.  Note: if 2 or more patients assigned to study 
therapy Dose level 1, during Cycle 1 experience a DLT due to grade 4 thrombocytopenia, the 
study will continue with the following actions: 
• 
The T-DM1 dose will be decreased to 3.0 mg/kg (T-DM1 level-1) for all patients 
subsequently enrolled on study. 
• 
The T-DM1 dose will not re-escalate.  T-DM1 dose 3.0 mg/kg will become the 
starting dose for all other study therapy dose levels.  (See Section 10.7.) 
• 
Grade 4 thrombocytopenia will remain a DLT during Cycle 1 for all subsequent dose 
levels. 
• 
Study therapy dose treatment management, after completion of Cycle 1, will continue 
as described in Section 10.  (See Tables 5, 6, and 9.) 
Patients will be enrolled at the next dose level when all evaluable patients at the same dose level 
have completed the first treatment cycle.  Enrolled patients will remain on the assigned dose level 
treatment until toxicity or disease progression. 
The sample size of the phase I portion of the study was 27 patients.  The sample size of the Phase 
II portion will be 22 evaluable patients (and 4 replacement patients).  The total study enrollment, 
phase Ib and II, will be a maximum of 50 patients.   
1.2 
Addendum 
On May 3, 2017 the FB-10 DLT evaluation of the four neratinib dose escalation levels was 
completed determining the maximum tolerated dose (MTD) at dose level 2 (160 mg);  
[dose level 1 at 120 mg: 6 patients/1 DLT; dose level 2 at 160 mg: 6 patients/0 DLTs; dose level 
3 at 200 mg: 8 patients/3 DLTs, and dose level 4 at 240 mg: 3 patients/ 2 DLTs]. 
Analysis of the secondary aims of progression-free survival (PFS) and clinical benefit rate (CBR) 
revealed comparable responses within the patient cohorts of Dose level 1 (120mg) and Dose level 
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In the Phase II portion of the FB-10 study women with metastatic, HER2-positive breast cancer 
will be treated using the RP2D dose level of neratinib 160mg (Phase 1b, dose level 2) in 
combination with T-DM1. 
The sample size of this Phase II study will be 22 evaluable patients.  Accrual is expected to occur 
over 12 to 14 months. 
Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events version 4.0. 
Submission of diagnostic tumor samples and blood samples for FB-10 correlative science studies 
will be a study requirement for all patients.  Blood samples for pharmacokinetics (PKs) and for 
future study will be collected prior to administration of study therapy on Cycle 1/Day 1, Cycle 
1/Day 8 and Cycle 2/Day 1.   
A tumor biopsy will be procured from an accessible site of metastasis before study therapy is 
initiated (after the patient has signed the consent and has been screened for eligibility).  The tissue 
will be sent to NSABP Division of Pathology for molecular studies including but not limited to 
confirmation of HER2-positivity and to Champions Oncology Laboratory for engraftment into an 
NOD/SCID mouse to develop a patient-derived xenograft (PDX) model.  The PDX model will 
undergo drug sensitivity testing and response determination in parallel with the clinical trial (co-
clinical trial). 
An optional blood sample and tumor biopsy will be procured from consenting patients from an 
accessible site of metastasis at the time of disease progression. 
 
 


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Metastatic HER2-Positive Breast Cancer with prior treatment with 
trastuzumab and pertuzumab as neoadjuvant therapy or in first line therapy 
for metastatic disease  
 
T-DM1 IV Day 1 of 
every cycle 
+ 
Neratinib 160 mg PO daily 
beginning on Day 1 of T-DM1 
Until disease progression 
(1 cycle = 21 days) 
•
T-DM1 3.6 mg/kg IV Day 1 of every cycle 
•
Neratinib 160 mg PO daily beginning on Day 1 of T-DM1 and continuing until 
disease progression or intolerable toxicity  
1 cycle = 21 days 
Study Entry 
 
Phase II Stratification 
Trastuzumab and pertuzumab in: 
• Neoadjuvant 
• Adjuvant 
• First line metastatic 
Figure 1 
NSABP FB-10 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 
BACKGROUND 
2.1 
Overview of HER2 targeted therapy 
HER2 overexpression occurs in 20 to 25% of breast cancers (Baselga 1996). HER2 activates 
multiple signaling pathways including the phosphatidylinositol 3-kinase (PI3K) and mitogen-
activated protein kinase (MAPK) cascades.  This results in increased cell proliferation and is 
associated with a poor clinical outcome.  Trastuzumab, a monoclonal antibody, binds to the 
extracellular domain IV of the HER2 receptor, inhibits downstream signaling which leads to 
increases in p27kip (Baselga 1996) levels promoting cell cycle arrest and apoptosis (Nahta 2006).  
Data from in vivo experiments and clinical trials indicate that the efficacy of trastuzumab could 
be partly related to an immune response via  antibody dependent cytotoxicity (ADCC) (Gennari 
2004; Cooley 1999; Clynes 2000)  The Fc ﻻportion of the monoclonal antibody may play a 
significant role in the in vivo activity as it engages Fc ﻻreceptors on immune effector cells such 
as macrophages, NK cells or cytotoxic T cells which release cytotoxic enzymes causing cell lysis.  
A recent clinical finding is that Fc ﻻreceptor polymorphisms may be determinants of trastuzumab 
response in breast cancer patients and supports the potential role of ADCC in trastuzumab-based 
therapies (Musolino 2008). 
The early studies with trastuzumab showed a 12% to 15% response rate as monotherapy in 
extensively treated patients with metastatic disease (Baselga 1996; Cobleigh 1999).  The response 
rate increased to approximately 50% when combined with chemotherapy in patients with 
metastatic disease (Slamon 2001).  In the adjuvant setting and reported in the  joint analysis of 
NSABP B-31/NCCTG 9831, incorporation of a year of trastuzumab into standard adjuvant 
chemotherapy regimen in patients with HER2-gene-amplified or protein-overexpressing breast 
cancer, demonstrated a major improvement in disease recurrence and death.  These findings, 
confirmed by the BCIRG 006 and HERA trials, changed the standard adjuvant therapy for 
women with the HER2-positive breast cancer subtype (Salamon 2006; Perez 2007; Smith 2007).  
In the neoadjuvant setting limited to HER2-positive patients, pCR rates of 40% to 60% have been 
observed, and those that achieve a pCR have a more favorable prognosis than, in particular, those 
who have residual invasive disease (Buzdar 2005; Gianni 2010).  All patients do not benefit from 
trastuzumab and in patients with metastatic disease (Rimm 2012), the vast majority of responders 
to trastuzumab eventually develop resistant disease.  Mechanisms of resistance to trastuzumab 
have been intensively studied and in general include: 1) obstacles for trastuzumab binding to 
HER2 such as truncated HER2, p95HER2 (Scaltriti 2007; Scaltriti 2010); 2) upregulation of 
HER2 downstream signaling; 3) signaling through alternative pathways; and 4) impaired 
immune-mediated cytotoxicity, among others (Pohlmann 2009).  In an effort to increase the 
efficacy of ErbB family blockade, two recently conducted neoadjuvant trials have shown that 
dual blockade of the HER2 receptor with a HER2 antibody and tyrosine kinase inhibitor or two 
antibodies resulted in higher pathologic complete response (pCR) rates than single agent therapy 
(Baselga 2012; Gianni 2012).  In the NeoALTTO trial (N= 455), patients received lapatinib or 
trastuzumab or lapatinib plus trastuzumab for 6 weeks followed by the assigned anti-HER therapy 
plus paclitaxel for 12 weeks, prior to definite surgery (Baselga 2012).  Locoregional total 
pathologic complete response (tpCR) defined as no evidence of invasive disease in breast and 
lymph nodes was statistically higher with lapatinib/trastuzumab (46.8%) than with trastuzumab 
(27.6%,  p=0.0007) alone with no significant difference between the trastuzumab or lapatinib 
(20%, p=0.13) alone groups.  In the NeoSphere trial (N=417) there were four neoadjuvant arms: 
trastuzumab plus docetaxel, pertuzumab and trastuzumab plus docetaxel, pertuzumab and 
trastuzumab or pertuzumab and docetaxel (Gianni 2012).  After four cycles, eligible patients went 
to surgery.  Using the same definition for pCR, tpCR rates were 21.5%, 39.3%, 11.2% and 
17.7%, respectively.  Thus, both studies showed an improved tpCR with dual therapy, and 
importantly, this was achieved without incurring significant additional toxicity. 


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Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically 
deliver the maytansinoid anti-microtubule agent DM1 to the antigen-expressing HER2-positive 
cells improving the therapeutic index of the cytotoxic agent (Lewis Phillips 2008).  In vitro 
studies have shown that T-DM1 and trastuzumab have similar binding affinities for HER2 
(Junttila 2011).  DM1 and trastuzumab are linked by the chelating agent, succinimidyl 4-[N-
maleimidomethyl] cyclohexane-1-carboxylate, through non-reducible thioester bonds.  An 
average of 3.5 DM-1 molecules is conjugated to the Fc region of trastuzumab.  The cytotoxic 
agent DM1, a highly potent antimitotic drug, binds to microtubules similar to vinca alkaloids.  
While maytansine given systemically demonstrated modest antitumor activity, there was 
significant toxicity as a free drug.  Thus, after binding it is postulated that T-DM1-HER complex 
is endocytosed and degraded in lysosomes resulting in the intracellular release of an active 
metabolite, Lys-MCC-DM1 (Austin 2004; Erickson 2006). 
Evaluation of other agents such as tyrosine kinase inhibitors that target this pathway have shown 
promising results in trastuzumab-resistant breast cancer (Geyer 2006; Burstein 2010).  There are 
four receptors in the ErbB family and include: EGFR/ErbB-1, HER-2/ErbB-2, HER-3/ErbB-3, 
and HER-4/ErbB-4.  All four receptors are tyrosine kinases and consist of an extracellular 
binding domain, a single membrane spanning domain, and regulatory domains.  HER1, HER2 
and HER4 have an intracellular tyrosine-kinase domain, HER3 does not.  HER2 is ligandless but 
functions as a co-receptor and is actually the preferred partner for the other ErbB family 
members.  Heregulin is the major HER3 ligand which promotes its engagement with HER2 
kinase and the subsequent transphosphorylation of HER3 (Wallasch 1995).  The heterodimer 
HER2:HER3 has the most potent downstream signaling.  Formation of multiple combinations of 
ErbB receptor homo- and heterodimers, results in activation of the cytoplasmic kinase domain.  
This is turn promotes the phosphorylation of specific tyrosine residues, leading to the stimulation 
of multiple signal transduction pathways (Badache 2004). 
Several oral, small molecule, dual tyrosine kinase inhibitors of HER2 and EGFR have 
demonstrated non-cross resistance with trastuzumab in preclinical studies and activity in women 
with HER2-positive, metastatic breast cancer progressing on trastuzumab (Geyer 2006; Konecny 
2006, Ritter 2007).  The FDA approved agent, lapatinib, is a reversible inhibitor that binds to the 
intracellular domains of HER2 and EGFR at the ATP-binding sites and prevents phosphorylation 
and activation of downstream signaling pathways. 
The investigational agent of interest, neratinib (HKI-272), is an orally administered small 
molecule and is an irreversible inhibitor of pan ErbB receptor tyrosine kinase, which 
distinguishes it from the small molecule lapatinib.  Because of the high degree of homology 
between kinase domains of EGFR and HER2, neratinib inhibits the kinase activity both EGFR 
and HER2 homo- and heterodimers (Rabindaran 2004). 
2.2 
Background for T-DM1 
Data from selected clinical trials of T-DM1 are summarized as follows. In a phase II study 
(n=110) in which T-DM1 was evaluated in patients having disease progression after at least two  
HER-directed therapies, trastuzumab and lapatinib, the objective response rate was 32% as 
assessed by independent review of tumor response (Krop 2012).  The only grade 4 adverse event 
noted was thrombocytopenia in a small percentage of patients. 
The EMILIA study (n=991) is a phase III randomized trial involving patients with locally 
advanced or metastatic HER2-positive breast cancer who previously received trastuzumab and a 
taxane.  In this study T-DM1 was compared with lapatinib plus capecitabine.  The progression-
free survival in patients receiving T-DM1 was 9.4 months compared to 6.4 months in the 
lapatinib-capecitabine arm (HR 0.65; 95% CI 0.55 to 0.77; p<0.001).  The objective response rate 


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was higher with T-DM1 compared to lapatinib-capecitabine, 43.6% vs. 30.8% (p, 0.001).  Rates 
of grade 3 or 4 adverse events were higher in the lapatinib-capecitabine arm that in T-DM1 (57% 
vs. 41%).  The frequency of grade 3 or 4 toxicities >2% with T-DM1 include thrombocytopenia 
(12.9%), elevated AST (4.3%), elevated ALT (2.9%), anemia (2.7%), fatigue (2.4%), 
hypokalemia (2.2%), and neutropenia (2.0%) (Verma 2012). 
A phase III study, MARIANNE (NCT01120184), (n=1095) for HER2-positive patients with 
recurrent locally advanced or metastatic disease compares T-DM1 plus pertuzumab vs. T-DM1 
plus pertuzumab-placebo versus trastuzumab plus taxane in the first-line.  This study has 
completed enrollment and has been reported as an abstract presentation (Ellis 2015). PFS for T-
DM1-containing arms were non-inferior to the control arm (trastuzumab + taxane) but was not 
superior. The ORR for T-DM1 and T-DM1 + pertuzumab was 59.7 % and 64.2% respectively, 
and PFS was 14.1 months and 15.2 months (p=0.31). 
In a retrospective review of the activity of T-DM1 in patients with prior trastuzumab, 
pertuzumab, the tumor response rate was reported as 17.9% (tumor response was determined by 
the treating physician in context of routine care taking into account imaging assessment and 
clinical evaluation). The median duration of therapy was 4.0 months (Dzimitrowicz 2016). 
2.3 
Background for neratinib 
2.3.1 
Data as monotherapy 
In a Phase I clinical trial of neratinib, the dose-limiting toxicities (DLT) were diarrhea, 
nausea and vomiting, anorexia, and rash.  DLT was reached at 320 mg orally per day. 
The maximum tolerated dose (MTD) for phase II study was determined to be 240 mg/day 
(Wong 2006).  The overall response rate observed in breast cancer patients in the Phase I 
study was 32% (8/25). 
A Phase II study evaluated neratinib as monotherapy at a dose of 240 mg per day in 
patients with HER2-positive tumors.  In 63 evaluable patients (cohort A) with previous 
treatment with trastuzumab, response was seen in 16 (24%) patients with a  
progression-free survival of 22.3 weeks; in another cohort of 64 evaluable patients 
(cohort B) who were trastuzumab-naïve, 36 patients responded (56%) with a  
progression-free survival of 39.6 weeks.  The most common adverse events, all grades, in 
both cohorts included diarrhea 89% to 97%, nausea 30% to 42%, and rash/dermatitis 
13% to 27%.  Hand-foot syndrome was not observed.  Grade 3 or greater diarrhea 
occurred in a total of 43% of patients.  Diarrhea occurred early in the course of therapy 
with the median time of onset 2 to 3 days and lasted up to a week.  The diarrhea abated 
with continued treatment.  Thus, while 70% to 90% of patients experienced diarrhea 
during the first week of therapy, this decreased to 10% to 15% with continued therapy 
and the use of antidiarrheals and dose modification.  Rarely did diarrhea necessitate 
discontinuation of neratinib (Burstein 2010). 
2.3.2 
Data for combining neratinib and paclitaxel or trastuzumab 
In a Phase I study, neratinib plus paclitaxel was tested in solid tumor patients with 
ascending doses of neratinib from 160 mg daily to 240 mg daily with paclitaxel at  
80 mg/m2 on days 1, 8, and 15 of a 28-day schedule.  For paclitaxel toxicity the dose 
could be decreased to 70 mg/m2.  No dose limiting toxicities occurred with the paclitaxel 
80 mg/m2 and neratinib 240 mg dosing (Chow 2013).  In the Phase II extension study, 
102 patients with measurable, metastatic, HER2-positive breast cancer were treated with 
neratinib 240 mg daily and paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle.  
There were two cohorts with Group A including patients with ≤ 1 prior chemotherapy 
regimen and no prior lapatinib and Group B with ≤ 3 prior chemotherapy regimens and 


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lapatinib permitted.  The most common grade 3/4 toxicities occurring in > 10% of 
patients included diarrhea (29%), and neutropenia (20%).  Dose reductions of neratinib 
and paclitaxel occurred in 19% and 37% of patients, respectively.  The overall response 
rate was 73%.  Response rate observed in patients with prior trastuzumab was 71%, with 
prior lapatinib 77%, and with prior taxane 81%.  The median PFS for all patients was 
57.0 weeks (95% CI 47.7-81.6 weeks) (Chow 2013). 
A Phase I/II study with the combination of neratinib and trastuzumab in the treatment of 
patients with advanced breast cancer was reported at ASCO in 2009 (Swaby 2009).  In 
the Phase I portion, standard full doses of trastuzumab were used and neratinib was 
escalated from 160 mg/day to 240 mg/day.  This later dose was taken into the Phase II 
portion (n=37).  At neratinib 240 mg/day and trastuzumab 4 mg/kg loading dose 
following by a weekly dose of 2 mg/kg weekly, the major grade 3 toxicities included 
diarrhea (11%), nausea, vomiting, and anorexia < 5%.  There was 1 patient with a > 10% 
fall in LVEF to a value < 50% but without any cardiac symptoms.  Dose reductions 
occurred in 8% of the Phase II patients.  The overall response rate was 29%, clinical 
benefit rate was 35%, and the complete response rate was 7%.  The PFS at 16 weeks was 
45%. 
2.3.3 
Data for combining neratinib, trastuzumab, and paclitaxel 
NSABP FB-8 is a phase I study in heavily pretreated metastatic HER2-positive patients 
which demonstrated that the three–drug combination of neratinib, trastuzumab and 
paclitaxel was both safe and efficacious. Diarrhea occurred in 19 patients (grade 1 = 8; 
grade 2 = 3; grade 3 = 8).  No patients experienced grade 4 diarrhea.  Most patients 
experienced diarrhea within one to three days of initiating study therapy, with 
diminishing symptoms during the first two weeks.  Mandatory prophylactic diarrhea 
management was implemented for all patients at the RP2D of 200 mg/day.  With 
prophylactic management there were no grade 3 or higher diarrhea events at the  
200 mg/day dose.  Best response was a CR in two patients and PR in six patients 
resulting in an objective response in eight of 21 patients (38%).  One patient experienced 
complete resolution of skin disease defined as SD (non-CR/non-PD) by RECIST.  Two 
additional patients had SD lasting greater than 24 weeks including a patient with CNS 
disease who remained stable for 16 months.  The overall clinical benefit rate was 11 of  
21 patients (52%).  Median time to progression (TTP) was 3.7 months.  The three patients 
with prior T-DM1 responded with CR, PR, and SD (Jankowitz 2012). 
2.4 
Phase Ib results (FB-10) of T-DM1 plus neratinib  
T-DM1 binds to HER2 and prevents homodimerization, and to some extent ligand-independent 
dimerization of HER2: HER3 (Garrett 2011).  Its activity likely combines the effects of ADCC 
and the internalization of the potent maytansinoid anti-tubular agent DM1.  It has been 
demonstrated to overcome resistance to trastuzumab.  Neratinib has different mechanism of 
actions inhibiting kinase activity of the heterodimers of HER1:HER3 and HER2:HER3 and 
because the kinase inhibition occurs downstream of the antibody binding domain, it is postulated 
that it would retain activity if HER2 were truncated (p95HER2).  Preclinical data combining 
paclitaxel and neratinib in SKBR-3 breast cancer cells demonstrated a strong additive effect in 
arresting cell proliferation, suggesting that inhibition of microtubule genes potentiates neratinib 
drug response (Seyhan 2011).  Clinical data seems to support this as demonstrated in a study of 
previously treated, HER2-positive metastatic breast cancer patients; the combination of  neratinib 
and the anti-tubular agent, paclitaxel, resulted in an ORR of 73% with responses observed in 
patients with prior trastuzumab (71%), lapatinib (77%), and taxane therapy (81%) (Chow 2013). 


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The Phase Ib study (NSABP FB-10) enrolled HER2-positive metastatic breast cancer patients 
who had previously been treated with chemotherapy and the combination of trastuzumab and 
pertuzumab.  Study treatment consisted of the standard dose of ado-trastuzumab emtansine at 3.6 
mg/kg administered intravenously every 3 weeks and neratinib administered orally at escalating 
doses of 120, 160,200 and 240 mg/day.  The RP2D was 160 mg/day.  For the 16 patients who 
were evaluable for efficacy, the objective response rate (complete plus partial responses) was 9 of 
16 (56%).  There were 3 patients with complete responses lasting 17.1 months, 11.9 months and 
12+ months.  The dose-limiting toxicity was diarrhea. (Abraham 2017). 
Taken together, the combination of T-DM1 and neratinib combines agents with different 
mechanisms of action and different toxicity profiles.  The agents as monotherapy have been 
shown to overcome resistance to trastuzumab.  
2.5 
Rationale for incorporation of patient-derived xenografts as co-clinical trial 
Drug discovery and development in oncology is associated with a high rate of attrition (Di Masi 
2013).  The highest attrition of new agents occurs in the resource intensive Phase II and III 
evaluations.  Such high attrition rates have renewed interest in developing preclinical models 
which are more predictive of clinical outcome (Burgenske 2014). 
While the opportunity of Next Generation Sequencing (NGS) is the generation of highly detailed 
tumor genomic data, the information is frequently overly complex and may not directly translate 
to meaningful treatment decisions.  In addition, while NGS generates important genomic 
hypotheses, this does not guarantee clinical benefit in an individual patient, as not every mutation 
identified will be the oncogenic driver for a patient’s tumor.  Ultimately, it is not until the patient 
has undergone treatment that the clinical benefit can be assessed.  Thus, the opportunity to 
functionally test the NGS-based genomic hypotheses as a corollary to the patient's response to 
treatment could further optimize future treatment selection.  One promising approach that could 
achieve such benefit is testing of therapeutic options in a preclinical model of the patient’s tumor, 
such as a patient-derived xenograft (PDX) model and taking advantage of adequate tissue 
samples to investigate mechanisms of response or resistance. 
Patient-derived xenografts are generated by direct transfer of human tumor fragments from 
patients to immune-deficient mice.  Serial passage of tumors in mice avoids artificial in vitro cell 
culture conditions.  A number of studies confirm the fidelity between the host tumor and the 
mouse models derived from them (Stebbing 2014; Garralda 2014; Weroha 2014; Einarsdottir 
2014).  Histologic concordance has been verified with differentiation between the human and 
mouse engraftment being virtually identical.  Analyses of gene expression profiles, copy-number 
alterations and exome sequencing data all show no substantive differences between donor tumors 
and their PDX.  Using unsupervised clustering analysis, paired donor tumor and PDX models 
cluster together in most studies.  Genes involved in the stroma compartment and immune function 
are less represented in the models due to replacement of the human stroma by murine elements. 
The rationale for incorporating drug testing in PDX models to correlate with clinical outcome is 
several-fold.  First, there is accumulated evidence that an objective response in the PDX models 
will predict response in the patient when tested with the same agents (see Figure 2).  The rationale 
being that the best predictor of response is response itself, and in this case response in the patients 
personalized PDX model.  This should avoid future enrollment on the study of a large number of 
non-responders.  Second, target identification and validation are critical in understanding 
mechanism of response and resistance to a drug combination.  It is becoming clear that predicting 
response to known oncogenes is complex and is altered by different genetic background.  
Redundancies in signaling pathways may result in lack of response in some patients who express 
the oncogenic target.  While clinical samples from the patient are the most relevant biologic 


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samples, acquisition of these samples in adequate quantity is difficult, if not impossible.  PDX 
models afford an opportunity to analyze sufficient quantity of tissue to support target 
identification and functional validation of a target and the opportunity to interrogate the models of 
responders and non-responders to increase understanding of response and mechanisms of 
resistance.  Thirdly, PDX models provide a viable tumor bank for future hypothesis testing 
including testing agents of interest to maximize benefit and potentially block resistance pathways. 
PDX models have the potential of being informative in the patient population being tested in this 
study.  The results from the clinical trial, Emilia, in which second line T-DM1 was given to 
patients after first-line metastatic disease treated with trastuzumab and a taxane reported an 
objective tumor response of 43% (Verma 2012).  Since that trial was conducted, the standard 
treatment for first-line HER2+ MBC includes a taxane plus both trastuzumab and pertuzumab.  
There is anecdotal evidence that the response to T-DM1 after dual anti-HER2 antibody therapy is 
substantially reduced.  While the current trial is evaluating T-DM1 plus neratinib in patients who 
have had prior trastuzumab and pertuzumab, testing PDX models with T-DM1 alone, neratinib 
alone and the combination of T-DM1 plus neratinib may provide evidence as to the value of the 
combination and an opportunity to determine pharmacodynamic interactions. 
 
Figure 2.  PDX accuracy and clinical response correlation 
 
  
 
 


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3.0 
STUDY AIMS AND ENDPOINTS 
3.1 
Primary aim and endpoint for the Phase I part of the study 
Aim: To determine the safety and tolerability of T-DM1 and neratinib in patients with metastatic 
HER2-positive breast cancer 
Endpoint: Recommended doses of T-DM1 and neratinib that can be administered as a 
combination in a Phase II trial (RP2D) 
3.2 
Primary aim and endpoint for the Phase II part of the study 
Aim: To determine the overall response rate (ORR) in patients with measurable metastatic breast 
cancer treated with T-DM1 and neratinib  
Endpoint: Objective response rate (CR/PR) 
3.3 
Secondary aims and endpoints (Phase I and Phase II) 
(Note: Secondary aims and endpoints for Phase I and Phase II of the study will be analyzed 
separately.) 
3.3.1 
Progression-free survival (PFS) 
Aim: To determine the PFS in patients who present with measurable metastatic disease 
Aim: To determine the percentage of first progression in the central nervous system (CNS) 
Endpoint: Time to progression 
3.3.2 
Clinical benefit rate (CBR) 
Aim: To determine objective tumor decrease and stable disease (SD) by RECIST 1.1 
criteria 
Endpoint: Measurement of disease status by continuous tumor measurement 
3.3.3 
Toxicity 
Aim: To evaluate the overall toxicity for the combination of T-DM1 and neratinib 
Endpoint: Frequency and severity of adverse events categorized using the NCI Common 
Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) 
3.4 
Exploratory translational science 
Aim: To explore molecular and genetic correlatives for the degree of benefit from T-DM1 
and neratinib.  
Aim: To determine pharmacokinetics of neratinib.  
Aim: To explore the effect of current and future drugs in PDX models 
 
 


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4.0 
PATIENT ELIGIBILITY AND INELIGIBILITY 
4.1 
Patient selection guidelines 
Although the guidelines in Section 4.1 are not inclusion/exclusion criteria, investigators should 
consider each of these factors when selecting patients for the FB-10 trial.  Investigators should 
also consider all other relevant factors (medical and non-medical), as well as the risks and 
benefits of the study therapy, when deciding if a patient is an appropriate candidate for the FB-10 
trial. 
• 
Co-morbid conditions should be taken into consideration, but not the diagnosis of metastatic 
breast cancer. 
• 
Submission of breast tumor samples from the diagnostic biopsy is required for all patients 
(see Section 7.1).  Therefore, the local pathology department policy regarding release of 
tumor samples must be considered in the screening process.  Patients whose tumor samples 
are located in a pathology department that by policy will not submit any samples for research 
purposes should not be approached for participation in the FB-10 trial. 
4.2 
Conditions for patient eligibility 
A patient cannot be considered eligible for this study unless all of the following conditions are met: 
4.2.1 
The patient must have consented to participate and, prior to study entry, must have signed 
and dated an appropriate IRB-approved consent form that conforms to federal and 
institutional guidelines (see treatment consent form). 
4.2.2 
Patients must be female. 
4.2.3 
Patients must be ≥ 18 years old. 
4.2.4 
The ECOG performance status must be ≤ 2 (see Appendix A). 
4.2.5 
Patients must have the ability to swallow oral medication. 
4.2.6 
Patients must have histologic or cytologic confirmation of the diagnosis of invasive 
adenocarcinoma of the breast. 
4.2.7 
Patients must have had anti-HER2 based therapy with pertuzumab and trastuzumab for 
neoadjuvant therapy, adjuvant or with first line therapy for metastatic disease (which may 
include trastuzumab and pertuzumab either sequentially or in combination).  
4.2.8 
There must be documentation that the patient has evidence of measurable metastatic 
breast cancer (see Section 13.0) that is accessible to biopsy at study entry. 
4.2.9 
Patients must have ER analysis performed prior to study entry.  If ER analysis is 
negative, then PgR analysis must also be performed.  (Patients are eligible with either 
hormone receptor-positive or hormone receptor-negative tumors.) 
4.2.10 Breast cancer must be determined by local testing to be HER2-positive prior to study 
entry using ASCO-CAP HER2 test guidelines. 
4.2.11 At the time of study entry, blood counts performed within 4 weeks prior to study entry 
must meet the following criteria: 
• 
ANC must be ≥ 1000/mm3; 
• 
platelet count must be ≥ 100,000/mm3; and 
• 
hemoglobin must be ≥ 9 g/dL. 
 
(Note: Patient must have discontinued growth factors ≥ two weeks prior to entry labs.) 


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4.2.12 The following criteria for evidence of adequate hepatic function performed within  
4 weeks prior to study entry must be met: 
• 
Total bilirubin must be ≤ 1.5 x ULN, and 
• 
AST and ALT must be ≤ 1.5 x ULN for the lab or ≤ 5 x ULN if liver metastasis. 
4.2.13 Serum creatinine performed within 4 weeks prior to study entry must be ≤ 1.5 x ULN for 
the lab. 
4.2.14 The LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days 
prior to study entry must be ≥ 50% regardless of the facility's LLN. 
4.2.15 Patients with reproductive potential must agree to use an effective non-hormonal method 
of contraception during therapy, and for at least 7 months after the last dose of study 
therapy. 
4.3 
Conditions for patient ineligibility 
Any patient with one or more of the following conditions will be ineligible for this study: 
4.3.1 
Previous therapy with T-DM1 or any HER2 TKI including neratinib for any malignancy. 
4.3.2 
Symptomatic brain metastases or brain metastases requiring chronic steroids to control 
symptoms. 
4.3.3 
Active hepatitis B or hepatitis C with abnormal liver function tests; HIV positive patients 
receiving antivirals. 
4.3.4 
Lung disease resulting in dyspnea at rest. 
4.3.5 
Active infection or chronic infection requiring chronic suppressive antibiotics. 
4.3.6 
Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the 
stomach or small bowel, or other disease or condition significantly affecting 
gastrointestinal function. 
4.3.7 
Persistent ≥ grade 2 diarrhea regardless of etiology. 
4.3.8 
Conditions that would prohibit intermittent administration of corticosteroids for T-DM1 
premedication. 
4.3.9 
Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day 
methylprednisolone equivalent (excluding inhaled steroids). 
4.3.10 Uncontrolled hypertension defined as a systolic BP > 150 mmHg or diastolic BP  
> 90 mmHg, with or without anti-hypertensive medications.  (Patients with hypertension 
that is well controlled on medication are eligible.) 
4.3.11 Cardiac disease (history of and/or active disease) that would preclude the use of any of 
the drugs included in the treatment regimen.  This includes but is not confined to: 
Active cardiac disease: 
• 
symptomatic angina pectoris within the past 90 days that required the initiation of or 
increase in anti-anginal medication or other intervention; 
• 
ventricular arrhythmias except for benign premature ventricular contractions; 
• 
supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication; 
• 
conduction abnormality requiring a pacemaker;  
• 
valvular disease with documented compromise in cardiac function; and 
• 
symptomatic pericarditis 


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History of cardiac disease: 
• 
myocardial infarction documented by elevated cardiac enzymes or persistent regional 
wall abnormalities on assessment of LV function; 
• 
history of documented CHF; and 
• 
documented cardiomyopathy. 
4.3.12 Other nonmalignant systemic disease that would preclude the patient from receiving 
study treatment or would prevent required follow up. 
4.3.13 Pregnancy or lactation at the time of study entry.  (Note: Pregnancy testing should be 
performed within 14 days prior to study entry according to institutional standards for 
women of childbearing potential.) 
4.3.14 The investigator should assess the patient to determine if she has any psychiatric or 
addictive disorder or other condition that, in the opinion of the investigator, would 
preclude her from meeting the study requirements. 
4.3.15 Use of any investigational agent within 4 weeks prior to study entry. 
 
 


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5.0 
CARDIAC SAFETY MONITORING 
5.1 
LVEF assessments 
5.1.1 
Timing of assessments 
LVEF assessments are required prior to study entry and every 3 months while receiving 
study therapy.  Additional LVEF assessments during study therapy and following 
discontinuation of study therapy are at the investigator’s discretion. 
5.1.2 
LVEF assessment guidelines 
• 
2-D echocardiogram is the preferred method for LVEF assessments.  However, 
LVEF assessment by MUGA scan is permitted. 
• 
All LVEF assessments should be performed by the same method, either 2-D 
echocardiogram or MUGA scan that was performed at baseline (before study entry). 
• 
Investigators are strongly urged to schedule the LVEF assessment at the same cardiac 
imaging facility that performed the patient's baseline LVEF assessment. 
5.1.3 
Reporting LVEF assessments 
• 
The LVEF value must be reported on the LVEF Assessment eCRF as a numerical 
value that is a whole number. 
− 
If the facility performing the assessment has not reported the LVEF as a whole 
number, decimals reported as ≥ 5 should be rounded up and decimals reported as 
< 5 should be rounded down.  For example, an LVEF of 54.5% will be rounded 
up and reported as 55%; an LVEF of 54.4% will be rounded down and reported 
as 54%. 
− 
If the facility performing the assessment will only report the LVEF as a range, 
the mean (average) of the values used for the range should be calculated so that a 
single numerical value can be reported. 
• 
Submission of the eCRF with the echocardiogram or MUGA scan report to 
DSSM is required within 14 days after the LVEF assessment.  The eCRF must be 
submitted for every LVEF assessment done for any reason until 3 months following 
discontinuation of study therapy. 
5.2 
Protocol-defined cardiac events 
The cardiac events listed below, as defined by CTCAE v4.0, are the protocol-defined cardiac 
events for the FB-10 trial.  Follow the instructions in Section 12.0 for SAE and AE reporting 
requirements. 
• 
Grade 3 or grade 4 left ventricular dysfunction (congestive heart failure). 
• 
Definite cardiac death: Death due to congestive heart failure, myocardial infarction, or 
documented primary arrhythmia. 
• 
Probable cardiac death: Sudden death without documented etiology. 
 
 


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6.0 
REQUIREMENTS FOR STUDY ENTRY DURING TREATMENT, AND FOLLOW-UP 
Tests, exams and other studies required prior to study entry are listed on Table 1.  Requirements 
following study entry are outlined on Table 2. 
TABLE 1.  Tests, exams, and other requirements prior to study entry 
Required Assessments 
Prior to study entry 
Determination of local pathology department's policy regarding 
submission of tumor samples (Section 4.1)a 
X 
Consent form signed by the patient 
X 
Determination of hormone receptor status (Section 4.2.9) 
X 
Determination of HER2 status (Section 4.2.10) 
X 
History & physical examb 
X 
Within 4 weeks 
Performance status (Appendix A) 
X 
Height & weight 
X 
Assessment of concurrent therapiesc 
X 
Assessment of BP and BP meds 
X 
Determination of measurable disease 
X 
Measurement of target lesion(s) (see Section 13.0)d 
X 
CBC/differential/platelet count 
X 
Serum creatinine 
X 
Total bilirubin/alk phos/AST/ALT 
X 
Serum chemistries: calcium/potassium/sodium/chloride/bicarbonate or 
carbon dioxide/albumin/BUN or urea/glucose/total protein 
X 
Pregnancy teste 
X 
Within 2 weeks 
2-D echocardiogram (or MUGA scan) 
X 
Within 90 days 
Submission of tumor blockf 
X 
After consent is 
signed and 
eligibility 
screening is 
completed 
Required core biopsy to procure samples for submission to NSABP 
Division of Pathologyg 
X 
Core biopsy to procure samples for submission to Champions 
Oncologyh 
X 
Whole blood  to Champions Oncologyh 
Table 1 continues on the next page. 
 
 


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TABLE 1.  Tests, exams, and other requirements prior to study entry (continued) 
a The archived primary tumor tissue from the diagnostic biopsy must be requested and the pathology 
department must agree before study entry to archived tumor block (see Section 7.0).  
b Complete H&P by physician or other healthcare professional. 
c    See Sections 9.3.5, 9.3.6, 11.2.3, and Appendix B. 
d Imaging technique is at the investigator's discretion. 
e 
For WOCBP: Pregnancy testing should be performed according to institutional standards. 
f    Submission of diagnostic tumor block is required for all patients within 60 days following study entry. 
See Information resources, Section 7.1, and the FB-10 Pathology and Correlative Science 
Instructions. 
g    Required submission of tumor tissue (1 core) from an accessible metastatic site in 10% buffered 
formalin submitted to the NSABP Division of Pathology. 
h   Required submission of fresh tumor samples (2-3 cores) and whole blood collection submitted to 
Champions Oncology; see Section 7.0, Section 7.4  
See the FB-10 Pathology and Correlative Science Instructions, and the Champions Oncology 
Overview-Tumor Collection Logistics PDX Model Development for additional tumor and blood 
collection and submission instructions. 


 
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TABLE 2.  Tests, exams, and other requirements following study entry 
Required studies 
(see footnote a) 
Within 72 hours before Day 1 of 
every cycle unless indicated 
otherwise 
(Beginning with Cycle 1) 
Follow-up 
(30 days +/- 7 days f 
following discontinuation of  
study therapy) 
History & physical examb 
X 
Xd 
Weight 
X 
 
Measurement of target lesionsc 
X 
(every 3 cycles during study 
therapy) 
 
Review of concurrent therapiesd 
X 
 
Adverse event assessmente 
X 
Xd 
(at 30 days) 
CBC/differential/platelets 
X 
X 
Serum creatinine; total 
bilirubin/AST/ALT/alkaline  
phosphatase; calcium, 
potassium, sodium, BUN or urea 
X 
 
2-D echocardiogram (or MUGA 
scan)f 
X 
(every 3 months during study 
therapy) 
X 
(If not completed in past 4 
weeks) 
Submission of tumor blockg 
X 
 
Required blood samplesh 
X 
(Cycle 1/Day 1, Cycle 1/Day 8 
and Cycle 2/Day1 only) 
Xi 
(at time of disease progression) 
Optional core biopsyi 
 
X 
(at time of disease progression) 
a 
At the discretion of the investigator, additional exams, bloodwork, x-rays, scans, and other testing may be 
performed as clinically indicated. 
b 
Updated H&P with exams (by physician or other healthcare professional on the FDA 1572)  
c 
Scans will be done every 3 cycles.  The same imaging method used at baseline should be used at all other target 
lesion assessment time points.  Assessment of measurable disease is by RECIST 1.1 criteria (see Section 13.0). 
d     See Sections 9.3.5, 9.3.6, 11.2.3, and Appendix B. 
e 
Should the patient stop study therapy (e.g., due to disease recurrence/progression or second primary) and begin 
a new treatment prior to the 30 day assessment, AE assessment should be collected only up to the date the new 
therapy begins. 
f 
Same method of LVEF assessment that was performed at baseline should be performed. 
g 
Submission of diagnostic tumor block is required for all patients within 60 days following study entry; see 
Section 7.1, and the FB-10 Pathology and Correlative Science Instructions. 
h     Blood collection on Cycle 1/Day 1 and Day 8, and Cycle 2/Day 1 prior to taking neratinib:  Patients should be 
instructed not to take the daily neratinib dose on Cycle 1/Day 1 and Day 8, and Cycle 2/Day 1 until after blood 
collection.  See Section 7.0 . 
i 
When disease progression has been confirmed by imaging per RECIST 1.1 criteria the following optional blood 
and tissue samples are to be collected from consenting patients within 30 days following discontinuation from 
study therapy and prior to initiating any new therapy: 
− 
The optional blood sample will be sent to the NSABP Division of Pathology. 
− 
The optional core biopsy specimens (2 to 4 cores) from an accessible metastatic site or one that increased 
in size when compared to the previous imaging scan result.  Samples should be submitted to Champions 
Oncology on the same day as procurement. See Section 7.0. 
See FB-10 Pathology and Correlative Science Instructions and the Champions Oncology Overview-Tumor 
Collection Logistics PDX Model Development for additional instructions.  


 
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7.0 
PATHOLOGY AND CORRELATIVE SCIENCE STUDIES 
7.1 
Overview of requirements 
Collection and submission of all patient samples are listed below.  By signing the FB-10 consent 
form, the patient has agreed to all required tumor and blood sample collections and submissions. 
See Table 3.  Non-submission of required patient samples will be a protocol violation. 
In the phase II portion of FB-10, procurement and submission of core biopsy tumor specimens 
before study entry (mandatory).  At the time of progression an optional biopsy procedure and 
tissue sample submission will be requested only from consenting patients.  (See treatment consent 
form and optional biopsy consent form.) 
TABLE 3.  Summary of FB-10 patient sample submission requirements 
Study Requirements for 
ALL Patients 
(unless indicated otherwise) 
Prior to Study Entry 
Day 1 of 
Cycle 1 
Day 8 of 
Cycle 1 
Day 1 of 
Cycle 2 
At time of  
disease 
progression 
Submission of a paraffin block 
from the diagnostic biopsy 
samplea 
  Yesa 
(Samples must be submitted 
within  
60 days after study entry) 
 
 
 
 
Core biopsy to procure fresh 
tumor samples and whole blood 
for submission to Champions 
Oncology 
Yesb, after consent signed 
and eligibility screening is 
complete 
Samples should be submitted 
on same day as procurement  
 
 
 
 
Yese 
Optional 
Core biopsy to procure a tumor 
sample for submission to: 
NSABP Division of Pathologyc 
Yesc, after consent signed 
and eligibility screening is 
complete 
Samples should be submitted 
on same day as procurement 
 
 
 
 
Required collection and 
submission of blood samples to 
NSABP Division of Pathology 
 
Yesd 
Yesd 
Yesd 
Yesf 
Optional 
 
Table 3 continues on the next page 
 
 


 
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TABLE 3.  Summary of FB-10 patient sample submission requirements (continued) 
a Submission of an alternative tumor sample is permitted. 
b PDX Samples (whole blood and tumor) to Champions Oncology:. 
     Required: Core biopsy specimens (2-3 cores) from an accessible metastatic site, preferably a metastatic hepatic 
lesion, and a whole blood sample will be collected for PDX prior to study entry from all patients.  Fresh tumor 
and whole blood samples must be submitted overnight on the same day as procurement to Champions Oncology. 
(see Section 7.5.1 ) for PDX procurement and submission  See Section 7.4.2 and Section 7.4.3.   
c    Required: Core biopsy specimens (1 core) from an accessible metastatic site, preferably a metastatic hepatic 
lesion, will be collected prior to study entry from all patients.  See Section 7.4.2.  Submission of tumor samples 
(1 core) in 10% buffered formalin will be submitted to NSABP Division of Pathology.  
d    Required research and pharmacokinetic (PK) blood sample collection must be drawn prior to neratinib and  
T-DM1 dosing: Cycle 1/Day 1, Cycle 1/Day 8 and Cycle 2/Day 1.  Patients should be instructed not to take the 
daily neratinib dose on Cycle 1/Day 1, Cycle 1/Day 8, and Cycle 2/Day 1 until AFTER blood sample collection.  
Note: The blood samples will be sent to the NSABP Division of Pathology.  See Section 7.0. 
e     When disease progression has been confirmed by imaging per RECIST 1.1 criteria, biopsy specimens 
preferably from a new accessible metastatic lesion or one that increased in size when compared to the previous 
imaging scan result are to be collected from consenting patients.  The optional tissue specimen collection must 
be obtained within 30 days following discontinuation from study therapy and prior to initiating any new therapy.  
Tissue samples should be submitted to Champions Oncology on the same day as procurement.  See Sections 
7.4.4 and 7.4.5. 
f 
When disease progression has been confirmed by imaging per RECIST 1.1 criteria, blood samples are to be 
collected from consenting patients. The optional samples will be sent to the NSABP Division of Pathology.   
Refer to the FB-10 Pathology and Correlative Science Instructions for tumor and blood sample submission 
instructions and to the Champions Oncology Overview-Tumor Collection Logistics PDX Model Development. 
7.2 
Use of specimens 
The blood and tumor samples collected in this study will be used for FB-10 studies as described 
in Section 7.2 and for analyses to be conducted in the future related to the purposes of the FB-10 
study but not currently described in the protocol document.  Additionally, the specimens procured 
may be used for future studies involving gene and protein conferring susceptibility to cancer or 
other diseases.  If hereditary genetic studies are conducted, an anonymization process will be 
used.  Results of the correlative science studies, including raw sequencing data, will not be 
reported directly to the patient or the physician and will not have any bearing on patient 
treatment. 
The results of the study will be communicated through publication, in peer reviewed scientific 
literature and/or through presentations at scientific meetings.  Anonymized or de-identified 
research data (as deemed appropriate by the NSABP), including genome sequencing data, may be 
submitted to public research databases for data sharing with controlled access to scientific 
researchers outside of the NSABP. 
7.3 
Tumor and blood sample submission procedures 
The required FB-10 blood samples are submitted to the NSABP Division of Pathology /or 
Champions Oncology (see 
) where the samples will be logged into the 
database and assigned a unique code number.  The samples will be stripped of any remaining 
patient identifiers (except the NSABP FB-10 Patient ID numbers), processed, and stored.  A 
portion of the samples may be shipped to collaborating laboratories.  Refer to the FB-10 
Pathology and Correlative Science Instructions for blood specimen collection and submission 
instructions. 


 
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Tumor tissue samples and blood samples, with the exception of fresh tumor tissue and whole 
blood for PDX, are to be submitted to the NSABP Division of Pathology (
 
) where the samples will be logged into the database and assigned a unique code 
number.  The samples will be identified by the unique code number, processed, and stored.  A 
portion of the samples may be shipped to collaborating laboratories.   
7.4 
Required tissue and blood samples 
7.4.1 
Archived primary tumor tissue block   
Archived paraffin block of primary tumor tissue is required.  Submitted diagnostic tumor 
tissue blocks from the primary tumor will be returned if possible upon requests from the 
sites.  Refer to the FB-10 Pathology and Correlative Science Instructions for tumor tissue 
specimen collection and submission instructions. 
7.4.2 
Required tissue samples  
• To Champions Oncology 
Core biopsy specimens (2 to 3 cores) from an accessible metastatic site will be collected 
from all patients prior to starting study therapy for PDX procurement and submission. 
See Section 7.5.1.  Refer to the Champions Oncology Overview-Tumor Collection 
Logistics PDX Model Development for tissue and blood collection instructions specific to 
the processing of PDX samples. 
• To NSABP Division of Pathology 
Core biopsy tumor tissue (1 core) will be submitted in 10% buffered formalin. 
7.4.3 
Required research blood samples  
To Champions Oncology:  
• A blood sample for PDX will be collected with the core biopsy prior to starting study 
therapy and sent to Champions Oncology.   See Section 7.5.1. 
To NSABP Division of Pathology: 
• Pharmacokinetic (PK) blood samples will be collected on: 
− Cycle 1/ Day 1 
− Cycle 1/Day 8, and 
− Cycle 2/Day 1. 
Note: Patients must be instructed not to take the daily neratinib dose on Cycle 1/ 
Day 1, Cycle 1/Day 8 and Cycle 2/Day1 until AFTER blood sample collection. 
• Blood samples for future analysis will also be collected at time points coinciding with 
PKs: 
− Cycle 1/ Day 1 
− Cycle 1/Day 8, and 
− Cycle 2/Day 1. 
7.4.4 
Optional blood and tissue sample procurement 
When disease progression has been confirmed by imaging per RECIST criteria the 
following optional blood and tumor tissue samples should be collected from consenting 
patients: 
• Core biopsy specimens procured from consenting patients, preferably from a new 
accessible metastatic lesion or one that increased in size when compared to the 
previous imaging scan result.  Tissue samples should be submitted to Champions 
Oncology on the same day as procurement.  See Section 7.5. 


 
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• Blood samples are to be collected from consenting patients. The optional samples 
will be sent to the NSABP Division of Pathology. 
Note: Biopsy specimens and blood samples at the time of progression must be 
collected within 30 days following discontinuation from study therapy and prior to 
initiating any new therapy. 
7.5 
Patient derived xenografts (PDX) 
7.5.1 
PDX tissue and blood samples:  
As a requirement of FB-10 phase II, patients will have a baseline fresh tumor tissue 
biopsy, and a blood sample submitted to Champions Oncology for generation of the PDX 
model.  Upon disease progression an optional biopsy (preferably from a new accessible 
metastatic lesion or one that increased in size when compared to the previous imaging 
scan result) will be collected from consenting patients and submitted to Champions 
Oncology.  Specimens will be placed into vials containing transport medium that will be 
provided by Champions Oncology and labeled with a unique trial number identifier.  
Refer to Champions Oncology Overview-Tumor Collection Logistics PDX Model 
Development for tissue and blood collection instructions specific to the processing of 
PDX samples. 
• 
Tumor Tissue 
Fresh tumor tissue will be obtained through surgical procedure or biopsy.  To 
maximize the success of tumor engraftment in the immune-deficient mouse, it 
is requested that 0.5 cm3 or 3 to 4 x 18 gauge biopsies be obtained.  
Transportation of the specimen to the designated implantation site will be 
arranged in advance with Champions Clinical Operations team.  Ideally, the 
time from tumor extraction to placement in media should be as soon as 
possible but less than 30 minutes.  Exact times will be recorded.  Refer to the 
Champions Oncology Overview-Tumor Collection Logistics PDX Model 
Development for tissue collection instructions specific to the processing of 
PDX samples. 
• 
Whole Blood Sample 
A whole blood sample will also be submitted at the time of tumor biopsy or 
surgical procedure to Champions Oncology.  This will enable a comparison of 
normal DNA profile to tumor DNA.  Once collected, whole blood samples 
will be included with tissue specimen collection in an insulated container for 
transport to the designated implantation site.  
7.6 
PDX Model Development 
7.6.1 
Tumor graft 
Upon receipt of the tumor specimen at the designated implantation site, tumor tissue will 
be implanted into immune-deficient mice following the standard operating procedures 
(SOPs).  The expected success rate in generating a viable model in metastatic breast 
cancer for drug testing is approximately 50%.  
7.6.2 
Assessment of response in the tumor graft 
Drugs selected for testing in this model will be determined by the same agents that the 
patient will receive in the clinical study except in the PDX, the agents will be tested as 
single agents and in combination. 


 
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Agent Efficacy: All test agents will be formulated according to manufacturer’s 
specifications for testing in a mouse model.  Cohorts of mice will be randomized into 
treatment groups. Drug sensitivity testing will last for a total of 28 days.  Beginning Day 
0, tumor dimensions will measured twice weekly by digital caliper and data, including 
individual and mean estimated tumor volumes (Mean TV ± SEM), are recorded for each 
group.  Tumor volume was calculated using the formula: TV= width2 x length x π/2. 
Tumor Growth Inhibition: At study completion, percent tumor growth inhibition (%TGI) 
values will be calculated and reported for each treatment group (T) versus control (C) 
using initial (i) and final (f) tumor measurements by the formula: %TGI=[1-(Tf-Ti)/(Cf-
Ci)] x 100.  
RECIST: Individual mice reporting a tumor volume >120% of the Day 0 measurement 
are considered to have progressive disease (PD).  Individual mice with neither sufficient 
shrinkage nor sufficient tumor volume increases are considered to have stable disease 
(SD).  Individual mice reporting a tumor volume ≤70% of the Day 0 measurement for 
two consecutive measurements over a seven day period are considered partial responders 
(PR).  If the PR persisted until study completion, percent tumor regression (%TR) is 
determined using the formula: %TR= (1-Tf /Ti) x 100; a mean value is calculated for the 
entire treatment group.  Individual mice lacking palpable tumors for two consecutive 
measurements over a seven day period are classified as complete responders (CR). All 
data collected in this study will be managed electronically and stored on a redundant 
server system.  
7.7 
Rationale for correlative science studies 
Obtaining core biopsy samples pretreatment and at disease progression for molecular profile 
provides a unique opportunity to discover candidate predictive markers of response or potential 
resistance to the study drugs and opportunity to understand the mechanism of resistance to study 
drugs. 
Since T-DM1 is an antibody-drug conjugate directed to HER2 overexpressing tumor cells, HER2 
expression level is expected to be the main predictor of response, with higher levels associated 
with better response.  On the other hand neratinib is a pan-HER family tyrosine kinase inhibitor 
and therefore is expected to be effective for tumor cells with dependence on any members of 
HER family of receptors. 
Hence our primary hypothesis is that T-DM1/neratinib in combination would be effective in 
tumors dependent on any member of the HER family receptors.  We hypothesize that intrinsic 
resistance to T-DM1/neratinib could happen due to activation of other receptor signaling pathway 
such as IGFR or MET bypassing HER receptors, or through activation of downstream signaling 
pathway (such as PIK3CA or AKT) due to activating mutation.  Since tumor cells with high 
levels of HER2 expression may be readily killed by T-DM1 regardless of PIK3CA mutation due 
to its chemotherapy effect, it is hypothesized that HER2 positive tumors with relatively lower 
levels of HER2 and PIK3CA mutation would be relatively resistant to T-DM1/neratinib 
combination therapy. 
In order to address the hypotheses delineated above, we may perform molecular profiling of 
procured tumor tissue samples from consenting patients through comprehensive gene expression 
profiling (using RNAseq or nCounter assay), phosphoprotein profiling with reverse phase protein 
array, and mutation profiling (with next generation sequencing or hotspot mutation profiling with 
mass spec).  Tissue from PDX models will be obtained to provide greater insight into these 
molecular analyses. 


 
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PDX models have the potential of being informative in the patient population being tested in this 
study.  The results from the clinical trial, Emilia, in which second line T-DM1 was given to 
patients after first-line metastatic disease treated with trastuzumab and a taxane reported an 
objective tumor response of 43% (Verma 2012).  Since that trial was conducted, the standard 
treatment for first-line HER2+ MBC includes a taxane plus both trastuzumab and pertuzumab.  
There is anecdotal evidence that the response to T-DM1 after dual anti-HER2 antibody therapy is 
substantially reduced, tumor response rate 17% (Dzimitrowicz 2016). 
While the current trial is evaluating T-DM1 plus neratinib in patients who have had prior 
trastuzumab and pertuzumab, testing PDX models with T-DM1 alone, neratinib alone and the 
combination of T-DM1 plus neratinib may provide evidence as to the value of the combination 
and provide tissue for understanding potential mechanisms of sensitivity and resistance. 
In addition to proposed experiments listed above, blood samples collected on Day 1 of Cycle 1 
(prior to receiving the first dose of study therapy), at Cycle 1/Day 8 and also on Day1 of Cycle 2 
before study therapy dosing may be used for determinations of pharmacokinetic interactions and 
therapeutic drug monitoring (TDM).   TDM analysis measures the plasma concentrations of a 
therapeutic agent and metabolites in patients to individualize appropriate drug dosages and 
schedules (Gao 2012).  Individual pharmacokinetic variations in absorption, metabolism and 
elimination ultimately affect total drug concentration and drug exposure resulting many times in 
under-dosing of patients or overdosing leading to toxicities.  Therefore, TDM can potentially be 
used to adjust individual drug dosages by correlating with drug exposure and pharmacodynamic 
response, resulting in maximum drug efficacy while decreasing relative toxicities. 
Blood will be collected at various time points before and during treatment and may be used to 
quantify and characterize circulating tumor DNA (ctDNA),  sequencing of circulating free tumor 
DNA and assay for ADCC as well as other analyses as they pertain to this study.  


 
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8.0 
DOSE ESCALATION 
Note: Accrual to the Phase I dose escalation portion of FB-10 was closed on May 3, 2017.   
See Section 9.0 for the study therapy regimen of the Phase II portion. 
8.1 
Dose escalation design  
TABLE 4.  Dose escalation design  
Dose level 
Neratinib 
T-DM1 
No. of Patients 
1 
120 mg/day PO 
3.6 mg/kg IV Day 1 
every 3 weeks 
3 to 6 
2 
160 mg/day PO 
3.6 mg/kg IV Day 1 
every 3 weeks 
3 to 6 
3 
200 mg/day PO 
3.6 mg/kg IV Day 1 
every 3 weeks 
3 to 6 
4 
240 mg/day PO 
3.6 mg/kg IV Day 1 
every 3 weeks 
3 to 6 
The first cohort will be treated at dose level 1.  If 1 of 3 patients in this cohort experiences a  
DLT, 3 more patients will be added at the same dose level.  If 0 of 3 initial patients or 1 of 6 
patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated 
to dose level 2; otherwise, the combination will be considered too toxic.  However, if 2 or more 
patients assigned to study therapy Dose level 1, Cycle 1 experience a DLT due to grade 4 
thrombocytopenia, the study will continue with the following actions: 
• 
The T-DM1 dose will be decreased to 3.0 mg/kg (T-DM1 level-1) for all patients 
subsequently enrolled on study. 
• 
The T-DM1 dose will not re-escalate.  T-DM1 dose 3.0 mg/kg will become the 
starting dose for all other study therapy dose levels.   
• 
Grade 4 thrombocytopenia will remain a DLT during Cycle 1 for all subsequent dose 
levels. 
• 
Study therapy dose treatment management, after completion of Cycle 1, will continue 
as described in Section 10.  
Similarly, at dose level 2 and subsequent dose levels if 1 of 3 patients experiences a DLT, 3 more 
patients will be added.  If ≥ 2 DLTs are experienced at any dose level, the combination will be 
considered too toxic and the next lower dose level will be considered the MTD.  If only 3 patients 
were treated at the MTD, an additional 3 patients will be entered into the cohort.  The MTD at 
which < 2 of 6 patients experience a DLT will be the RP2D. 
In addition to DLT identification that occurs during Cycle 1, the overall emerging toxicity profile 
will be taken into consideration when determining the MTD.  Given that diarrhea is the most 
frequent DLT, an overall safety profile of < 25% grade 3 diarrhea is expected.  Should ≥ 25% 
grade 3 diarrhea lasting more than 24 hours be observed cumulatively at a given dose level while 
receiving optimal diarrhea management, the MTD may be decreased by one dose level. 
8.2 
Definition of dose-limiting toxicity (DLT) 
Toxicities should be attributable to the study drugs (possible, probable, or definite) to constitute 
DLT.  Occurrence of one or more of the following during the first cycle of treatment will 
constitute a DLT: 
• 
Diarrhea (any grade) that is associated with fever or dehydration requiring IV fluids 


 
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• 
Grade 3 diarrhea lasting > 2 days on optimal medical therapy 
• 
Grade 4 diarrhea of any duration 
• 
Grade 3 or 4 neutropenia associated with fever 
• 
Grade 4 neutropenia lasting > 7 days 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 or 4 nonhematological toxicity (excluding grade 3 rash or allergic 
reaction/hypersensitivity) 
• 
Toxicity-related delay of > 2 weeks to initiate cycle 2. 
Patients will be enrolled in the next dose level when all evaluable patients at the same dose level 
have been completed the first treatment cycle. 
8.3 
Dose escalation rules 
• 
Only DLTs observed during Cycle 1 of treatment will affect dose escalation.   
• 
Patients who do not continue on study and are not evaluable for toxicity assessment during 
the first cycle will be replaced. 
 
 


 
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9.0 
STUDY TREATMENT 
Note: On May 3, 2017, the Cycle 1 DLT evaluation of the four neratinib dose escalation levels 
was completed. 
See Section 9.1, Table 5 for the Phase II portion of the study. 
9.1 
Treatment regimen 
Study therapy should begin within 2 weeks following study entry. 
TABLE 5.  Treatment regimen – Phase II 
Drug 
Dose 
Dosing Interval 
Planned Duration 
T-DM1 
First dose: 3.6 mg/kg IV over 90 mina,b 
Subsequent doses: 3.6 mg/kg IV over  
30 mina,b 
(Premeds at investigator's discretion) 
Day 1 of a 3-
week cycle (q 21 
days) 
Until study therapy is 
stopped due to toxicity 
 or  
disease progression 
 
Neratinib 
160 mg PO once daily (40 mg tablets 
taken with food, preferably in the 
morning)c 
Daily beginning 
on Day 1 of the 
first  
T-DM1 cycle 
a The first infusion of T-DM1 will be administered over 90 minutes (+/- 10 minutes). 
• 
Vital signs must be assessed before and after each dose administration. At the physician's 
discretion, premedication e.g., dexamethasone, diphenhydramine, and an H2-blocker may be 
used. 
• 
Infusions may be slowed or interrupted for patients experiencing infusion-related symptoms.   
• 
Observe patients for 60 minutes following the initial dose for fever, chills, or other infusion-
related symptoms. 
• 
If prior infusions were tolerated well, subsequent doses may be administered over 30 minutes 
(+/- 10 minutes) with a minimum 30 minute observation period after the infusion. 
b See Section 10.5 and Table 8 for instructions regarding T-DM1 infusion-related allergic reactions and 
anaphylaxis. 
c Other neratinib instructions: 
See Section 10.6 for mandatory prophylactic antidiarrheal therapy instructions and Appendix C. 
• 
If a neratinib dose is missed at the usual time, it should be taken as soon as possible within 12 
hours following the time the dose should have been taken.  If >12 hours, the dose will be 
missed for that day. 
• 
If a patient vomits after taking neratinib, the patient should be instructed to not take another 
dose that day (unless the tablets can be seen).  The patient should resume taking neratinib at 
the next scheduled dose.  If vomiting persists, the patient should be instructed to notify the 
investigator.  See Section 10.2.1. 
• 
Neratinib absorption is dependent on stomach acidity.  See Sections 9.3.5, , and 11.2.3 for 
neratinib dosing and concomitant medication guidance. 
• 
Mandatory telephone calls are required during Cycle 1 as per Section 10.6.1. 
Use of a patient diary, calendar, or other tool for the patient to record neratinib doses should be 
strongly encouraged. 
 
 
 


 
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9.2 
Dose determinations 
9.2.1 
Calculation of drug doses 
• 
Starting doses for T-DM1 must be based on the patient’s baseline weight. 
9.2.2 
Rounding doses 
Rounding of T-DM1 dose is optional.  If the treating physician decides to round the dose, 
follow these guidelines.  (These also apply to dose modifications.)  T-DM1 should be 
rounded to the nearest 20 mg.  See Table 5, Section 10.8.1 and Table 6. 
9.3 
Supportive therapy 
9.3.1 
G-CSF 
• 
Prophylactic use of growth factors, e.g., G-CSF, GM-CSF, is not permitted. 
9.3.2 
Erythropoietin 
Use of an erythropoiesis-stimulating agent is not permitted.  (See Section 10.4 for 
instructions regarding ≥ grade 3 anemia.) 
9.3.3 
Antiemetic therapy 
Antiemetic therapy should be administered according to NCCN or ASCO Clinical 
Practice Guidelines. 
9.3.4 
Management of diarrhea 
Diarrhea is a commonly occurring toxicity with the therapy included in FB-10.  Primary 
antidiarrheal prophylactic medication must begin with the first dose of neratinib.    
Patients must be instructed to have ready access to antidiarrheal agents (loperamide and 
budesonide) at home, starting on Day 1 of treatment.  Patients must also be instructed 
regarding the importance of prompt reporting of diarrhea, use of antidiarrheal 
medications and non-pharmacologic interventions.  See Section 10.6 and Appendix C for 
diarrhea management instructions and Table 8 in Section 10.9 for T-DM1/neratinib 
treatment management instructions. 
Patients taking neratinib who have multiple loose bowel movements in a day or any 
worsening of fatigue, nausea, vomiting, right upper quadrant abdominal pain or 
tenderness, fever, rash, or eosinophilia should be promptly evaluated for changes in liver 
function.  (See Appendix C for sample patient instructions for diarrhea management.) 
9.3.5 
Proton pump inhibitors 
Avoid concomitant use of proton pump inhibitors (PPI).  It has been observed that a 
single 240-mg dose of neratinib combined with a proton pump inhibitor lowered the 
absorption of neratinib up to seven-fold.  It is not known whether separating the time of 
taking a proton pump inhibitor and neratinib reduces the interaction. 
9.3.6 
H2-receptor antagonists and antacids 
The absorption of neratinib in the stomach is dependent on stomach acidity.  Medications 
that reduce the secretion of gastric acid in the stomach such as H2-receptor antagonists 
(e.g., ranitidine) may affect how neratinib dissolves in the stomach.  It is not known 
whether separating the time of taking an H2-blocker and neratinib reduces the interaction. 
If antacids are necessary, the antacid dose and the neratinib dose should be separated by 3 
hours. 
 
 


 
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9.4 
Prohibited therapies 
The following types of treatment, in addition to any cancer therapy other than the therapy 
specified in this protocol, are prohibited while on study therapy. 
9.4.1 
Chemotherapy 
Administration of chemotherapy other than the chemotherapy specified in this protocol is 
prohibited. 
9.4.2 
Targeted therapy 
Administration of targeted therapy for malignancy (other than the assigned targeted 
therapy regimen) is prohibited. 
9.4.3 
Radiation therapy 
Radiation therapy (RT) to target lesions is prohibited.  Palliative RT to non-target lesions 
is permitted. 
9.4.4 
CYP3A4/5 inhibitors 
Concomitant use of strong CYP3A4/5 inhibitors (such as ketoconazole and itraconazole) 
with T-DM1 and neratinib should be avoided.  An alternate medication with no or 
minimal potential to inhibit CYP3A4/5 should be considered.  If a strong CYP3A4/5 
inhibitor is co-administered with study therapy (T-DM1 and neratinib), patients should 
be closely monitored for reactions.  (See Appendix B.)  
9.5 
Participation in other clinical trials 
If an FB-10 patient is considering participation in another clinical trial (including supportive 
therapy trials), contact the DSSM (
). 
 
 


 
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10.0 
TREATMENT MANAGEMENT 
10.1 
General instructions 
• 
The NCI CTCAE v4.0 must be used to grade the severity of AEs. 
• 
All treatment decisions must be based on the AE requiring the greatest modification. 
• 
Drug doses that have been reduced may not be escalated. 
• 
Patient compliance with neratinib must be maintained by pill count prior to beginning each 
cycle. 
10.2 
Treatment management for T-DM1 and neratinib 
The T-DM1 treatment schedule should be maintained.  If necessary, the timing of a treatment 
may be adjusted to 3 days earlier or 3 days later than the scheduled date of treatment. 
10.2.1 Treatment decisions when therapy must be held 
• 
See Table 8 for treatment management. 
• 
If T-DM1 and neratinib are held for > 3 days but < 2 weeks, the date when T-DM1 
and neratinib are resumed becomes Day 1 of the next cycle. 
• 
If study therapy must be held for > 2 weeks of continuous delay, study therapy must 
be discontinued (see Section 10.2.2). 
• 
NOTE:  If the patient experiences acute vomiting or diarrhea with concomitant  
T-DM1 and neratinib, on subsequent cycles neratinib may be held for up to 4 days 
(e.g., Day 1 T-DM1 administered; neratinib held on days 1, 2, 3, 4).  Resume 
neratinib daily.  Record doses of neratinib held. 
10.2.2 Treatment decisions when therapy must be discontinued 
• 
If a patient experiences a T-DM1 adverse event requiring drug discontinuation,   
neratinib may be continued at the current dose level.  If a patient experiences an 
adverse event attributable to neratinib requiring discontinuation, T-DM1 may be 
continued at the current dose level.  This option is available after a patient has 
demonstrated an objective response or stable disease per RECIST criteria. 
• 
If alternative (non-protocol) therapy is given at any time, study therapy must be 
discontinued. 
• 
If study therapy is discontinued, further therapy is at the investigator's discretion. 
10.3 
Study therapy following tumor progression 
If tumor progression occurs during study therapy, study therapy must be discontinued.  Further 
therapy is at the investigator's discretion. 
10.4 
Management of anemia 
Transfusion is acceptable for improving the hemoglobin value to allow therapy to continue 
without delay.  Use of erythropoiesis-stimulating agents is prohibited. 
10.5 
Infusion reactions/allergic reaction - T-DM-1 
See Table 8 for treatment management instructions. 
• 
Grade 1 infusion reaction:  
− Slow the infusion and assess the patient; management is at the investigator's 
discretion. 
 
 


 
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• 
Grade 2 infusion reaction: 
− 
Decrease the infusion rate by 50% (or interrupt) and monitor closely for 
worsening condition. 
− 
Administer appropriate therapy per investigator's discretion.  
− 
Restart at 50% infusion rate, may increase rate by 50% increments every 30 
minutes as tolerated. 
− 
When symptoms resolve to ≤ grade 1, infusion may be resumed later that day or 
on the next day with premedications.  
− 
Premedications should be used for all subsequent treatments.  
− 
Infusions may be restarted at full rate at the next cycle with appropriate 
monitoring for all subsequent treatments. 
• 
Grade 3 infusion reaction: 
− 
If determined by the investigator to be non-serious, follow the instructions for 
grade 2 infusion reaction 
− 
If determined by the investigator to be serious, immediately and permanently 
discontinue T-DM1. 
10.6 
Management of diarrhea 
Diarrhea is a commonly occurring toxicity with the therapies included in FB-10.  Monotherapy 
with neratinib has a median time of 3 days to onset of diarrhea.  With combination therapy, it is 
anticipated that diarrhea may occur earlier.  For the majority of patients, diarrhea subsides after 
about first cycle.  Therefore it is critical that intensive prophylactic measures begin at the 
start of therapy.  (See Section 10.6.1 and Appendix C.)  
10.6.1 Intensive primary prophylaxis  
Recent preclinical studies suggest that multiple mechanisms may be involved in the 
pathogenesis of neratinib-induced diarrhea, including elements of secretory and 
inflammatory diarrhea (Puma biotechnology, on file).  Interim analysis of CONTROL 
study reported a cohort of patients testing budesonide, a locally acting corticosteroid used 
for inflammatory gastrointestinal conditions, had reduced grade 3 diarrhea by 
approximately 50% ( to 16%) (Barcenas 2016).  Budesonide has a high first-pass 
metabolism with minimal systemic absorption. It is therefore felt to cause fewer side 
effects than traditional glucocorticosteroids and to be generally well tolerated (O'Donnell 
2010).   
Antidiarrheal medications must begin with the first dose of neratinib.  Inform 
patients that they will experience diarrhea while taking neratinib. 
• 
Loperamide (Imodium®) 
− 
Patients must receive an initial dose of loperamide 4 mg (2 tablets) with the first 
dose of neratinib. 
− 
Following the initial dose of loperamide patients should take loperamide 4 mg  
(2 tablets) every 6 hours for the first 48 hours (total: 8 tablets /day).  
− 
After the first 48 hours if diarrhea is < grade 2, the patient should be instructed to 
take loperamide 2 mg (1 tablet) every 4 hours while awake, and 4 mg (2 tablets) 
at bedtime for the first 2 weeks of therapy.  If diarrhea persists, the patient should 
be instructed to continue loperamide 4 mg (2 tablets) every 6 hours until diarrhea 
is < grade 2 (see Section 10.6.2 and Appendix C.) 
 
 


 
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− 
After the first 2 weeks of Cycle 1, instruct patients to take loperamide 2 mg  
(1 tablet) every 6 to 8 hours.  After Cycle 1 loperamide may be titrated 
loperamide as needed to keep diarrhea < 4 stools a day.  See Appendix C for 
further patient instructions. 
• 
Budesonide (Entocort, Uceris, or Pulmicort) 
− 
Patients must receive an initial dose of budesonide 9 mg by mouth with the first 
dose of neratinib and be instructed to take budesonide 9 mg once daily during 
Cycle 1 and Cycle 2. 
− 
Patients should be instructed to take budesonide 9 mg by mouth (once daily in 
the morning) with a full glass of water (8 ounces/240 milliliters) with or without 
food.  Patients should be instructed to swallow this medication whole; do not 
crush or chew.  If patients will be using the extended-release tablets, they should 
not split the tablets unless they have a score line and they are instructed to do so.  
Patients should swallow the whole or split tablet without crushing or chewing. 
(Note: The participating study site will dispense a packet containing 30 (2 mg) tablets of 
loperamide to each study patient for the start of diarrheal prophylaxis.  Subsequent 
loperamide doses will be the responsibility of the patient.  Loperamide is available OTC. 
Budesonide will be provided or reimbursed for Cycle 1 and 2.) 
• 
Mandatory telephone calls must be made to patients by a clinical trial team member 
during Cycle 1, Days 2, 3, and 4 (i.e., approximately 24, 48, and 72 hours after start 
of study therapy).  Documentation should include: 
− 
Date of call; 
− 
Response of patient's report of adverse events; and 
− 
Any action taken. 
− 
Telephone calls should continue as needed during cycle 1. 
• 
Patients must be instructed to: 
− 
Start prophylactic loperamide on Day 1, with the first dose of neratinib. 
− 
Start prophylactic budesonide on Day 1, with first dose of neratinib. 
− 
Continue prophylactic therapy as directed. 
− 
Promptly report diarrhea symptoms.  
Note: Patients taking T-DM1/neratinib who have multiple loose bowel 
movements and any worsening of fatigue, nausea, vomiting, right upper quadrant 
abdominal pain or tenderness, fever, rash, or eosinophilia should be promptly 
evaluated for changes in liver function.  See Section 10.11. 
− 
Record the number of stools per day. 
− 
Record each dose of antidiarrheal medicine taken each day. 
− 
Report constipation before taking any laxatives or stopping antidiarrheal 
medication.  
10.6.2 Pharmacologic diarrhea management 
• 
For patients with persistent grade 1 diarrhea on loperamide, diphenoxylate 
hydrochloride and atropine sulfate (Lomotil) 1 tablet every 6 to 8 hours may be 
added. 
• 
For Grade 3 or Grade 4 diarrhea with complicating features (dehydration, fever, 
and/or Grade 3-4 neutropenia). 
− 
Hold study therapy. 
− 
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 


 
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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). 
− 
Use IV therapy as appropriate. 
− 
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.  Positive 
results from occult blood, fecal leukocyte stain, Clostridium difficile, 
Campylobacter, Salmonella, and Shigella testing, if performed, must be reported 
using the appropriate eCRF. 
− 
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. 
− 
Recommend dietary measures outlines in Section 10.6.3. 
− 
See Table 8 for study therapy dose management. 
• 
Patients should be monitored for constipation and prophylaxis adjusted accordingly.  
Do not discontinue antidiarrheals completely; doses may be adjusted. 
• 
For the second and subsequent cycles, the dose of loperamide should be titrated to 
keep diarrhea controlled to < 4 stools a day. 
10.6.3 Dietary management 
Instruct patients to: 
• 
Stop all lactose-containing products (milk, yogurt, cheese, etc.). 
• 
Drink 8-10 large glasses (64-80 ounces) of clear liquids per day. 
• 
Eat frequent small meals. 
• 
Maintain a low fat diet enriched with rice, bananas, and applesauce, and/or toast. 
10.6.4 Dose modifications 
For study therapy dose modifications, see Section 10.8, and Table 6, Table 7 and Table 8. 
Note: Hematological dose modifications should be made on the basis of values obtained 
for Day 1 of each cycle and not on interim laboratory values that may be obtained in 
between cycles.  However, should the patient experience clinical symptoms or associated 
toxicities, dose adjustment may be made at the investigator's discretion in conjunction 
with the study team. 
Refer to the ASCO Recommended Guidelines for Treatment of Cancer Treatment-
Induced Diarrhea for additional recommendations regarding diarrhea (Benson 2004). 
10.7 
Management of dermatologic toxicities 
10.7.1 Management of paronychia and fissures in fingertips 
Note: Paronychia and fissures involving the fingertips have not been determined to be an 
effect of neratinib, but are an effect of similar drugs.  Therefore, the following 
management instructions are provided: 
• 
Paronychia 
For treatment of paronychia, antiseptic bathes and topical corticosteroids are 
recommended.  Other topical measures include use of silver nitrate applications.  
Topical or oral antibiotics should be considered if local infection is present.  If no 
improvement is seen, a dermatology consultation is recommended.  See Table 8 for 
dose modifications and delays for paronychia.  (See also Appendix D, Figure 3.) 


 
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• 
Fissures in fingertips 
For fissures in the fingertips, an application of zinc oxide 30% (or higher) ointment 
may be used. 
10.8 
Dose modifications for T-DM1 and neratinib 
Dose modifications for T-DM1 are based on dose level changes outlined in Table 6.  Dose level 
changes for neratinib are outlined in Table 7. 
10.8.1 Dose modifications for T-DM1 
 
TABLE 6.  Dose levels for T-DM1 (Phase II) 
 
Dose Level 0 
Starting Dose 
Dose Level −1 
Dose Level −2 
Dose Level −3 
T-DM1 
3.6 mg/kg 
3.0 mg/kg 
2.4 mg/kg 
Discontinue 
10.8.2 Dose modifications for neratinib 
 
TABLE 7.  Dose levels for neratinib (Phase II) 
 
Dose Level 0 
Starting Dose 
Dose Level −1 
Dose level −2 
Neratinib 
160 mg 
(3 tablets) 
 120 mg 
DC 
10.9 
Management of toxicities during T-DM1 and neratinib  
The instructions for management of toxicities during T-DM1 and neratinib are outlined in Table 8.  
See Table 9 for T-DM1 and neratinib management based on LVEF assessments. 
TABLE 8.  Treatment management for T-DM1 and neratinib (Phase II) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v 4.0 
Grade 
Action to be Taken 
T-DM1 
Neratinib 
Blood and lymphatic system disorders 
Febrile neutropenia 
3 
Hold until ≤ grade 1 
1st appearance: ↓ one dose level  
2nd appearance:↓ one dose level 
3rd appearance: Discontinue 
Hold until ≤ grade 1 
1st appearance: Maintain dose  
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
4 
Hold until ≤ grade 1 
1st appearance: ↓ one dose level 
                          or Discontinue 
2nd appearance: Discontinue  
Hold until clinically stable 
1st appearance: ↓ one dose level 
2nd appearance: Discontinue 
Cardiac Disorders 
• Acute coronary 
syndrome 
• Myocardial 
infarction 
2 
Hold study therapy and conduct a cardiac evaluation.  Based on this 
evaluation, continuation of study therapy is at the investigator's 
discretion. 
3, 4 
Discontinue 
Table 8 continued on next 4 pages. 
 
 
 


 
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TABLE 8.  Treatment management for T-DM1 and neratinib (Phase II) (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v 4.0 
Grade 
Action to be Taken 
T-DM1 
Neratinib 
• Conduction 
disorder 
• Supraventricular 
and nodal 
arrhythmia 
• Ventricular 
arrhythmia 
2 
Hold until rhythm is controlled; then resume (maintain doses) 
3, 4 
Discontinue 
Gastrointestinal disorders 
 
Diarrhea 
(Attributed to 
therapy, see Sections 
10.2.1, 10.6 and 
Appendix C) 
1 
Maintain dose without delay; adjust antidiarrheal medication. 
2 
 
Lasting more than 24 hours: 
Hold until neratinib can be 
resumed, then maintain dose 
Hold until ≤ grade 1; adjust 
antidiarrheal medication; 
1st appearance:  Maintain dose 
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
3 
Hold until neratinib can be 
resumed, then maintain dose 
 
Hold until ≤ grade 1 
1st appearance: ↓ one dose level 
2nd appearance: Discontinue 
4 
Discontinue 
Mucositis 
2 
Hold until neratinib can be 
resumed, 
1st appearance:↓ one dose level 
2nd appearance: ↓ one dose 
level 
3rd appearance: Discontinue 
Hold until ≤ grade 1 
1st appearance: Maintain dose 
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
3, 4 
Discontinue 
Vomiting 
(Despite anti-
emetics) 
See Section 10.2.1. 
 
2 
 
Maximize anti-emetics, IV hydration as needed 
Hold until ≤ grade 1 
1st appearance: ↓ one dose 
level  
2nd appearance: ↓ one dose 
level  
                           or Discontinue 
3rd appearance: Discontinue 
Hold until ≤ grade 1 
1st appearance: Maintain dose 
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
3, 4 
Discontinue 
Hepatobiliary Disorders  
For any signs of liver dysfunction ≥ Grade 3 AST/ALT or Grade ≥ 2 bilirubin elevation, discontinue 
study therapy, and consider patient evaluation by a hepatologist.  If there are signs of portal 
hypertension (e.g., ascites or varices) and a cirrhosis-like pattern on CT scan of the liver, the possibility 
of Nodular Regenerative Hyperplasia (NRH) should be considered.  (See Table 8, "Investigations": 
AST/SGPT, AST/SGOT, and bilirubin.) 
Table 8 continued on next 3 pages 
 
 
 


 
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TABLE 8.  Treatment management for T-DM1 and neratinib (Phase II) (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v 4.0 
Grade 
Action to be Taken 
T-DM1 
Neratinib 
Immune System Disorders  
Allergic 
reaction/infusion 
reaction 
See Section 10.5 for 
instruction on infusion 
rate adjustments 
and/or supportive 
therapy 
1 
Maintain dose 
Adjustments per Section 10.5. 
Maintain dose with no delay 
2 
Decrease infusion rate by 50% 
(or interrupt) 
Adjustments per Section 10.5. 
 
Hold until ≤ grade 1;  
Maintain dose 
3 
Hold until ≤ grade 1; or decrease 
infusion rate 
1st appearance: ↓ one dose level  
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue. 
If determined by the investigator 
to be non-serious  
Hold until ≤ grade 1;  
Maintain dose 
If determined by the investigator 
to be serious, or 3rd appearance, 
permanently discontinue. 
4 
Discontinue 
Infections and infestations 
Infection  
(By site with normal 
ANC or grade 1 or 2 
decrease in 
neutrophils) 
3 
Hold until ≤ grade 1 
1st appearance: ↓ one dose level  
2nd appearance: Discontinue  
Hold until ≤ grade 1 
1st appearance: Maintain dose  
2nd appearance: Discontinue 
4 
Discontinue 
Paronychia 
(Note: See Section 
10.7.1 and Appendix 
D, Figure 3.) 
2 
Hold until neratinib can be 
resumed, then maintain dose. 
1st appearance: Continue without 
delay or hold until improvement 
and maintain dose 
2nd appearance: If recurrent or 
intolerable, hold until improving 
and ↓ one dose level  
3rd appearance: Maintain dose or 
↓ one dose level or Discontinue if 
intolerable 
3 
Hold until neratinib can be 
resumed,  
1st appearance: ↓ one dose level 
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
Hold until ≤ grade 2 
1st appearance: Maintain dose 
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
4 
Discontinue 
Table 8 continued on next 2 pages. 
 
 
 


 
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TABLE 8.  Treatment management for T-DM1 and neratinib (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v 4.0 
Grade 
Action to be Taken 
T-DM1 
Neratinib 
Investigations 
Alanine 
aminotransferase 
(ALT)/Aspartate 
aminotransferase 
(AST) increased 
(See Sections 10.11 
and 12.3.3 for 
information and 
reporting 
requirements related 
to potential Hy's Law 
cases.) 
2-3 
Hold until stable ≤ grade 1 
1st appearance:↓ dose level 
2nd appearance: Discontinue 
Hold until ≤ grade 1 
1st appearance: ↓ one dose level 
2nd appearance: Discontinue 
4 
Discontinue 
Blood bilirubin 
increased 
(See Sections 10.11 
and 12.3.3 for 
information and 
reporting 
requirements 
related to Hy's Law 
cases.) 
2 
Hold until stable ≤ grade 1 
1st appearance:↓ dose level 
2nd appearance: Discontinue 
Hold until ≤ grade 1 
1st appearance: ↓ one dose level  
2nd appearance: Discontinue 
3, 4 
Discontinue 
Neutrophil count 
decreased 
(See Section 9.3.1) 
3 
Hold until ≥ 1000/mm3. 
1st appearance: ↓ one dose level 
2nd appearance: Discontinue 
Hold until ≥ 1000/mm3 
1st appearance: ↓ one dose level  
2nd appearance: Discontinue 
4 
Discontinue 
Platelet count 
decreased 
Assessment should be 
based on the platelet 
count from the 
bloodwork for Day 1 
of the cycle.  (See 
Section 10.8.1 for  
T-DM1 dosing.) 
2. 3 
Hold until ≥ 75,000/mm3. 
Hold until neratinib can be 
resumed, then maintain dose 
1st appearance: ↓ one dose level 
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
Hold until ≥ 75,000/mm3 
1st appearance: Maintain dose 
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
4 
Discontinue 
Nervous system disorders 
Peripheral 
neuropathy 
(associated with 
T-DM1 infusion) 
3 
Hold until ≤ grade 2, then: 
1st occurrence: ↓ one dose level  
2nd occurrence: ↓ one dose level 
3rd appearance: Discontinue 
Hold until ≤ grade 2, then: 
Continue without delay. 
4 
Discontinue 
Table 8 continued on next page. 
 
 
 


 
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TABLE 8.  Treatment management for T-DM1 and neratinib (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v 4.0 
Grade 
Action to be Taken 
T-DM1 
Neratinib 
Respiratory, thoracic, and mediastinal disorders 
Dyspnea 
2 
Hold study therapy until ≤ grade 1 and CHF and interstitial 
pneumonitis have been ruled out. 
• 
If caused by CHF or interstitial pulmonary toxicity, discontinue 
study therapy 
• If caused by infection or asthmatic process, resume therapy 
when symptoms have resolved to ≤ grade 1 
3, 4 
Discontinue 
Pneumonitis/ 
pulmonary 
infiltrates/other 
pulmonary events 
Hypoxia 
Pneumonitis 
Pulmonary fibrosis 
2 
Hold study treatment until pneumonitis is evaluated. 
• If infection is documented, treatment may be resumed when 
pulmonary AEs have resolved to ≤ grade 1. 
• If non-infectious interstitial lung disease is confirmed, study must 
be discontinued 
3, 4 
Discontinue 
Skin and subcutaneous tissue disorders 
Rash acneiform 
(See Section 10.7.1) 
 
2 
Hold until neratinib can be 
resumed, then: 
1st appearance: Maintain dose 
2nd appearance: ↓ one dose level 
3rd appearance: Discontinue 
1st appearance: hold until 
improvement then:  
Maintain dose  
2nd appearance: If recurrent or 
intolerable, hold until improving 
and ↓ one dose level  
3rd appearance: Discontinue 
3 
Hold until neratinib can be 
resumed, then 
1st appearance: ↓ one dose level 
2nd appearance: Discontinue 
Hold until ≤ grade 2 
1st appearance: ↓ one dose level 
2nd appearance: Discontinue 
4 
Discontinue 
Other 
• Other AEs 
requiring dose 
modification per 
investigator 
(Note: Investigator 
must determine 
attribution of AE and 
only follow dose 
modifications for the 
causal agent.) 
2 
Hold until ≤ grade 1 then: 
1st appearance: ↓ one dose level 
2nd appearance: Discontinue 
1st appearance: Continue without 
delay or hold until improvement; 
Maintain dose or ↓ one dose level 
2nd appearance: Discontinue 
3, 4 
Discontinue 
 
 
 


 
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10.10 Cardiac left ventricular dysfunction 
10.10.1 Symptomatic decrease in LVEF 
• 
Congestive heart failure (grade 3): 
Patients should be monitored for signs and symptoms of CHF (e.g., dyspnea, 
tachycardia, cough, neck vein distention, cardiomegaly, hepatomegaly, paroxysmal 
nocturnal dyspnea, orthopnea, peripheral edema).  If the patient develops any of these 
signs and symptoms, T-DM1 and neratinib must be held. 
The investigator must confirm the diagnosis of CHF with either an echocardiogram 
or a MUGA scan.  Once the diagnosis of CHF is confirmed, study therapy must be 
discontinued, and all reports must be submitted with FB-10 Form SAER and the 
appropriate eCRF to DSSM.  See Section 12.0 for expedited reporting requirements.  
Further therapy is at the investigator’s discretion. 
• 
Severe refractory/poorly controlled CHF (grade 4): 
Discontinue study therapy and submit FB-10 Form SAER and other required forms 
and materials (if applicable).  See Section 12.0 for expedited reporting requirements. 
10.10.2  Asymptomatic decrease in LVEF 
Reminder: Study therapy must be discontinued for patients who have a symptomatic 
decrease in LVEF (see Section 10.10.1). 
• 
All FB-10 patients will undergo scheduled LVEF assessments by echocardiogram or 
MUGA scan (see Section 5.1). 
• 
For asymptomatic patients, the decision to continue or stop study therapy is based on 
the value of the measured ejection fraction. 
 
TABLE 9.  T-DM1 and neratinib management based on LVEF assessments 
Table 9 provides instructions for patients who have an asymptomatic decrease in LVEF during study 
therapy. 
LVEF 
Asymptomatic decrease in LVEF from baseline 
≥ 50% 
Continue targeted therapy 
45–49% 
Continue targeted therapy and repeat echo/MUGA in 3 weeks 
≤ 44% 
Discontinue study therapy 
 
10.11 Liver dysfunction (Hy's Law) 
Hy’s Law is based on the observation that pure hepatocellular injury sufficient to cause 
hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver 
injury.  A diagnosis of potential drug-induced liver injury caused by a study drug can only be 
determined/inferred by excluding other potential causes of liver injury (e.g., other drugs or viral 
hepatitis) and by ruling out an obstructive cause for the elevated bilirubin (e.g., alkaline 
phosphatase should not be substantially elevated)(FDA 2009; Temple 2006). 
10.11.1 Definition of cases potentially meeting Hy's Law criteria 
Patients who present with the following laboratory abnormalities should be evaluated 
further to definitively determine the etiology of the abnormal laboratory values: 
• 
Patients with AST or ALT baseline values within the normal range who subsequently 
present with AST or ALT ≥ 3 times the ULN concurrent with a total bilirubin  


 
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≥ 2 times the ULN with no evidence of hemolysis and an alkaline phosphatase  
≤ 2 times the ULN or not available. 
• 
Patients with pre-existing AST or ALT baseline values above the normal range who 
subsequently present with AST or ALT ≥ 2 times the baseline values and ≥ 3 times 
the ULN, or ≥ 8 times the ULN (whichever is smaller) concurrent with a total 
bilirubin of ≥ 2 times the ULN and increased by one ULN over baseline or > 3 times 
the ULN (whichever is smaller) with no evidence of hemolysis and an alkaline 
phosphatase ≤ 2 times the ULN or not available. 
10.11.2 Evaluation of potential Hy's Law cases 
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation 
should include laboratory tests, detailed history and physical assessment.  In addition to 
repeating AST and ALT, laboratory tests should include albumin, creatine kinase, total 
bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase (GGT), international 
normalized ratio (INR) and alkaline phosphatase. A detailed history, including relevant 
information, such as review of ethanol, 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. The possibility of progressive disease should be 
considered. 
Potential Hy's Law cases should be reported as serious adverse events (see  
Sections 12.4.3 and 12.8.2). 
 
 


 
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11.0 
DRUG INFORMATION 
11.1 
T-DM1 
T-DM1 is available as commercial supply. 
For further details regarding the study drug, see the trastuzumab emtansine (T-DM1)  
U.S. Package Insert as well as local prescribing information. 
11.2 
Neratinib (HKI-272) 
11.2.1 Description 
Neratinib is an orally administered potent, irreversible pan-epidermal growth factor 
receptor (erbB) inhibitor that blocks signal transduction through the receptors erbB1, 
erbB2, and erbB4.  The irreversible binding to their respective intracellular tyrosine 
kinase domains results in sustained inhibition of these growth-promoting pathways. 
Neratinib 40 mg tablets will be provided for the FB-10 study.  The open label neratinib 
will be packaged with 210 tablets per bottle. 
11.2.2 Toxicity 
Refer to the current neratinib IB for toxicity information. 
11.2.3 Concomitant medications and other substances 
• Medications that reduce the secretion of gastric acid in the stomach, proton pump 
inhibitors (such as lansoprazole), should be avoided.  Antacids and H2-receptor 
antagonists (such as ranitidine) may affect how neratinib dissolves in the stomach.  
See Section 9.3.5 and 9.3.6. 
• Patients should be instructed to avoid agents known to be strong cytochrome P450 
(CYP) 3A4 inducers or inhibitors (e.g., ketoconazole) for the duration of the study 
therapy.  Patients should also avoid grapefruit and herbal remedies, including St 
John's Wort.  Refer to Appendix B for a list of selected inhibitors and inducers of the 
cytochrome P450 CYP3A4, 5, 7 isoenzymes. 
• 
Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids.  Steroids given for physiological replacement, as premedication for 
T-DM1, 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 concomitant anticoagulant therapy (e.g., warfarin or its derivatives, 
low molecular weight heparin, unfractionated heparin) should be monitored regularly 
for changes in relevant coagulation parameters as clinically indicated, as well as for 
any clinical bleeding episodes.  The dose of anticoagulant should be adjusted as 
needed. 
• 
Concomitant administration of neratinib and digoxin, a P glycoprotein (P-gp) 
substrate with a narrow therapeutic window, could result in increased plasma 
concentrations of digoxin and potential digoxin toxicity.  Patients taking concomitant 
digoxin should have digoxin levels monitored closely and their digoxin dose adjusted 
as needed.  Neratinib monotherapy did not have a significant effect on QTc interval. 
However, subjects using drugs known to cause QT/QTc prolongation should be 
monitored closely using ECG. 
 
 


 
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11.2.4 Administration 
• 
Refer to Section 9.1 (Table 5) for neratinib administration instructions.  Patients must 
be carefully instructed by study staff as to how to take neratinib. 
• 
Patients should be strongly encouraged to use a patient diary, treatment calendar, or 
other tool to record neratinib doses. 
• 
Instruct patients to bring all unused neratinib and empty bottles to the treating site.  
Local site personnel must count and record the number of neratinib tablets at the first 
study visit for each of the treatment cycles.  Drug accountability records must be 
maintained. 
11.2.5 Procurement of neratinib 
Neratinib will be supplied free of charge by Puma Biotechnologies, Inc., and distributed 
via an external vendor.  Neratinib must be requested by the principal investigator (or 
his/her authorized designee) at each participating institution. See 
 
for the e-mail address to be used for ordering study drug.  The initial supply of neratinib 
may be requested at the time the first patient signs the FB-10 consent form.  Neratinib 
will be shipped directly to the investigator whose sites are participating in FB-10. 
11.2.6 Shipping 
Bottles of neratinib are shipped at room temperature by overnight express delivery 
Monday through Thursday excluding holidays. 
11.2.7 Storage/stability 
Neratinib should be stored at room temperature (up to 25°C [77°F]) with desiccant  
(do not freeze).  Unopened bottles of neratinib are stable until the date indicated on the 
package label when stored at room temperature (up to 25°C [77°F]).  Excursions up to 
30°C (86°F) are permitted. 
11.2.8 Transfer of neratinib 
Neratinib may not be used outside the scope of FB-10, nor can neratinib be transferred or 
licensed to any party not participating in this clinical trial. 
11.2.9 Destruction of neratinib 
• 
All unopened, partially used, or empty bottles of neratinib shall be destroyed by study 
sites in accordance with the local institution standard operating procedures after the 
monitoring review of neratinib accountability by DSSM. 
• 
Written documentation of destruction must contain the following: 
− 
identity (batch numbers) of neratinib destroyed; 
− 
quantity of neratinib destroyed; 
− 
date of destruction (date discarded in designated hazardous container for 
destruction); and 
− 
name and signature of the person who discarded the neratinib in a hazardous 
container for destruction. 
11.2.10 Drug accountability 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, disposition, and return of all drug received through the  
FB-10 study using an investigational agent accountability record form. 


 
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12.0 
ADVERSE EVENT REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an adverse event (AE) or a serious adverse event (SAE), as provided in this 
protocol.  Routine and expedited adverse event report forms and their supporting documentation 
must be submitted to DSSM according to the instructions in Section 12.0. 
12.1 
Definition of an AE 
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, 
laboratory findings, or other physiologic observations occurring in a patient participating in  
FB-10.  The event does not need to be causally related to study therapy or other requirements of 
the FB-10 trial to be considered an AE. 
• 
Examples of an AE include, but are not limited to, the following: 
− 
Any toxicity related to study therapy. 
− 
Any clinically significant worsening of a pre-existing condition. 
− 
An AE occurring from a symptomatic overdose of any study therapy, whether accidental 
or intentional.  Overdose is a dose greater than that specified in the protocol. 
− 
A symptomatic AE that has been associated with the discontinuation of the use of any of 
the agents included in the study therapy. 
− 
An AE occurring during a clinical study that is not related to the study therapy, but is 
considered by the investigator or sponsor to be related to the study requirements, for 
example, an AE may be an untoward event related to a medical procedure required by the 
protocol. 
• 
Examples of clinical events that should not be considered AEs: 
− 
Medical or surgical procedure (e.g., endoscopy, appendectomy).  Note, the condition that 
leads to the procedure may be an AE, but the procedure itself is not. 
− 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
12.2 
Definition of adverse events of special interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor.  An AESI may be serious or non-serious.  The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
The events in this section are considered potential risks with neratinib monotherapy and are not 
considered ADRs with neratinib at this time. A potential risk is an untoward occurrence for which 
there is some basis for suspicion of an association with the medicinal product of interest but 
where this association has not been confirmed.  These AESIs are being closely monitored in 
clinical studies with neratinib monotherapy and combination therapy.   
For instructions on reporting AESIs, see Sections 12.4.2 and 12.8.2. 
AESIs observed with neratinib include: 
• 
Interstitial lung disease (ILD)/pneumonitis 
• 
Cardiac toxicity (left ventricular ejection fraction decrease)  
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the neratinib Investigator Brochure. 


 
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12.3 
Definition of an SAE 
An SAE is any untoward medical occurrence that, at any dose causes one of the following: 
• 
Results in death. 
• 
Is life-threatening. 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event.  It does not refer to an event, which might have 
caused death, if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization is any inpatient admission to a health care facility even if for less than  
24 hours.  Hospitalization or prolongation of a hospitalization constitutes a criterion for an 
AE to be serious; however, it is not in itself considered an SAE.  In the absence of an AE, a 
hospitalization or prolongation of a hospitalization should not be reported as an SAE.  For 
example, the following hospitalizations would not require expedited reporting for an SAE: 
− 
a hospitalization or prolongation of hospitalization needed for a procedure required by the 
protocol or as part of another routine procedure; or 
− 
a hospitalization for a pre-existing condition that has not worsened. 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
This is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma  
(e.g., sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect 
Also, appropriate medical judgment should be exercised in deciding whether SAE reporting is 
required in other situations, such as important medical events that may not result in death, be  
life-threatening, or require hospitalization, but may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the definition of an 
SAE (Section 12.3).  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or development of drug dependency or drug abuse. 
12.4 
Events requiring expedited reporting 
All events listed in Section 12.4 must be reported in an expedited manner according to the 
instructions in Section 12.8. 
12.4.1 SAEs 
All events meeting the definition of an SAE (Section 12.3) require expedited reporting. 
12.4.2 Other events requiring expedited reporting 
Other events (such as AESIs ≥ Grade 2; see Section 12.2) that must be recorded, 
reported, and followed up as indicated for an SAE (see Sections 12.5 and 12.8 for 
reporting procedures).  This includes the following events: 
• 
Pregnancy exposure to study therapy (If a pregnancy is confirmed, use of study 
therapy must be discontinued immediately.  See Sections 12.5.) 
• 
Inadvertent or accidental exposure to study therapy, with or without an AE 
• 
Medication errors involving study therapy with an AE, including overdose, product 
confusion and potential product confusion.  (A medication error is any preventable 


 
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event that may cause or lead to inappropriate use or harm while the study therapy is 
in control of the healthcare professional or patient.  Examples of reportable 
medication error include administration of unassigned treatment and administration 
of expired neratinib, when associated with an AE/SAE.) 
• 
Death, excluding death due to progression of breast cancer. 
• 
Potential Hy's Law cases (see Sections 12.4.3 and 12.8.2). 
12.4.3 Clinical laboratory abnormalities 
• 
Not every laboratory abnormality qualifies as an AE.  A laboratory test results should 
be reported as an AE (and SAE) if it meets any of the following criteria: 
− 
Accompanied by clinical symptoms 
− 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
− 
Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy 
− 
Clinically significant in the investigator's judgment 
• 
Special reporting requirements related to Hy’s Law: All cases confirmed on repeat 
testing as meeting one of the criteria described in Section 10.11.1 with no other cause 
for LFT abnormalities identified at the time should be considered potential Hy’s Law 
cases regardless of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs. Such potential Hy’s Law cases should be 
reported as serious adverse events (see Section 12.8.2). 
12.4.4 Disease-related events and/or disease-related outcomes not qualifying as SAEs 
An event which is part of the natural course of breast cancer does not need to be reported 
as an SAE.  Progression and recurrence of breast cancer will be reported on the 
appropriate page of the CRF.   
12.5 
Pregnancy 
• 
The investigator will collect pregnancy information on any patient who becomes pregnant 
while participating in this study.  The investigator will record pregnancy information on the 
FB-10 Pregnancy Notification Form and submit it to DSSM within 2 weeks of learning of 
a patient’s pregnancy. 
• 
Any serious pregnancy complication or elective termination of a pregnancy for medical 
reasons will be recorded as an AE or SAE.  A spontaneous abortion is always considered to 
be an SAE and will be reported as such. 
• 
Any SAE occurring in association with pregnancy brought to the investigator's attention after 
the patient has completed the study and considered by the investigator as possibly related to 
study therapy, must be reported to DSSM. 
12.6 
Protocol-defined AE reporting exceptions 
AE reporting is not required for AEs related to estrogen deficiency, e.g., hot flashes, vaginal 
discharge, vaginal dryness, dyspareunia, sweating, and irregular menses. 
12.7 
Grading the severity of the AE 
The NCI CTCAE v4.0 must be used to determine the grade of the AE.  The CTCAE provides 
descriptive terminology and a grading scale for each AE listed.  Information regarding the 


 
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CTCAE can be found on the CTEP homepage at http://ctep.info.nih.gov/reporting/ctc.html.  If 
you need further assistance, contact DSSM (
). 
12.8 
Expedited reporting instructions 
12.8.1 Time period for reporting SAEs and other events requiring expedited reporting 
• 
All SAEs and other events as noted in Section 12.2 and 12.4 regardless of 
relationship to study therapy will be reported in an expedited manner as described in 
12.8.2.  Reporting SAEs (and other applicable events) regardless of relationship to 
study therapy begins with the first dose of study therapy and continues until 30 days 
after the last dose of study therapy. 
• 
Any SAE assessed as related to study participation (e.g., protocol-mandated 
procedures) will be recorded from the time a patient consents to participate in the 
study up to and including the 30 day post study therapy assessment. 
• 
Following the AE assessment 30 days after the last dose of study therapy, only SAEs 
determined to be related to study therapy will be reported in an expedited manner 
using FB-10 Form SAER. 
• 
The investigator must follow up on all SAEs until the events have subsided, until 
values have returned to baseline, or until the condition has stabilized. 
12.8.2 Reporting instructions 
All SAEs and other events requiring expedited reporting must be reported using  
FB-10 Form SAER and submitted to DSSM within 1 working day of the study site 
personnel's initial notification of the event (
). 
• 
When reporting potential Hy's Law cases, Form SAER should include the following: 
− 
Seriousness Criteria = Important Medical Event 
− 
Narrative: Include the term “Potential Hy’s Law case” in the narrative; the text 
should also detail what additional study results are available at the time of 
reporting and what other studies are planned or results pending to further 
investigate alternative causes of the abnormal ALT/AST or bilirubin that 
triggered the report. The timing of planned patient follow-up should also be 
noted. 
• 
NSABP will forward the expedited report forms and their supporting documentation 
for SAEs that meet reporting requirements to the FDA and also to Puma 
Biotechnology, Inc. 
• 
Investigators are responsible for reporting AEs that meet specific criteria to their 
local IRBs. 
12.9 
Time period and frequency for routine reporting of AEs 
• 
Patients will be monitored for the occurrence of AEs at each scheduled assessment and 
during any contact with the patient during the study. 
• 
All AEs, including SAEs and other AEs that have been reported on FB-10 Form SAER, 
regardless of relationship to study therapy, will be recorded on the AE eCRF from the first 
dose of study therapy until 30 days after the last dose of study therapy (up to the date that a 
new therapy begins after disease recurrence/progression, or second primary). 
• 
For routine reporting, all ≥ grade 1 AEs will be reported on the AE eCRF. 
• 
The investigator must follow up on all AEs until the events have subsided, until values have 
returned to baseline, or until the condition has stabilized. 


 
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• 
Following the AE assessment 30 days after the last dose of study therapy, routine reporting is 
no longer required.  (See Section 12.9 for expedited reporting requirements.) 
12.10 Documentation requested following death 
For deaths that occur within 30 days of the last dose of study therapy: 
• 
Autopsy reports should be secured whenever possible and should be submitted to the  
DSSM. 
• 
A copy of the death certificate should be forwarded to DSSM if it is readily available or if it 
contains important cause-of-death information that is not documented elsewhere. 
• 
Please submit the last clinic/office note made before the death or the investigator’s note 
summarizing events resulting in death. 
 
 


 
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13.0 
ASSESSMENT OF EFFECT 
13.1 
Definitions 
Tumor response and progression will be evaluated in this study using the Response Evaluation 
Criteria in Solid Tumors (RECIST v.1.1) (Eisenhauer 2009).  Changes in only the longest 
diameter (unidimensional measurement) of the tumor lesions are used in RECIST.  Lesions will 
be classified as measurable or non-measurable using the criteria below.  A maximum of five 
measurable lesions will be used to monitor response. 
13.1.1 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques 
(PET/CT, CT scan, or MRI) or as ≥ 10 mm with spiral CT scan with 5 mm cuts or by 
clinical exam with caliper measurements.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).  The same method (CT or MRI) used at 
baseline should be used at all other tumor measurement time points. 
13.1.2 Non-measurable disease 
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions.  
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural 
or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin, or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
13.1.3 Bone lesion measurability 
When evaluating bone lesions, the following should be considered: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
13.1.4 Target lesions 
Up to a maximum of five measurable lesions (maximum 2 lesions/organ), should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements by CT scan or MRI.  A sum of the longest 
diameter (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. 
13.1.5 Non-target lesions 
All sites of disease which are not used as target lesions should be identified as non-target 
lesions.  All sites of non-target lesions must be assessed along with the target lesions. 
 
 


 
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13.2 
Response criteria 
13.2.1 Evaluation of target lesions 
• 
Complete response (CR) 
Disappearance of all target lesions 
• 
Partial response (PR) 
At least a 30% decrease in the sum of the of 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 baseline or the appearance of one or more 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 baseline. 
13.2.2 Evaluation of non-measurable/non-target lesions 
• 
Complete response (CR): disappearance of all non-target lesions 
• 
Incomplete response/stable disease (SD): persistence of one or more non-target 
lesion(s) 
• 
Progressive disease (PD): appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
13.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). Refer to Table 10 for a summary of the 
criteria that contribute to the determination of response. 
 
TABLE 10.  Determination of response 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
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 
13.4 
Symptomatic deterioration 
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."  This is also true for "symptomatic deterioration" after therapy is completed.  
Every effort should be made to document objective progression even after discontinuation of 
treatment. 


 
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14.0 
PATIENT ENTRY PROCEDURES 
14.1 
Patient consent form 
Before study entry, the consent form including any addenda, must be signed and dated by the 
patient and the person obtaining informed consent.  In addition, before study entry, a copy of 
the signed and dated consent form must be forwarded to DSSM.  All patient signatures 
(except initials of first, middle, and last names) should be expunged prior to submission. 
14.2 
Study entry 
DSSM will verify that the institution has current IRB approval for the study.  Entry will not take 
place if the IRB approval is not current for the institution with IRB oversight responsibility. 
All patients must be enrolled through DSSM.  Once the entry eCRFs have been completed, 
submit the redacted signed consent form, and supporting documents to 
 
The entry material must be received by DSSM no later than 4:00 p.m. Eastern Time, Monday 
through Friday, excluding holidays.  Once received the review process will begin.  When the 
review is complete and approved, an enrollment confirmation will be sent.  This process could 
involve some unavoidable delays.  Therefore, it is necessary to plan adequate time (at least 
24 hours) between study entry and the initiation of the patient’s study therapy. 
14.3 
Patient study number and treatment assignment 
After all the entry materials have been reviewed, the institution will receive the following via  
e-mail: 1) confirmation of registration and study entry; 2) the patient’s study number. 
14.4 
Investigator-initiated discontinuation of study therapy 
In addition to the conditions outlined in the protocol, the investigator may require a patient to 
discontinue study therapy if one of the following occurs: 
• 
the patient develops a serious side effect that cannot be tolerated or that cannot be controlled 
with other medications, 
• 
the patient’s health gets worse, 
• 
the patient is unable to meet the study requirements, or 
• 
new information about the study drugs or other treatments for breast cancer becomes 
available. 
If study therapy is stopped, study data and other materials should be submitted according to the 
study schedule unless the patient withdraws from the study. 
14.5 
Patient-initiated discontinuation of study therapy 
Even after a patient agrees to take part in this study, she may stop study therapy at any time.  If 
study therapy is stopped but she still allows the study doctor to submit information, study data 
and other materials should be submitted according to the study schedule. 
14.6 
Patient-initiated withdrawal from the study 
If a patient chooses to have no further interaction regarding the study, the investigator must 
provide DSSM with written documentation of the patient’s decision to fully withdraw from the 
study. 
 
 


 
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15.0 
DATA HANDLING AND RECORDKEEPING 
Please refer to the "FB-10 eCRF Completion Guidelines" for detailed instructions regarding data 
collection, AE reporting, and electronic case report form completion. 
 
 


 
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16.0 
STATISTICAL CONSIDERATIONS 
16.1 
Statistical considerations for the Phase I part of the study 
Note:  On May 3, 2017, accrual to the Phase 1b portion of FB-10 was completed. 
In the phase I portion of this study, the safe dose of neratinib with T-DM1 will be established. 
 
TABLE 11.  Dose escalation design 
Dose level 
Neratinib 
T-DM1 
No. of Patients 
1 
120 mg/day PO 
3.6 mg/kg IV Day 1 
q 3 weeks 
3 to 6 
2 
160 mg/day PO 
3.6 mg/kg IV Day 1 
q 3 weeks 
3 to 6 
3 
200 mg/day PO 
3.6 mg/kg IV Day 1 
q 3 weeks 
3 to 6 
4 
240 mg/day PO 
3.6 mg/kg IV Day 1 
q 3 weeks 
3 to 6 
The first cohort will be treated at dose level 1.  If 1 of 3 patients in this cohort experiences a  
DLT, 3 more patients will be added at the same dose level.  If 0 of 3 initial patients or 1 of 6 
patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated 
to dose level 2; otherwise, the combination will be considered too toxic.  NOTE: If 2 or more 
patients assigned to study therapy Dose level 1, Cycle 1 experience a DLT due to grade 4 
thrombocytopenia, the study will continue with the following actions: 
• 
The T-DM1 dose will be decreased to 3.0 mg/kg (T-DM1 level-1) for all patients 
subsequently enrolled on study. 
• 
The T-DM1 dose will not re-escalate.  T-DM1 dose 3.0 mg/kg will become the 
starting dose for all other study therapy dose levels.  (See Section 10.8.) 
• 
Grade 4 thrombocytopenia will remain a DLT during Cycle 1 for all subsequent dose 
levels. 
• 
Study therapy dose treatment management, after completion of Cycle 1, will continue 
as described in Section 10.  (See Tables 5, 6 , 7, and 8.) 
Similarly, at dose level 2 and subsequent dose levels if 1 of 3 patients experiences a DLT, 3 more 
patients will be added.  If ≥ 2 DLTs are experienced at any dose level, the combination will be 
considered too toxic and the next lower dose level will be considered the MTD.  If only 3 patient 
were treated at the MTD, an additional 3 patients will be entered into that cohort.  The MTD at 
which < 2 of 6 patients experience a DLT will be the RP2D. 
In addition to DLT identification that occurs during Cycle 1, the overall emerging toxicity profile 
will be taken into consideration when determining the MTD.  Given that diarrhea is the most 
frequent DLT, an overall safety profile of < 25% grade 3 diarrhea is expected.  Should ≥ 25% 
grade 3 diarrhea be observed cumulatively at a given dose level, the MTD may be decreased by 
one dose level. 
Safety will be assessed by physical examination, interim history, and laboratory assessment.  
Clinical activity will be assessed by performing tumor measurements/assessments for all subjects 
at baseline and then after every 2 cycles (6 weeks) of treatment.  Patient will continue on therapy 
until progression or discontinuation of study drugs due to toxicity. 


 
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In the phase Ib portion of this study the safety, tolerability, and MTD of neratinib in combination 
with T-DM1 will be determined.  The RP2D will be at the MTD taking into account the toxicity 
profiles of both study therapy agents.  No formal statistical analysis is planned.  AE rates will be 
described by dose level without regard to causality.  Analysis of secondary endpoints will be 
descriptive. 
16.2 
Statistical considerations for the Phase II part of the study 
The purpose of this phase II trial is to reject the experimental treatment (T-DM1 + neratinib) from 
further study if it were insufficiently active, and to accept it for further study if it were active 
using the Sargent three-outcome design (Sargent 2001): 
• 
Null hypothesis (H0): 25% Objective Response Rate 
• 
Alternative hypothesis (HA): 45% Objective Response Rate 
• 
Alpha = beta = 10%  
• 
Probabilities of true positive = probability of false negative = 70% 
With these assumptions, the sample size required is 22 and the decision rules are to declare 
success if > 8 responses; to declare failure if < 7 responses; and to consider the trial inconclusive 
if 7 or 8 responses (7 / 22 = 32%, 8 / 22 = 36%). 
So at end of randomized trial, pending toxicity considerations, the following decisions can be 
made: 
Table 12. Response criteria for study continuance 
No. responses 
Decision 
< 7 
Drop further development 
= 7 or 8 
Do further trials 
> 8 
Do phase III trial  
Secondary endpoints will be analyzed with a descriptive intent only, with due allowance for the fact that 
the sample size is insufficient to yield precise estimates of the secondary parameters. 
16.3 
Sample size 
A sample size of between 2 and 24 evaluable patients is needed in the phase I portion of the trial.   
In Phase II, 22 patients will be evaluated.  Up to 4 patients can be replaced in order to reach the 
required sample size of 22 evaluable patients.  All patients who receive a dose of neratinib will be 
considered evaluable.  Patients who enter the trial but are not treated for any reason will be 
replaced. 
No formal interim analysis is planned for this study.  The FDA does not require or recommend 
Data Monitoring Committees (DMC) for clinical trials at early stages of product development 
(FDA 2006). 
 
 


 
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16.4 
Accrual time and study duration 
The anticipated accrual rate for the phase II study is approximately 2 patients per month for the 
first 4 months followed by approximately 3 patients per month for 6 months.  Therefore the 
accrual period is expected to be approximately 12 to 14 months. 
16.5 
Medical Oversight 
• 
During phase Ib: The Protocol Officer and designated DSSM staff will participate in a 
weekly call with investigators who have patients enrolled on the FB-10 study.  Investigators 
who have enrolled a patient are required to participate.  All FB-10 investigators and study 
team members are encouraged to attend. 
• 
During  phase II: A medical review team comprising the Protocol Chair, NSABP Medical 
Director, study statistician, designated physician(s), and designated DSSM staff will formally 
monitor the study on a monthly basis to identify accrual, toxicity, and any endpoint problems 
that might be developing. 
• 
All grades for each type of toxicity will be recorded for each patient, and frequency tables 
will be reviewed to determine toxicity patterns. 
 
 


 
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17.0 
PUBLICATION INFORMATION 
The publication or citation of study results will be made in accordance with the publication policy 
of the NSABP that is in effect at the time the information is to be made publicly available. 
 
 


 
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18.0 
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APPENDIX A 
 
ASSESSMENT OF PERFORMANCE STATUS AND ACTIVITIES OF DAILY LIVING 
 
1.0 
DETERMINATION OF PERFORMANCE STATUS 
 
ECOG or Zubrod Scale 
 
Karnofsky Score 
0 
Fully active; able to carry on all pre-
disease performance without 
restriction 
90–100% 
1 
Restricted in physically strenuous 
activity but ambulatory 
70–80% 
2 
Ambulatory and capable of self-care, 
but unable to carry out any work 
activities 
50–60% 
3 
Capable of only limited self-care; 
confined to bed or chair more than 
50% of waking hours 
30–40% 
4 
Completely disabled 
10–20% 
 
 
 
 
2.0 
NCI DEFINITION FOR ACTIVITIES OF DAILY LIVING 
 
 
Activities of daily living (ADL) are the tasks of everyday life.  These activities include: 
• 
eating 
• 
dressing 
• 
getting into or out of bed or chair 
• 
taking a bath or shower 
• 
using the toilet 
 
 


 
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APPENDIX B 
 
CONCOMITANT MEDICATIONS AND OTHER SUBSTANCES PROHIBITED 
DURING STUDY THERAPY 
 
TABLE B1.  List of selected inhibitors and inducers of the Cytochrome P450 CYP3A4, 5, 7 isoenzymes 
INHIBITORS* 
INDUCERS* 
3A4 
OTHER 
34A 
OTHER 
Clarithromycin 
Amiodarone 
Carbamazepine 
Barbiturates 
Erythromycin 
Cannabinoids 
Dexamethasone** 
Cotrimoxazole 
Fluvoxamine 
Fluoxetine 
Phenobarbital 
Efavirenz 
Grapefruit juice 
Lopinavir 
Phenytoin 
Ethosuximide 
Grapefruit-containing 
products 
Metronidazole 
Primidone 
Methadone 
Indinavir 
Quinine 
Rifabutin 
Metyrapone 
Ketoconazole 
Sertraline 
Rifampin 
Mexiletine 
Mibefradil 
Zafirlukast 
St John's Wort 
Nevirapine 
Miconazole 
 
 
Oral contraceptives 
Nefazodone 
 
 
Troglitazone 
Nelfinavir 
 
 
 
Norfloxacin 
 
 
 
Ritonavir 
 
 
 
Saquinavir 
 
 
 
Troleandomycin 
 
 
 
Voriconazole 
 
 
 
* 
In boldface are identified strong CYP3A4, 5, 7 inducers/inhibitors.  This list is not meant to be  
 
considered all inclusive.  From:  Tatro BO.  Drug Interaction Facts 2003: The Authority on Drug  
 
Interactions, 2003. 
** Dexamethasone is permitted when given as premedication for T-DM1 (see Section 9.1). 
 
 


 
 
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APPENDIX C  
 
NSABP FB-10 SAMPLE PATIENT INSTRUCTIONS 
FOR THE MANAGEMENT OF DIARRHEA 
Please review these instructions with your study doctor/team. 
Once all of your questions are answered, make sure you are given a copy of these instructions to 
take home. 
Diarrhea is the most common side effect you may have while taking part in this study.  Diarrhea can start 
within a few hours to a few days of the first dose of study therapy.  You will be given antidiarrheal 
medication on the first day you receive study therapy to take at home to prevent diarrhea from occurring. 
If you had diarrhea with previous chemotherapies or trastuzumab/pertuzumab in the past, you may be at 
high risk for developing diarrhea with neratinib.  Make sure you take the antidiarrheal medications as 
explained by your doctor and described below. 
Your study doctor/team will instruct you to take the following medication(s) to prevent the diarrhea: 
Loperamide: also known as Imodium® 
Loperamide is available without prescription (over-the-counter, [OTC]).  You will be given a packet of 
loperamide to take at home at the start of study therapy to prevent diarrhea.  You will need to purchase 
loperamide OTC for the remainder of your study treatment.  Take loperamide as instructed below. 
• 
With the first dose of neratinib, take 4mg (2 tablets) of loperamide. 
• 
Following the first dose of loperamide, take 4mg (2 tablets) by mouth, every 6 hours for the first 
48 hours (8 tablets/day):  
− every 6 hours _______, ________, _______, ________, (time) on _______, (Date) and  
− every 6 hours  _______, ________, _______, ________, (time) on _______,  
and  
(Date). 
If you continue to have persistent diarrhea, (4 to 6 stools more per day than is normal for you), 
continue taking loperamide 4 mg (2 tablets) every 6 hours until your diarrhea decreases to less 
than 4 stools per day above what is normal for you.  If you continue to have diarrhea (more than 4 
episodes a day) on the recommended dose of loperamide, you may start taking lomotil as 
prescribed by your doctor. 
You will need to have loperamide at home to continue taking antidiarrheal medication as instructed.  You 
may take up to 8 tablets of loperamide a day for diarrhea. 
• 
After the first 48 hours on  
 
 (Date), or when you are having less than 4 stools per 
day above what is normal for you, begin taking loperamide 2 mg (1 tablet) every 4 hours during 
the day (for example: 8am, 12pm, 4pm, 8pm) and take 4mg (2 tablets) at bedtime for the first  
2 weeks of therapy, from  
 
 (Date) to  
 
 (Date).  
• 
After two weeks, and if your stools are less than 4 per day, after discussion with your physician, 
you may begin to take loperamide 2mg (1 tablet) every 6 to 8 hours daily while you are on study 
therapy. 
Budesonide also known as Entocort, Uceris, or Pulmicort 
You will be given a packet of budesonide to take at home at the start of study therapy to prevent diarrhea.  
You will receive an initial dose of budesonide 9 mg to take by mouth with the first dose of neratinib.  You 
will take budesonide 9 mg by mouth once every day during Cycle 1 and Cycle 2.   
 
 


 
 
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APPENDIX C (continued) 
Take budesonide as instructed below: 
• 
Take budesonide 9 mg by mouth (once daily in the morning) with a full glass of water (8 ounces) 
with or without food.   
• 
Swallow this medication whole; do not crush or chew the tablets.   
• 
Do not split the tablets unless you are instructed to do so by your study doctor. 
Be sure to write in the number of loose stools you have and all antidiarrheal treatment you take during the 
study on the same record (diary, calendar, etc.) that you use to record your daily dose of neratinib.  Bring 
the completed record at each visit. 
If you become constipated, notify your doctor/team. Do not take laxatives or stop loperamide.  Your 
doctor/team will change how often or how much loperamide to take. 
Treating diarrhea as soon as it starts is very important to prevent it from getting worse. 
Your study doctor/team will advise you about which antidiarrheal medication(s) to have at home. 
Call your study doctor/team at phone number _______________________ to let them know you are 
having diarrhea, so they can work with you to control the diarrhea. 
If you are dizzy or weak because of diarrhea, go to the study doctor’s office or go to the hospital 
immediately. 
Provide as much of the information as possible to your study doctor/team, in order to help your study 
doctor/team to assess the diarrhea and decide on the best treatment for you.  Information to provide when 
talking to your study doctor/team is listed below: 
• 
Number of stools per day compared to your normal bowel habits 
• 
Presence of diarrhea during the night 
• 
Presence of fever, dizziness, abdominal pain/cramping, or weakness 
• 
What the stool looks like, that is, watery stools, blood, or mucus   
• 
When you took your last dose of neratinib 
• 
Any other information that could explain your diarrhea (food, recent travel, contact with other 
people with diarrhea) 
• 
Name and amount of anti-diarrheal medications that you have been taking. 
If you continue to have persistent diarrhea while taking the loperamide, your doctor may add other 
antidiarrheal medications.  Other medications include: 
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, 
you may receive IV fluids, antibiotics and/or other medications. 
 
 


 
 
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APPENDIX C (continued) 
Changes to your diet to treat diarrhea 
If you have diarrhea, you 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, including bananas, rice, applesauce, and/or toast. 
Your doctor/team may have other suggestions for you (study doctor/team to write in any suggestions). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neratinib adjustments 
If you are experiencing a fever, dizziness, abdominal pain, or weakness along with diarrhea while on 
antidiarrheal medication, stop taking neratinib (if you have not already stopped) and contact your study 
doctor/team immediately for further instructions.  


 
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Page 76 
Moderate (Grade 2) or Severe (Grade 3) 
• Begin or continue doxycycline 100 mg 
PO BID and emollients 
• Initiate use of topical steroid BID 
Mild (Grade 1) 
Notes:  
1.  Dermatology consultation at the investigator's discretion unless noted otherwise. 
2. Emollients (alcohol-free): Eucerin®, Cetaphil®, Aquaphor®, CeraVe®,or other  
 
similar product 
3. Topical steroid: Hydrocortisone 2.5% cream or alclomethasone 0.05% cream. 
4. Treatment with medication(s) referenced should be based on evaluation  
 
of the patient and the recommended uses and associated risks with the 
 
medication(s) as outlined in the associated prescribing information. (Oiski 2008) 
• Continue doxycycline 100 mg PO BID and emollients 
• Initiate or continue topical steroid BID 
• Culture & sensitivity: then appropriate antibiotics (topical 
or oral) 
• Dermatology consult for consideration of intralesional 
steroids, partial or total nail avulsion, or other measures 
APPENDIX D  
 
MANAGEMENT OF PARONYCHIA 
Figure 3.  Management of paronychia  
NOTE:  See Section 10.7.1 and Table 8 for neratinib dose modification instructions