Tolerability of the Combination of Lapatinib and Trastuzumab in Adults Age 60 or Older With HER2 Positive Locally Advanced or Metastatic Breast Cancer
Phase: PHASE2
Conditions: Breast Neoplasms, HER2/Neu Positive, Geriatric Health Services
Sponsor: City of Hope Medical Center

IRB # 10112 
04/19/2019 
Version: 27 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
 
TITLE: TOLERABILITY OF THE COMBINATION OF LAPATINIB AND TRASTUZUMAB IN ADULTS 
AGED 60 OR OLDER WITH HER2 POSITIVE LOCALLY ADVANCED OR METASTATIC 
BREAST CANCER  
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: 
IRB # 10112 
VERSION: 27 
 
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                           COH Amendment 27                    Title Page dated 04/19/19                                                    Version: 27
 
 
 
SITE: 
Breast  
HISTOLOGY: 
HER2/Neu+ Breast Cancer 
STAGE: 
IV  
MODALITY: 
Chemotherapy 
TYPE: 
Phase II 
 
PRINCIPAL INVESTIGATOR: 
 Daneng Li, MD 

IRB # 10112 
04/19/2019 
Version: 27 
 
COLLABORATING INVESTIGATOR: Medical Oncology: Joanne Mortimer, M.D., Ammar Chaudhry, 
M.D. 
 
Biostatistics: Suzette Blanchard, Ph.D, Can-Lan Sun, Ph.D. 
 
 
Analytic Pharmacology: Timothy Synold, Pharm. D. 
 
 
 
PARTICIPATING CLINICIANS: 
Daphne Stewart, MD, James Waisman, M.D, Yuan Yuan, M.D,  
 
PARTICIPATING INSTITUTIONS: 
City of Hope, Duarte, CA 
 
Duke University Medical Center, Durham. NC 
 
Jefferson University, Philadelphia, PA 
                            
Roswell Park Cancer Institute 
 
 

 
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Experimental Design Schema 
 
Pre-Study 
(up to 14 days 
prior to 
enrolling)j 
Cycl 1 
Day 1 
(21 day 
cycle) 
Cycl 1 
Day 
8 
Cycl 1 
Day 
15 
Cycl 2 
Day 1
Cycl 2 
Day 8
Cycl 3 
Day 1
Cycl 4 
Day 1 
Cycl 5 
Day 1 
Every 
cycle 
There- 
after 
Every 
4 
cycles
 
Off 
Studyi
Lapatinib (day 1-7 of each 
wk)a 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Trastuzumab (±1 day if qwk, 
±3 days if q3wk)a,b  
 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Physical exam (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
Vital signs (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight (± 1 wk) 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
Performance Status (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
CBC w/diff, plts (± 1 wk) 
X 
Xc 
 
 
X 
 
X 
X 
X 
X 
 
X 
Complete Metabolic Paneld (± 
1 wk) 
X 
Xc 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Nurse brief toxicity evaluation 
 
 
X 
X 
 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic samples (± 1 
days)k 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Adherence evaluation (pill 
count, diaries) (± 1 wk) 
 
 
 
 
X 
 
X 
X 
X 
 
X 
 
Adverse event evaluation (± 1 
wk) 
 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
Tumor measurements using 
CT or PET-CT (± 1 wk) 
Xe 
 
 
 
 
 
 
 
X 
 
Xf 
Xg 
LVEF Assessment 
Xe 
 
 
 
 
 
 
 
X 
 
Xf 
Xg 
Geriatric Assessment Survey 
(±1 wk) 
X 
 
 
 
 
 
 
 
X 
 
X 
Xh 
a:    Dose as assigned; lapatinib 1000mg orally daily; trastuzumab 4mg/kg IV cycle one day 1, 2mg/kg IV every week thereafter; OR trastuzumab 
8mg/kg cycle 1, day 1, 6mg/kg each cycle (3 wks) thereafter. Doses held due to toxicity will not be made up. 
b:    X in schema for trastuzumab applies to q3 week schedule. 
c: 
If baseline laboratory tests are done within 14 days of start of treatment, these labs do not need to be repeated prior to day 1. 
d:    Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT[AST], 
SGPT[ALT], sodium. 
e: 
Baseline radiologic imaging may be done up to 30 days prior to start of treatment 
f:    Tumor measurements and LVEF assessment are repeated every 4 cycles ± 1 wk until patient comes off study.  Documentation (radiologic or 
clinical) must be provided for patients removed from study for progressive disease. 
g: 
Off-study radiologic evaluation will only be done if clinically indicated 
h:    Geriatric assessment should be repeated off study ONLY if it had not been administered within the previous month 
i:    Patients will be followed for 30 days following discontinuation of therapy in order to capture toxicity attributable to therapy 
j.    Chart review data must be within 14 days to determine if patient meets study criteria.  Once patient is deemed to meet study criteria, then 

 
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     all criteria must be within window specified in protocol from Day1 as indicated in column one in the schema above. 
k:    Phamacokinetic samples will be drawn after the patient has been taking lapatinib at the same dose level for a period of at least 7 days. 

 
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Protocol Synopsis 
Protocol Title: 
TOLERABILITY OF THE COMBINATION OF LAPATINIB AND TRASTUZUMAB IN 
ADULTS AGED 60 OR OLDER WITH HER2 POSITIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER 
Brief Protocol Title for the Lay Public (if applicable): 
Lapatinib/Trastuzumab in Older Adults 
Study Phase: 
Phase II 
Participating Sites: 
City of Hope Comprehensive Cancer Center , Duke University, Jefferson University, and Roswell 
Park Cancer Institute 
Rationale for this Study: 
Limited evidence exists to guide therapy with targeted agents in the older adult because older 
adults have been under-represented in clinical trials. Adults age 70 and older make up only 20% 
of subjects enrolled in FDA registration trials but 46% of all patients with cancer. Dose-finding 
studies specifically in older adults are not routinely performed.  This is despite changes in drug 
metabolism, absorption, and distribution with increasing age. Lapatinib is an oral targeted agent 
in the treatment of HER2+ breast cancer. Lapatinib is a tyrosine kinase inhibitor that binds to the 
intracellular domain of both the HER2 receptor and the EGFR receptor (HER1), thus inactivating 
downstream signaling essential to tumor proliferation. Though currently approved only in 
combination with capecitabine or letrozole, recent data suggest benefit of lapatinib in 
combination with trastuzumab, a monoclonal antibody directed to the extracellular domain of the 
HER2 transmembrane receptor. It is thought that lapatinib and trastuzumab, both HER2 targeted 
agents, may act synergistically against HER2 overexpressing tumors.  Additionally, it is believed 
that lapatinib combined with trastuzumab may potentiate the anti-tumor effects of trastuzumab, 
even after a patient has already progressed on trastuzumab, possibly by blocking a mechanism of 
drug resistance.  
The mean age of subjects to date on lapatinib trials is 58. The pivotal trial of lapatinib with 
capecitabine included patients up to age 83 but age distribution was not reported and no subset 
analysis of lapatinib safety or efficacy in older adults was performed. In the study by Blackwell et 
al which combined trastuzumab and lapatinib, the median age of patients was only 52, with few 
patients over age 60. 
The most common toxicities of lapatinib are diarrhea and rash. Though usually grade 2 or lower, 
even grade 2 diarrhea (4-6 stools per day over baseline) is often poorly tolerated in older adults 
secondary to limited fluid reserves and predisposition to dehydration. Trastuzumab has a known 
association with cardiomyopathy, thought to be directly related to HER2 blockade.  Lapatinib 
also carries this theoretical risk. While in younger adults, the combination did not appear to be 
related to unacceptable numbers of cardiac events, the cardiac toxicity profile in older adults 
could be different. It is important to elucidate the toxicity profile in older adults as the 
combination of trastuzumab and lapatinib would likely be very attractive to older adults and their 
oncologists as the combination is efficacious and as these agents do not tend to carry the 
traditional debilitating risks of cytotoxic chemotherapy. 

 
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This is an open label, single arm, phase II study of the combination of lapatinib and trastuzumab 
in 40 patients age 60 or over with HER2 positive locally advanced or metastatic breast cancer.  
The goal of this study is to estimate the tolerability of the combination of trastuzumab and 
lapatinib in older adults with locally advanced or metastatic HER2 overexpressing breast cancer 
as evidenced by rates of grade 3 or higher toxicities and rates of symptomatic serious cardiac 
adverse events. Secondary aims are to evaluate disease response in this population and to explore 
factors other than chronologic age that predict toxicity using a cancer-specific geriatric 
assessment. 
Primary Objective: 
To estimate the safety and tolerability of the combination of trastuzumab and lapatinib in adults 
age 60 or older with locally advanced or metastatic breast cancer 
Secondary Objective(s): 
1. To describe the full toxicity profile including all grades, including 
     - To estimate the rate of all grades of diarrhea, nausea, and vomiting 
     - To estimate the rate of all grades of cardiac toxicity 
2.To describe the pharmacokinetic parameters of lapatinib in older adults  
3.To estimate objective response rate and clinical benefit rate as defined by modified RECIST 
criteria 
4.To estimate median progression-free and overall survival  
5.To explore factors other than chronologic age that can affect toxicity rates as identified using a 
cancer-specific geriatric assessment 
6.To estimate adherence rates to lapatinib in older adults 
Study Design: 
The study will be an open label, single arm, phase II safety and tolerability study of the 
combination of lapatinib and trastuzumab in patients age 60 or over with HER2 positive locally 
advanced or metastatic breast cancer with a sample size of 40 patients. After 20 patients have 
completed one full cycle of therapy there will be an interim analysis, at which time the study team 
will review the data and access the toxicity profile and rates of dose reduction, delays, 
interruptions, and hospitalization related to the combination of ages. Within this interim analysis 
a specific review will be made of the data for the patients over 75 years of age. In response to the 
DSMB review of the planned interim analysis results, we are adding a second interim analysis 
after 30 patients have completed one full cycle of therapy.   
Primary Endpoint and Secondary Endpoints: 
Primary: 
Grade 3 or higher non-hematologic toxicities in patients taking the combination of lapatinib and 
trastuzumab, or symptomatic congestive heart failure 
Secondary: 
1. All toxicities associated with the combinations as measured by NCI CTCAE v.4.0 
2. Dose reductions, delays, and discontinuations 
3. Pharmacokinetic parameters 
4. Response as determined by RECIST criteria 
5. Progression free survival 
6. Overall survival 

 
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7. Percentage of doses of lapatinib taken 
Sample Size: 
40 
Estimated Duration of the Study 
48 months 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
1 
Locally advanced or metastatic Her2/Neu positive breast cancer (defined as IHC 3+ or 
FISH amplified ) Locally advanced breast cancer (LABC) includes breast cancers with advanced 
primary tumors, ie, large diameter (at least 5 cm) or those with skin and/or chest wall 
involvement, and advanced regional lymph node involvement. It also includes a rare subgroup, 
inflammatory breast cancer. 
 
 In the 2010 American Joint Committee on Cancer and the International Union for Cancer 
Control (AJCC-UICC) TNM breast cancer staging system, locally advanced breast cancer 
(LABC) includes patients with stage III disease. This comprises: 
 
Advanced primary tumors [Tumors > 5 cm in greatest dimension (T3). direct 
extension to the chest wall and/or to the skin (T4): ulceration, skin nodules, and/or  
 
edema (including peau d'orange) confined to the same breast, Inflammatory breast 
cancer (IBC, T4d)]  
 
Advanced regional lymph nodes [Ipsilateral level I, II axillary lymph nodes that are 
clinically fixed or matted or clinically detected internal mammary lymph nodes in 
the absence of axillary lymph node metastases (N2), Ipsilateral infraclavicular (level 
III axillary) lymph nodes, ipsilateral internal mammary lymph node(s) with axillary 
lymph nodes, or ipsilateral supraclavicular lymph nodes (N3)] 
 
2 
Age 60 or older 
3 
Life expectancy of greater than 12 weeks 
4 
ECOG performance status <2 (Karnofsky performance status >60%) 
5 
Normal organ and marrow function as defined below: 
      -     hemoglobin                                  >10g/dL (after transfusion, if necessary)  
-     absolute neutrophil count 
 
>1,500/mcL 
- 
platelets  
 
 
 
>100,000/mcL 
- 
total bilirubin 
 
 
within normal institutional limits 

 
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- 
AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal 
- 
creatinine clearance 
 
>30 mL/min 
6 
Cardiac ejection fraction >50% as measured by echocardiogram or MUGA scan.  Note that 
baseline and on treatment scans should be performed using the same modality and preferably 
at the same institution 
7 
The ability to provide informed consent 
8 
The ability to swallow and retain oral medication 
9 
Resolution of grade >2 toxicity from prior therapy (other than alopecia) 
10  Both measurable as well as unmeasurable disease will be allowed 
11  Patients may have received any number of prior chemotherapies or prior treatments for their  
cancer 
12  Prior treatment with lapatinib or trastuzumab are allowed, provided that the agents have never 
been given in combination 
Exclusion Criteria: 
1 
Concurrent investigational treatment, chemotherapy, or targeted therapy.  
2   All toxicities grade <2 must have resolved by the time of study commencement (except 
alopecia). However, prior chemotherapy, hormonal therapy, targeted therapy, and 
investigational agents are allowed. Prior trastuzumab and/or lapatinib therapy is allowed. 
3 
Unstable or symptomatic brain metastases (Patients with stable or treated brain metastases 
who do not require steroids at doses greater than 10mg prednisone daily or its equivalent may 
be enrolled)  
4 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to lapatinib or trastuzumab. However, patients with a history of infusion reaction 
to trastuzumab which was controlled with premedication on subsequent infusions without a 
recurring infusion reaction are eligible. 
5 
Concomitant medications that are inhibitors or inducers of CYP3A4.  (see Appendix C) 
6 
Ongoing or active infection (including HIV) or psychiatric illness/social situations that would 
limit compliance with study requirements 
7    Inability to take oral medication 
8   Malabsorption syndrome, (prior surgical procedures affecting absorption), or uncontrolled 
inflammatory GI disease (e.g., Crohn’s, ulcerative colitis)  
9 
Current active hepatic or biliary disease (with the exception of patients with Gilbert’s 
syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per 
investigator assessment) 
10 Active cardiac disease, defined as (but not limited to): 
 
History of documented congestive heart failure (CHF) or systolic dysfunction 
(LVEF < 50%) 
 
High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-
block, supraventricular tachycardias which are not adequately rate-controlled) 
 
Angina pectoris requiring antianginal medications 

 
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 
Evidence of transmural infarction on EKG 
 
Clinically significant valvular heart disease 
 
Poorly controlled hypertension (e.g. systolic >180mmHG or diastolic >100mm 
Hg) 
Investigational Product Dosage and Administration: 
Lapatinib will be given as 1000mg orally daily throughout the study period. Subjects will be 
instructed to take lapatinib >1 hour before or after a meal. 
Trastuzumab will be given in one of two schedules at the discretion of the treating physician. 
Dosing will be either: 
1) Weekly, first as a loading dose of 4mg/kg intravenously during week one, and then at a 
maintenance dose of 2mg/kg intravenously weekly thereafter, or 
2) Every three weeks, first as a loading dose of 8mg/kg intravenously during week one, and 
then at a maintenance dose of 6mg/kg intravenously every three weeks thereafter 
Patients initially started on weekly trastuzumab can be changed to a every 3 week regimen at the 
discretion of the treating physician.  Likewise, patients initially started on trastuzumab every 3 
weeks can be changed to weekly trastuzumab at the discretion of the treating physician. 
 
These medications will be continued until disease progression, death, drug intolerance or other 
limiting factor, removal from protocol due to patient or physician preference, or loss to follow-up.
Clinical Observations and Tests to be Performed: 
Patients who fulfill the eligibility criteria described above will undergo the full informed consent 
process. Prior to starting treatment, all subjects will undergo history and physical exam, and 
laboratories (CBC, CMP). Baseline disease will be documented with CT scan of chest, abdomen, 
and pelvis, or PET-CT as long as there is a diagnostic CT component (within 30 days prior to 
starting treatment). All subjects will have cardiac function evaluation (within 30 days prior to 
starting treatment) using either echocardiogram or MUGA scan, and an EKG. 
Each cycle will be three weeks with lapatinib continued daily and trastuzumab continued either 
weekly or every three weeks as described above.  During each cycle, history and physical, CBC 
and CMP (Chem-7, calcium, LFTs) will be performed once every three weeks (+/- 1 wk). 
Toxicity will be evaluated at these appointments as well as during the interim if the subject 
contacts the participating clinician with concerns. Evaluations will continue once per cycle until 
disease progression, death, discontinuation of the drug, or loss to follow-up.  
Due to the risk of early toxicity in this population, during the first cycle and part of the second 
cycle, the patient will be seen weekly at a brief nurse visit during those weeks in which no full 
physician assessment is required. During these visits, full case report forms will not be filled out, 
but limited history and physical exams will be done to ensure that any severe side effects that 
could benefit from intervention are identified. 
While on study, CT of the chest, abdomen, and pelvis (or PET-CT as above); and LVEF 
evaluation will be performed at the end of every four cycles (every 12 weeks). The modality of 
cardiac evaluation must be consistent throughout the study for each individual patient.   
A cancer specific geriatric assessment will be given at baseline and at the end of every four cycles 
(12 weeks). The cancer-specific geriatric assessment includes an evaluation of functional status, 
co-morbidity, cognition, psychological status, social functioning and support, and nutritional 
status.1 This assessment has been piloted in the CALGB.  

 
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Adherence to trastuzumab will be measured by proportion of doses given in the infusion center. 
Adherence to lapatinib will be measured by pill count as well as by patient self-report in 
dedicated patient diaries. Pill counts and review of diaries will be performed once per cycle until 
cycle 5, after which point they will be performed once every 4 cycles (12 weeks). In the event of 
discrepancy in these two measures of adherence, we will follow whichever indicates the lower 
measure of adherence (i.e. If patient states they took 13 of 14 doses, but only 10 doses are 
missing, we will count the patient as having taken only 10 days.  Alternatively, if 14 doses are 
missing, but the patient states she only took 11 doses, we will count the patient as having taken 
only 11 doses.) All toxicity related dose interruptions or reductions, hospitalizations, and adverse 
events will be noted. Subjects will be followed for toxicity outcomes for an additional 30 days 
after stopping the drug and until resolution of all grade >2 toxicities. 
Lapatinib troughs to assess drug pharmacokinetics will be drawn prior to daily lapatinib use at the 
beginnings of week 3, 4, and 5only, provided that the patient has taken lapatinib at the same dose 
level for each of the seven days prior to this study.  In the event that the lapatinib dose is held or 
the dose level is changed, pharmacokinetic sample will be rescheduled accordingly. 
Statistical Considerations: 
Tables will be created to summarize the toxicities and side effects for each dose schedule by dose, 
course, organ and severity for all patients.  We will describe all serious adverse events and other 
serious toxicities on a patient by patient basis.  Numbers of cycles received and dose reductions 
will be tabulated by dose. Rates and associated 95% exact Clopper and Pearson binomial 
confidence limits will be estimated for 1) grade 3 or higher toxicities, 2) all grade nausea, 
diarrhea and vomiting, 3) all grade cardiac events, 4) dose reductions, delays, interruptions and 
hospitalizations, and 5) the objective response rate (CR+PR) and clinical benefit rate 
(CR+PR+SD).  Descriptive statistics will be provided for study patient demographics and 
pharmacokinetic measures.  We will use general linear models of these data to determine if any of 
these factors independently predict toxicity, efficacy, and/or pharmacokinetic parameters of 
interest. 
Sponsor/Licensee: 
City of Hope Comprehensive Cancer Center 
Case Report Forms 
Paper or via Medidata Electronic Data Collection (EDC)) 

 
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Table of Contents 
 
SECTION 
PAGE 
Experimental Design Schema .......................................................................................................... 4 
Protocol Synopsis ............................................................................................................................. 5 
Abbreviations ................................................................................................................................. 16 
1.0 
Goals and Objectives (Scientific Aims) ............................................................................ 19 
1.1 
Primary Objective ................................................................................................ 19 
1.2 
Secondary Objectives .......................................................................................... 19 
2.0 
Background ....................................................................................................................... 19 
2.1 
Introduction/Rationale for Development ............................................................. 19 
2.2 
HER Signaling in Cancer ..................................................................................... 20 
2.3 
Trastuzumab ......................................................................................................... 20 
2.4 
Lapatinib .............................................................................................................. 21 
2.5 
Rationale for Combining Trastuzumab and Lapatinib ......................................... 21 
2.6 
Aging and Decreased Tolerance of Cancer Treatment ........................................ 22 
2.7 
Factors Other than Chronological Age that Impact Drug Tolerance ................... 23 
2.8 
Aging and Targeted Therapy ............................................................................... 24 
2.9 
Cardiac Toxicity of Lapatinib and Trastuzumab ................................................. 25 
2.9.1 
Cardiac Effects of Trastuzumab .......................................................................... 25 
2.9.2 
Cardiac Effects of Lapatinib ................................................................................ 29 
2.10 
Other Important Safety Issues with Lapatinib ..................................................... 30 
2.10.1  Interstitial Pneumonitis ....................................................................................... 31 
2.10.2  Liver Chemistry .................................................................................................. 31 
2.10.3  Diarrhea .............................................................................................................. 32 
2.11 
Overview of Proposed Study ............................................................................... 33 
2.11.1  Trastuzumab Dosing ........................................................................................... 33 
2.11.2  Strict Rules for Cardiac Toxicity ........................................................................ 33 
2.11.3  Secondary Objectives.......................................................................................... 34 
3.0 
Patient Eligibility .............................................................................................................. 34 
3.1 
Inclusion Criteria ................................................................................................. 34 
3.1.1 
Disease Status ...................................................................................................... 34 
3.1.2 
Age Criteria and Life Expectancy........................................................................ 35 

 
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3.1.3 
Child Bearing Potential ........................................................................................ 35 
3.1.4 
Protocol-Specific Criteria .................................................................................... 35 
3.1.5 
Informed Consent ................................................................................................ 35 
3.2 
Exclusion Criteria ................................................................................................ 36 
3.2.1 
Study-Specific Exclusions ................................................................................... 36 
3.2.2 
Non-Compliance .................................................................................................. 36 
3.3 
Inclusion of Women and Minorities .................................................................... 36 
4.0 
Screening and Registration Procedures............................................................................. 37 
4.1 
Screening Procedures ........................................................................................... 37 
4.1.1 
General Guidelines .............................................................................................. 37 
4.1.2 
Procedure for On-study and Treatment Deviations ............................................. 37 
4.2 
Informed Consent ................................................................................................ 37 
4.3 
Registration Requirements/Process ..................................................................... 37 
4.4 
Dose Assignment ................................................................................................. 39 
5.0 
Treatment Program ........................................................................................................... 39 
5.1 
Treatment Overview ............................................................................................ 39 
5.2 
Planned Duration of Therapy ............................................................................... 40 
5.3 
Criteria for Removal from Treatment .................................................................. 40 
5.3.1 
Criteria for Removal ............................................................................................ 40 
5.3.2 
Subject Follow-Up ............................................................................................... 40 
5.4 
Supportive Care and Other Concomitant Therapy ............................................... 40 
5.4.1 
Medications Prohibited in Combination with Lapatinib ...................................... 40 
5.4.2 
Medications Prohibited in Combination with Trastuzumab ................................ 40 
5.5 
Laboratory/Monitoring Studies ............................................................................ 41 
5.5.1 
Required Clinical, Laboratory and Disease Evaluation at Baseline .................... 41 
5.5.2 
Studies Obtained During the Trial ....................................................................... 42 
5.5.3 
Monitoring Studies .............................................................................................. 43 
6.0 
Dose Delays/Modifications for Adverse Events ............................................................... 44 
6.1 
Non-hematological adverse events ...................................................................... 44 
6.2 
Cardiac toxicity .................................................................................................... 45 
6.3 
Hepatic toxicity .................................................................................................... 46 
6.4 
Dermatologic toxicity .......................................................................................... 48 
6.5 
Gastrointestinal Toxicity ...................................................................................... 49 
6.5.1 
Nausea, Vomiting, or Both .................................................................................. 49 

 
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6.5.2 
Diarrhea ............................................................................................................... 49 
6.6 
Pulmonary Toxicity ............................................................................................. 50 
6.7 
Summary of Modifications due to Toxicity ......................................................... 51 
7.0 
Data and Safety Monitoring and Adverse Event Reporting.............................................. 52 
8.0 
Agent Information ............................................................................................................. 60 
8.1 
Drug Information for Lapatinib (Tykerb®) .......................................................... 60 
8.1.1 
Risks and Contraindications ................................................................................ 60 
8.1.2 
Supplier ................................................................................................................ 61 
8.1.3 
Concomitant Medications/Precautions ................................................................ 61 
8.1.4 
Dose and Administration ..................................................................................... 61 
8.1.5 
Storage ................................................................................................................. 61 
8.1.6 
Structure and Molecular Weight .......................................................................... 61 
8.1.7 
Formulation/Agent Preparation ........................................................................... 61 
8.1.8 
Stability ................................................................................................................ 62 
8.1.9 
Agent Accountability ........................................................................................... 62 
8.1.10  Agent Ordering ................................................................................................... 62 
8.2 
Drug Information for Trastuzumab (Herceptin©) ................................................ 62 
8.2.1 
Risks and Contraindications ................................................................................ 62 
8.2.2 
Supplier ................................................................................................................ 67 
8.2.3 
Concomitant Medications/Precautions ................................................................ 67 
8.2.4 
Dose and Administration ..................................................................................... 67 
8.2.5 
Storage ................................................................................................................. 68 
8.2.6 
Structure and Molecular Weight .......................................................................... 68 
8.2.7 
Formulation/Agent Preparation ........................................................................... 68 
8.2.8 
Stability ................................................................................................................ 69 
9.0 
Correlative/Special Studies ............................................................................................... 70 
10.0 
Study Calendar .................................................................................................................. 71 
11.0 
Evaluation Criteria/Measurement of Effect ...................................................................... 73 
11.1 
Definitions ........................................................................................................... 73 
11.2 
Disease Parameters .............................................................................................. 73 
11.3 
Methods for Evaluation of Measurable Disease .................................................. 74 
11.4 
Response Criteria ................................................................................................. 75 
11.4.1  Evaluation of Target Lesions .............................................................................. 75 
11.4.2  Evaluation of Non-Target Lesions ...................................................................... 75 

 
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11.4.3  Evaluation of Best Overall Response ................................................................. 76 
11.5 
Duration of Response ........................................................................................... 77 
11.6 
Progression-Free Survival .................................................................................... 77 
11.7 
Overall Survival ................................................................................................... 77 
12.0 
Data Reporting/Protocol Deviations ................................................................................. 77 
12.1 
Data Reporting ..................................................................................................... 77 
12.1.1  Method ................................................................................................................ 78 
12.1.2  Responsibility for Data Submission .................................................................... 78 
12.1.3  Confidentiality of Records .................................................................................. 78 
12.1.4  Subject Consent Form ......................................................................................... 78 
12.1.5  Data Collection Forms and Submission Schedule .............................................. 78 
12.2 
Multicenter Guidelines ........................................................................................ 79 
12.3 
Protocol Deviations .............................................................................................. 80 
12.3.1  Deviation Policy ................................................................................................. 80 
12.3.2  Reporting of Unplanned Deviations ................................................................... 80 
12.3.3  Resolving Disputes ............................................................................................. 80 
13.0 
Statistical Considerations .................................................................................................. 80 
13.1 
Study Design ........................................................................................................ 80 
13.1.1  Primary Endpoints .............................................................................................. 80 
13.1.2  Secondary Endpoints .......................................................................................... 80 
13.1.3  Methods for Stratification and Randomization ................................................... 80 
13.2 
Sample Size and Accrual Rate ............................................................................. 80 
13.3 
Interim Analyses and Stopping Rules .................................................................. 81 
13.4 
Analysis of Toxicity Data: ................................................................................... 82 
13.5 
Secondary analyses: ............................................................................................. 82 
13.5.1  Evaluation of response ........................................................................................ 82 
13.5.2  Pharmacokinetic parameters: .............................................................................. 83 
13.5.3  Factors other than chronologic age that can affect outcomes: ............................ 83 
14.0 
Human Subject Issues ....................................................................................................... 83 
14.1 
Institutional Review Board .................................................................................. 83 
14.2 
Recruitment of Subjects ....................................................................................... 83 
14.3 
Advertisements .................................................................................................... 84 
14.4 
Study location and Performance Sites ................................................................. 84 
14.5 
Confidentiality ..................................................................................................... 84 

 
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14.6 
Financial Obligations and Compensation ............................................................ 84 
14.7 
Informed Consent Processes ................................................................................ 85 
15.0 
References ......................................................................................................................... 86 
APPENDIX A: 
Performance Status Criteria .................................................................... 92 
APPENDIX B: 
Multicenter Guidelines ........................................................................... 93 
APPENDIX C: 
Lapatinib Prohibited Medication List ..................................................... 95 
APPENDIX D: 
Eligibility Checklist ................................................................................ 97 
APPENDIX E:  
Geriatric Assessment Survey ................................................................ 100 
APPENDIX F:                Data Coordinating Center……………………………………………101 
 

 
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Abbreviations 
 
Abbreviation 
Meaning 
AE 
Adverse Event 
AI 
Aromatase Inhibitor 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
CALGB 
Cancer and Leukemia Group B 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CMP 
Complete Metabolic Panel 
CNS 
Central Nervous System 
COH 
City of Hope 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DCIS 
Ductal Carcinoma in situ 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
ECHO 
EDC 
Echocardiogram 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EKG 
Electrocardiogram 

 
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ER 
Estrogen Receptor 
ErbB 
Epidermal Growth Factor 
FDA 
Food and Drug Administration 
FISH 
Florescence In Situ Hybridization 
GAS 
Geriatric Assessment Survey 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GI 
Gastrointestinal 
GSK 
GlaxoSmithKline 
HCG 
Human Chorionic Gonadotropin 
HER2 
Human Epidermal Growth Factor Receptor 2 (also HER-2/neu or 
ErbB2) 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hormone Receptor 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDS 
Investigational Drug Services 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LFTs 
Liver Function Tests 
LVEF 
Left Ventricular Ejection Fraction 
MBC 
Metastatic Breast Cancer 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multiple Gated Acquisition Scan 
NCI 
National Cancer Institute 

 
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NSABP 
National Surgical Adjuvant Breast and Bowel Project 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PgR 
Progesterone Receptor 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PMT 
Protocol Monitoring Team 
PO 
Per Os (orally) 
PR 
Partial Response 
q 
Every (as in q3 weeks, meaning “every three weeks”) 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SWOG 
Southwest Oncology Group 
TKI 
Tyrosine Kinase Inhibitor 
TOX 
Toxicity 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization  
Wk 
Week(s) 
 

 
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1.0 Goals and Objectives (Scientific Aims) 
1.1 Primary Objective 
To estimate the safety and tolerability of the combination of trastuzumab and lapatinib in adults age 60 or 
older with locally advanced or metastatic breast cancer 
1.2 Secondary Objectives 
1. To describe the full toxicity profile including all grades 
     - To estimate the rate of all grades of cardiac toxicity 
     - To estimate the rate of all grades of diarrhea, nausea, and vomiting 
2. To describe the pharmacokinetic parameters of lapatinib in older adults  
3. To estimate objective response rate and clinical benefit rate as defined by modified RECIST criteria 
4. To estimate median progression-free and overall survival  
5. To explore factors other than chronologic age that can affect toxicity rates as identified using a cancer-
specific geriatric assessment 
6. To estimate rates of adherence to lapatinib among older adults 
2.0 Background 
2.1 Introduction/Rationale for Development 
This proposal addresses a key research priority of the Cancer and Aging Research Group: the assessment 
of the pharmacology of cancer therapy in older adults.2 While several studies have demonstrated that 
older adults are more likely to experience chemotherapy toxicity,3-5 the comparative risk of targeted 
therapies has not been studied. Though chronological age does not entirely correlate with physiologic age, 
older adults do have changes in physiology that can predispose to drug toxicity.6 A progressive reduction 
in the functional reserve of various organ systems may alter the pharmacokinetics of anti-cancer 
therapies7-8 and increase the susceptibility of older individuals to complications of treatment.9-12 Normal 
tissues may be less able to repair the molecular damage caused by antineoplastic agents due to cellular 
senescence, resulting in greater potential cardiotoxicity, neurotoxicity, mucositis, and hematologic 
toxicities.6 And finally, there may be age-related changes in the biology of cancer which may impact the 
therapeutic efficacy and approach.13-14 Older adults are an important population to study because 60% of 
all cancer cases and 70% of cancer mortality occur in patients over the age of 65.15 Furthermore, the 
number of older adults with cancer is expected to rise significantly with the aging of the US population. 
Older adults with cancer are an understudied population. Cancer patients age 70 or greater made up only 
20% of subjects enrolled in FDA registration trials from 1995 to 1999, though they made up fully 46% of 
the US cancer population.16  
The goal of this study is to utilize a phase II design to examine the tolerability of anti-HER2 directed 
therapies among older adults with HER2 overexpressing breast tumors.  Specifically, we aim to study the 
effect of the combination of lapatinib, an oral small molecule tyrosine kinase inhibitor targeted at both the 
intracellular domains of HER2 and EGFR17 and trastuzumab, a humanized monoclonal antibody targeting 
the extracellular domain of HER2. There is significant interest in studying this drug among the elderly as 
it is an oral targeted therapy.  However, there is concern that without definitive studies in the older adult 
population, oncologists may have reservations in giving lapatinib or in dose reducing the agent without 
guidance.  

 
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2.2 HER Signaling in Cancer 
The human HER (ErbB) receptor family consists of four closely related transmembrane receptor tyrosine 
kinases.  Upon binding of ligands, HER receptors become activated and undergo hetero- or 
homodimerization.  Dimerization in turn, results in phosphorylation of specific receptor cytoplasmic 
tyrosines with subsequent recruitment of downstream signaling proteins.  Ligands have been identified for 
the HER1 (also known as EGFR), HER3 and HER4 receptors.  No ligand has yet been identified for 
HER2 (also known as Her-2/neu) which is the preferred dimerization partner for HER1, HER3, and 
HER4.18  HER3 possesses a defective tyrosine kinase and therefore, requires heterodimerization with 
another HER member to be activated.  HER4 has an active tyrosine kinase, but its role in breast cancer is 
currently unknown. 
HER1 (aka EGFR) and HER2 receptors are often upregulated in many human cancers.19-20  Elevated 
levels of the HER2 extracellular domain in sera of patients with breast cancer correlate with a poorer 
response to both chemotherapy and endocrine therapy.21-23 Additionally, increased expression of the EGF 
or TGF- ligands indicates a poor prognosis in some cancer patients.24-25  Expression of these ligands 
appears to be responsible for maintaining HER receptors in an activated state even in the absence of 
receptor over-expression.24, 26-27  Many therapeutic strategies have therefore been employed to block the 
HER signaling pathways as a means to improve the therapeutic efficacy of hormonal and chemotherapy 
regimens. 
2.3 Trastuzumab 
Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody that binds with high affinity 
to the extracellular domain of the HER2 protein, is currently approved as a first-line agent in combination 
with taxanes or as a single agent in advanced Her2/neu overexpressing breast cancer.28-29  In adjuvant 
trials, trastuzumab has been shown to decrease the risk of recurrence of breast cancer by 39-52%30-32 and 
decreases the risk of death by 33%.30  Trastuzumab has also been found effective in the neoadjuvant 
setting.33  
Though generally well tolerated, trastuzumab can produce cardiotoxicity in the form of either 
asymptomatic decreased ejection fraction or overt heart failure, particularly when given together with 
anthracycline containing chemotherapy regimens.28, 34-38   
Although trastuzumab based regimens have improved recurrence rates and overall survival in patients 
with HER2 positive breast cancer only 26% of patients treated with trastuzumab as a first-line single 
agent have an overall response.39 Additionally, most women who have response develop acquired 
resistance within months to years.40 The mechanisms behind HER2 refractoriness or resistance are varied. 
Recent data have shown that dysregulation of the HER2/HER2/PI3 kinase/PTEN pathway, PI3 kinase 
mutations, or PTEN depletion have are associated with resistance to HER2 targeted therapies.41-44  The 
full length HER2 (p185ErbB2) undergoes proteolytic cleavage shedding its extracellular domain which is 
detectable in cell culture media or patient sera.45 Cleavage of HER2 appears to be mediated by a member 
of the matrix metalloprotease (MMP) family.46  Truncated HER2 receptor (p95ErbB2) exhibits increased 
autokinase activity and transforming efficiency compared with p185ErbB2, implicating the extracellular 
domain as a negative regulator of HER2 kinase and oncogenic activity.47-48 One study found that 
p95ErbB2 is expressed more frequently in lymph node metastatic tissue than in primary breast tumors.49  
It is unlikely that an antibody such as trastuzumab directed against the extracellular domain of HER2 can 
bind to and/or inhibit the truncated, activated p95ErbB2 receptor.  Small molecule tyrosine kinase 
inhibitors may however, prove to be effective against p95ErbB2 positive breast cancer.49 
Small molecule HER tyrosine kinase inhibitors (TKI's) compete for the ATP binding site and inhibit the 
receptor's activity.  In principle, small molecule TKI's should inhibit the activity of HER1 (EGFR) in the 

 
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presence of elevated levels of ligand and should also inhibit the activity of ErbB receptors with truncated 
extracellular domains.  Single agent small molecule TKI's have been reported to exhibit clinical activity.50 
Additionally, members of the HER class of transmembrane proteins often heterodimerize.  HER2-
containing heterodimers elicit potent mitogenic signals and as such, targeting HER1 and HER2 
simultaneously may provide therapeutic synergy.51  
2.4 Lapatinib 
Lapatinib is an oral small molecule tyrosine kinase inhibitor directed at the intracellular domain of both 
HER2 and EGFR (HER1).17 A randomized phase III clinical trial including women with HER2-
overexpressing advanced breast cancer who had progressed on a regimen containing trastuzumab, showed 
that lapatinib in combination with capecitabine was superior to capecitabine alone.52 This study ultimately 
resulted in FDA approval for lapatinib in 2007 in combination with capecitabine. Additionally, a Phase III 
trial showing that lapatinib in combination with letrozole, an aromatase inhibitor, was effective in the 
first-line metastatic setting in a subset of 219 patients whose breast cancer was HER-2 positive and 
hormone receptor positive.  Median progression-free survival was 8.2 months for those receiving 
letrozole and lapatinib versus 3.0 months for those getting letrozole alone (HR 0.71 [0.53-0.96], 
p=0.019).53 
The pivotal trial that led to FDA approval of lapatinib involved the combination of lapatinib with 
capecitabine.  More recently, lapatinib has been given FDA approval in combination with the aromatase 
inhibitor letrozole for those patients who are both HER2 as well as hormone receptor overexpressing.  
Lapatinib is not currently approved as a single agent.  However, Phase III clinical trials are currently 
ongoing or completed that suggest that lapatinib is effective when given in combination with other agents, 
including trastuzumab, in both the first and second line treatment of metastatic breast cancer.53-55 An 
ongoing trial is testing lapatinib in the adjuvant treatment of breast cancer together with chemotherapy 
and/or trastuzumab.56 
As a member of the 4-anilinoquinazoline class of kinase inhibitors, lapatinib is thought to react with the 
ATP binding site of EGFR/ErbB2, resulting in inhibition of autophosphorylation and subsequent 
proliferative signaling.57 
The pharmacokinetics of lapatinib are similar in healthy volunteers and patients, demonstrating oral 
absorption that is incomplete, highly variable, and sometimes delayed.  After dosing, plasma 
concentrations rise to a peak at approximately 4 h and thereafter decline with measured half-lives 
averaging up to 14 h.  However, accumulation with daily dosing achieves steady state in 6-7 days, which 
suggests a true elimination half-life on the order of 24 h.  Administration of the same daily dose in a twice 
daily schedule results in 2-fold greater systemic exposure than a once daily schedule.  Despite this 
inconsistency, systemic exposure generally increases with increasing dose.  Absorption is increased by 
ingestion with food.  Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with 
negligible renal excretion.  Significant changes in systemic exposure to lapatinib result from co-
administration of drugs that are potent inhibitors or inducers of CYP3A.58 
2.5 Rationale for Combining Trastuzumab and Lapatinib 
Data from multiple lapatinib studies support the preclinical data that have shown a relative lack of cross-
resistance between trastuzumab and lapatinib.59  Despite both trastuzumab and lapatinib inhibiting the 
same HER2 receptor, the combination of the two drugs is potentially attractive because each agent targets 
a different part of the receptor: trastuzumab the extracellular domain,60 and lapatinib, the intracellular 
domain.61 In addition, the two drugs have different mechanisms of action.  Trastuzumab efficiently 
recycles with the HER-2 receptor following endocytosis and internalization and degradation of HER2, 
and its down-regulation seems to be less important to its mode of action.62 Trastuzumab leads to an initial 
stimulatory effect of HER-2 phosphorylation63 and lapatinib inhibits the HER2 tyrosine kinase activity 

 
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and that of its co-receptor EGFR.61, 64 EGFR may play an important role as a co-receptor for HER2 and 
the cooperation between EGFR and HER2 provides a rationale to target EGFR when HER2 is 
overexpressed.65 This may lead to sustained inhibition of activation of the HER2 receptors, and may 
constitute a superior way of inhibiting a dysregulated signaling network. 
Preclinical data indicate that lapatinib has a synergistic effect with trastuzumab in HER2 positive breast 
cancer cells.66 In addition, lapatinib shows activity against cells selected for long-term growth in 
trastuzumab-containing media, suggesting non-cross-resistance between the two agents.66 
A phase I study of lapatinib administered with trastuzumab in 54 heavily pretreated patients who had 
progressive disease during previous trastuzumab treatment and whose tumors overexpressed HER2 or had 
HER2 gene amplification (by IHC or FISH, respectively), demonstrated an overall response rate of 22%. 
The recommended phase 2 dose of lapatinib was 1000 mg daily with weekly trastuzumab (4mg/kg IV 
load followed by 2mg/kg IV once weekly), with fatigue being dose-limiting at higher doses and with no 
occurrence of symptomatic or asymptomatic decline in left ventricular ejection fraction.67-68 
Diarrhea, nausea, fatigue, and anorexia appear to be increased in both frequency and intensity with this 
combination.  All 54 subjects enrolled experienced at least one adverse event (AE) with a total of 864 
AEs reported; the majority of these were of Grade 1 or 2 intensities (797/864 or 92%).  The most 
frequently reported events were diarrhea (83%), nausea (61%), fatigue (57%), rash (57%), and anorexia 
(41%).  A total of 553 drug-related AEs were reported; thirty-four Grade 3 events in 20 subjects were 
drug related. No drug-related Grade 4 events were reported. Thirteen of 54 subjects experienced 29 
serious AEs; four events were considered drug-related: fatigue and diarrhea in one patient and nausea and 
vomiting in another. No deaths were reported. 
One patient experienced asymptomatic changes in LVEF values that included a decrease from a baseline 
value of 58% to 45% approximately 8 months after initiating treatment. During continued treatment, 
subsequent LVEF values have been 50% (9 months), 60% (11 months), and 55% (13 months). 
A phase III randomized, multicenter, open label trial was recently performed to compare the safety and 
efficacy of lapatinib alone versus lapatinib in combination with trastuzumab in patients with HER2 
positive metastatic breast cancer who had experienced progression on prior trastuzumab therapies.  The 
intent-to-treat population was 296 patients, and patients had received a median of three prior trastuzumab 
containing regimens.  Trastuzumab, when given, was given on a weekly schedule and lapatinib was given 
at 1000mg daily when together with trastuzumab, and at 1500mg daily as a single agent.  Median age was 
52, and 73% of patients had documented visceral disease.  Six month progression free survival was 28% 
in the combination arm compared to only 13% in the lapatinib alone arm.59 Recently, overall survival data 
has been reported, and median overall survival was 20 weeks longer in the combination arm than in the 
lapatinib alone arm (61 weeks versus 41 weeks).69 The combination was well tolerated with the most 
frequent events being diarrhea, rash, nausea, and fatigue.  The rate of diarrhea in the combination arm was 
60% compared to 48% in the lapatinib alone arm.  However, grade 3 and 4 diarrhea only occurred in 7% 
of patients in each arm.  Symptomatic cardiac events occurred in 2% of patients on the combination arm 
and 0.7% of patients on the lapatinib-alone arm.59 
2.6 Aging and Decreased Tolerance of Cancer Treatment 
Aging brings about a progressive decrease in physiologic reserve that affects each individual at a unique 
pace.70-71 The age-related physiological decline in organ systems typically begins in the 3rd decade of life 
and is not evident at times of rest but becomes most apparent when the body is stressed.72  Either cancer 
or cancer treatment can be considered a physiological stressor, and the age-related decrease in physiologic 
reserve may affect tolerance to cancer treatment. 
Several studies have demonstrated that older adults are more likely to experience chemotherapy toxicity,3-
5 and older adults are at greater risk for myelosuppression, cardiotoxicity, neurotoxicity, and mucositis.6  

 
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Older adults can in most cases tolerate chemotherapy in doses and schedules similar to those in younger 
adults, but side effects need to monitored closely and occasionally more aggressive prophylactic measures 
need to be employed.73  However, most studies to date have determined tolerability of cancer therapies in 
older adults retrospectively rather than using prospective interventional trials.  With some therapies it has 
been suggested that a lower starting dose in older adults, while causing less toxicity, does not impact 
efficacy.74 
A number of age-related changes in drug absorption, distribution, metabolism, and excretion with aging 
may contribute to differences in treatment tolerance between older and younger patients.  The absorption 
of drugs can be affected by decreased gastrointestinal motility, decreased splanchnic blood flow, 
decreased secretion of digestive enzymes, and mucosal atrophy.8, 75  With the increased use of oral 
therapy, medication compliance is an important issue as well.76  As a person ages, body composition 
changes, with an increase in body fat and decrease in lean body mass and total body water.  The increase 
in body fat leads to a rise in the volume of distribution for hydrophilic drugs. In the population of older 
adults with cancer, malnutrition and hypoalbuminemia may result in an increased concentration of drugs 
that are albumin-bound.12 
Hepatic mass and blood flow also decrease with age.70  The impact of the decline in hepatic mass and 
blood flow on hepatic enzyme function is controversial.77  In a study of 226 patients, the cytochrome P-
450 content in liver biopsy samples decreased by approximately 30% in patients over the age of 70.78 
Renal function also declines with age, and renal insufficiency is common in older adults.79-80 
A progressive reduction in the functional reserve of various organ systems may alter the pharmacokinetics 
of anti-cancer therapies7-8 and increase the susceptibility of older individuals to complications of 
treatment.9-12 Normal tissues may be less able to repair the molecular damage caused by antineoplastic 
agents due to cellular senescence, resulting in greater potential cardiotoxicity, neurotoxicity, mucositis, 
and hematologic toxicities.6 And finally, older adults may develop tumors that are more resistant to 
treatment.13-14 
In fact, pharmacokinetics and pharmacodynamics of antineoplastic agents have been shown in some cases 
to be affected by increasing age.  In a study of patients across different age groups receiving paclitaxel 
chemotherapy, the mean area under the curve significantly increased and the mean clearance significantly 
decreased with age.  Additionally, older patients experienced an increased incidence of grade 3 
neutropenia and lower absolute neutrophil count nadir than younger patients, though there was no 
increase in neutropenic fevers or hospitalizations.81  In a study of 73 women with advanced breast cancer 
between the ages of 65 and 89 (median age 73), 30% of participants taking standard doses of 
capecitabine, but only 5% of patients starting at a lower dose required dose reductions from the starting 
dose due to severe toxicity.  The two groups had similar rates of response and time to disease 
progression.74 
Older adults are an important population to study because 60% of all cancer cases and 70% of cancer 
mortality occur in patients over the age of 65.15 Furthermore, the number of older adults with cancer is 
expected to rise significantly with the aging of the US population. Older adults with cancer are also an 
understudied population. Accrual of older adults to clinical trials has been shown to be significantly lower 
than their proportion in the general population in both an analysis of SWOG trials82 as well as in studies 
of drugs approved by the FDA over a seven year period.16 Cancer patients age 70 or greater made up only 
20% of subjects enrolled in FDA registration trials from 1995 to 1999, though they made up fully 46% of 
the US cancer population.16 
2.7 Factors Other than Chronological Age that Impact Drug Tolerance 
Aging is a heterogeneous process.  While certain declines in organ function are universal as the human 
body ages, the rate of this decline and the consequences of this decline on everyday function proceeds at a 

 
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unique pace in each individual.  Therefore, chronologic age tells us relatively little about the specific 
individual.  A more detailed evaluation of an older adult patient is needed in order to capture factors other 
than chronological age that predict for morbidity and mortality.  A comprehensive geriatric assessment 
may serve this purpose.  The comprehensive geriatric assessment includes an evaluation of functional 
status, comorbid medical conditions, cognitive function, nutritional status, social support and 
psychological state, and a review of medications.  Conclusions from several studies are emerging 
regarding the benefits of performing a comprehensive geriatric assessment for older patients with cancer. 
1. Factors evaluated in a comprehensive geriatric assessment predicts survival;83 
2. Factors evaluated in a comprehensive geriatric assessment predicts toxicity to 
chemotherapy;84 
3. A comprehensive geriatric assessment uncovers problems not detected by routine history and 
physical in initial consultation and follow-up care;85 
4. Patients undergoing a comprehensive geriatric assessment and intervention based on the 
results had improved pain control;86 
5. A comprehensive geriatric assessment and intervention improves an older patient’s mental 
health and well-being.86 
Consensus guidelines recognize the benefits and recommend the inclusion of a geriatric assessment as 
part of the evaluation of an older patient.87 
2.8 Aging and Targeted Therapy 
Limited evidence exists to guide therapy with lapatinib in the older adult.  The pivotal trial of lapatinib 
included patients up to 83 years of age, however only 17% of adults in this study were 65 years or older 
and only 1% were 75 or older (Table 1).88 No subset analysis of lapatinib safety and efficacy in older 
adults was reported.52 Mean age of subjects on lapatinib trials to date has been 58 years.56 The effect of 
age on lapatinib pharmacokinetics has also not been formally evaluated.  Review of the data obtained 
from 326 subjects in Phase I trials, which included individuals ranging in age from 18 to 82 showed no 
apparent differences in systemic exposure related to age. However, pharmacokinetic parameters were 
only evaluated in a total of 11 patients over the age of 70 across all trials.  Clinically significant changes 
in pharmacokinetics associated with age generally emerge above the age of 70-75 years.  Therefore, the 
available data cannot be interpreted as indicating that patients older than 70-75 years will display similar 
pharmacokinetics to younger individuals.56 
 
Table 1: Lapatinib Exposure in Older Adults89 
 
There are rationales to indicate that lapatinib could reasonably have different pharmacokinetics and 
pharmacodynamics in older adults as well.  Lapatinib is highly protein bound in serum.90 In elderly 
patients with cancer, malnutrition and hypoalbuminemia might result in increased free concentrations of 
drugs, like lapatinib, that are heavily protein bound.12  Lapatinib is also extensively metabolized in the 
liver, and hepatic mass and blood flow decrease with age.70  Additionally, the most frequently reported 

 
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serious adverse event in trials with lapatinib is diarrhea.56  Diarrhea can be more serious in the older adult 
with little social support or impaired sensory or cognitive function, and could lead to dehydration, 
hospitalization, or even death at a rate greater than in younger adults.  
Trastuzumab has also not been well studied in older adults due to poor enrollment of older adults in the 
relevant clinical trials. While not associated with an increased risk of diarrhea as a single agent, it has 
been documented that age greater than 60 is a risk factor for developing trastuzumab-related 
cardiotoxicity.34-35 The HER2 protein is widely believed to play a role in cardiac contractility and 
myocyte survival, and as such, cardiomyopathy is likely a class effect of all HER2 directed agents.91  A 
recently reported study randomized 297 women previously treated with trastuzumab to either lapatinib 
monotherapy or lapatinib combined with trastuzumab.59  The results showed a clinically and statistically 
significant difference in overall survival.69 However, the median age in this study was only 52.59 Few 
patients were over the age of 60. However, this is a combination that would be potentially attractive to 
older adults and their physicians who may want to avoid cytotoxic chemotherapy treatment. Given the 
growing population of older adults with cancer additional study of the benefits and risks of targeted 
therapies remains an unmet need. 
2.9 Cardiac Toxicity of Lapatinib and Trastuzumab 
2.9.1 
Cardiac Effects of Trastuzumab 
Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac 
failure, cardiomyopathy, and cardiac death. Trastuzumab can also cause a symptomatic decline in left 
ventricular ejection fraction (LVEF). There is a 4−6 fold increase in the incidence of symptomatic 
myocardial dysfunction among patients receiving trastuzumab as a single agent or in combination therapy 
compared with those not receiving trastuzumab.28, 35-38 The highest absolute incidence occurs when 
trastuzumab is administered with an anthracycline.28   
 
As a single agent, the cardiotoxicity of trastuzumab is variable.  In Study H0650g, Vogel et al reported 
the results of one hundred fourteen women with HER2-overexpressing metastatic breast cancer who were 
randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg 
weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. Cardiac dysfunction occurred in 
only two patients (2%), and both had histories of cardiac disease and did not require additional 
intervention after discontinuation of trastuzumab.39  However, in the early study of trastuzumab given in 
the second or third line setting, the rates were different. Cobleigh et al, in Study H0649g, treated 213 
women with HER2-overexpressing metastatic breast cancer that had progressed after one or two 
chemotherapy regimens. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-
mg/kg maintenance dose at weekly intervals. In this group severe symptomatic cardiac dysfunction 
occurred in 4.7% of patients, including one death that may have been due to trastuzumab related cardiac 
failure,38 and symptomatic heart failure was seen in 8.5% of subjects in a retrospective analysis.37  It is 
thought that the difference in rates is likely due to previous treatment with an anthracyclines.  In study 
H0649g, trastuzumab was given in the second or third line.  Nine of ten patients with reported severe 
cardiac dysfunction had previously received an anthracyclines.  In study H0650g trastuzumab was given 
front line, and therefore the risk of having received an anthracyclines in the past was limited.37  
 
The risk of trastuzumab in combination with an anthracycline was elucidated in the pivotal trial of 
trastuzumab given in combination with chemotherapy in the metastatic setting. In study H0648g, Slamon 
et al. assigned 234 patients to receive standard chemotherapy and 235 to receive standard chemotherapy 
plus trastuzumab.  One hundred thirty eight of the 234 women receiving chemotherapy alone received an 
anthracycline and cyclophosphamide, while 96 received paclitaxel alone.  Of the 235 women who 
received chemotherapy with trastuzumab, 143 received trastuzumab with an anthracycline and 
cyclophosphamide, while 92 received trastuzumab with paclitaxel. In addition to showing a statistically 

 
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significant benefit in overall survival, the study identified “cardiac dysfunction” as the most important 
adverse event. It was not clearly specified what constituted cardiac dysfunction. A total of 27 percent of 
the group given an anthracycline and trastuzumab, but only 8 percent of the group given an anthracycline 
and cyclophosphamide alone, had cardiac dysfunction. In those who received paclitaxel and trastuzumab, 
13 percent of the group given paclitaxel and trastuzumab experienced cardiac dysfunction, compared to 
only 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, 
in some cases, life-threatening, the symptoms generally improved with standard medical management.28, 
92  
 
The presentation of the above data prompted retrospective analyses to evaluate cardiac safety in the above 
trastuzumab trials. On re-analysis of symptomatic heart failure alone in the study by Slamon et al., the 
rate of cardiac dysfunction was 8.8% in those who received paclitaxel together with trastuzumab (N=8). 
For the paclitaxel group alone, later analysis showed that 4.2% (N=4) of patients had received treatment 
for symptomatic heart failure events, as against 1% (N=1) in the earlier analysis. As had been reported in 
the initial analysis, the incidence of symptomatic cardiac dysfunction was significantly higher in patients 
receiving trastuzumab in combination with anthracyclines (28.0%; N=40) than in those receiving 
anthracyclines alone (9.6%; N=13).37 See Table 1 below for a summary of the findings of cardiac toxicity 
of trastuzumab in the early metastatic studies. 
 
Table 2. Retrospective analysis of data from pivotal trials: incidence of symptomatic heart failure in the 
pivotal trastuzumab trials, including follow-up to March 1999 (Roche data on file—Cardiac Task Force 
final report).37 
 
T=trastuzumab; P=paclitaxel; AC=anthracycline/cyclophosphamide. 
* Defined as congestive heart failure, cardiomyopathy, heart failure, left ventricular failure, lung 
edema or information from case report forms indicating cardiac failure (e.g. a combination of 
shortness of breath, dyspnea, increased coughing, or pulmonary congestion on X-ray, echo or 
MUGA scan).37 
 
In the adjuvant setting, trastuzumab related cardiotoxicity has been well studied. In the National Surgical 
Adjuvant Breast and Bowel Project (NSABP) trial B-31, doxorubicin and cyclophosphamide (AC) 
followed by paclitaxel was compared with AC followed by paclitaxel plus 52 weeks of trastuzumab 
beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. All 
patients required normal left ventricular ejection fractions between completion of AC and commencement 
of trastuzumab. If symptoms suggestive of congestive heart failure developed, source documents were 
 
Study  
 
 
 
 
 
 
H0649g  
H0650g  
H0648g  
 
 
 
 
T alone  
T alone  
T+P  
P  
T+AC  
AC  
Classification  
(N = 213) 
(N = 114) 
(N = 91) 
(N = 95) 
(N = 143)  
(N = 135)  
Symptomatic heart failure*  
8.5%  
2.6%  
8.8%  
4.2%  
28.0%  
9.6%  
NYHA III-IV  
5%  
<1%  
4%  
1%  
19%  
3%  

 
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blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a 
cardiac event, which was defined as New York Heart Association class III or IV CHF or 
possible/probable cardiac death. Among patients with normal post-AC LVEF who began post-AC 
treatment, five of 814 control patients subsequently had confirmed cardiac events compared with 31 of 
850 trastuzumab-treated patients. The difference in cumulative incidence at 3 years was 3.3% (4.1% for 
trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Cardiac events 
were more frequent in older patients and patients with lower post-AC LVEF (50-55%). Fourteen percent 
of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued 
trastuzumab because of symptomatic cardiotoxicity.34 
 
In the Intergroup adjuvant trial (NCCTG N9831), patients with Her2-positive early breast cancer were 
assigned to AC followed by either paclitaxel, paclitaxel followed by trastuzumab, or paclitaxel together 
with trastuzumab followed by trastuzumab alone. Left ventricular ejection fraction (LVEF) was evaluated 
at registration and 3, 6, 9, and 18 to 21 months. Of 1944 patients with satisfactory LVEF following AC, 
CHF developed in 2.8%, and 3.3%, in the two trastuzumab containing arms, compared with only 0.3% in 
the paclitaxel alone arm. Cardiac function improved in most CHF cases following trastuzumab 
discontinuation and cardiac medication. Older age, lower registration LVEF, and antihypertensive 
medications were associated with increased risk of cardiac dysfunction in patients receiving trastuzumab 
following AC.36 
 
In the Herceptin Adjuvant (HERA) trial, an open-label randomized trial which compared 1 or 2 years of 
trastuzumab given once every 3 weeks with observation in patients with HER-2-positive breast cancer, 
cardiac toxicity was also well elucidated. Data were available for 1,693 patients randomly assigned to 1 
year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab 
discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher 
in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 
0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most 
patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated 
cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m2 v 257 mg/m2) 
or epirubicin (480 mg/m2 v 422 mg/m2) and had a lower screening LVEF and a higher body mass index.93 
 
In summary, the above data demonstrate the risk of symptomatic congestive heart failure with 
trastuzumab. This risk is amplified by concurrent administration of anthracyclines, increased age, lower 
baseline LVEF, and higher cumulative doses of prior anthracyclines. As a result of this experience, it is 
recommended that thorough cardiac assessment, including history, physical examination, and 
determination of LVEF by echocardiogram or MUGA scan, be conducted prior to the first dose of 
trastuzumab. The following schedule was used to monitor cardiac function in clinical studies: 
• Baseline LVEF measurement immediately prior to initiation of trastuzumab 
• LVEF measurements every 3 months during and upon completion of trastuzumab 
• LVEF measurements every 6 months for at least 2 years following completion of trastuzumab 
• Repeat LVEF measurement at 4 week intervals if trastuzumab is withheld for significant left ventricular 
cardiac dysfunction  
It is recommended in the Herceptin© package insert to withhold trastuzumab for a ≥16% absolute 
decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 
10% absolute decrease in LVEF from pretreatment values.94  
 
2.9.2 
Cardiac Effects of Lapatinib 
Left Ventricular Ejection Fraction (LVEF) has been evaluated using MUGA scans or echocardiogram 
during lapatinib phase I, II and III trials. A total of 300 subjects on lapatinib clinical trials sponsored by 

 
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GSK experienced 323 events of decreased LVEF, regardless of investigational product received, as of 
December 2009.  These 300 subjects/323 events are summarized below in Figure 1. Eighty eight percent 
of the reports were for female subjects, which may be attributed to the fact that the majority of large 
studies in the lapatinib program are for breast cancer.89 The protocol-specific definition of a serious 
cardiac event is defined as follows: 
 
NCI CTC Grade 3 or 4 left ventricular systolic dysfunction  or 
 
LVEF decrease ≥20% relative to baseline value  and  below the institutions lower limit of 
normal 
Figure 1: Summary of decreased LVEF reports which met the protocol specific definition as of  
December 4, 200989 
 
 
Of the 251 patients whose LVEF decrease met the protocol specific serious definition, 164 (with 182 
events) received lapatinib, giving an incidence of 0.9% (164/17,687) or 1.1% if all 39 subjects who 
remain blinded as of the latest safety evaluation received lapatinib.89  Of note, one subject received 
capecitabine monotherapy then crossed to lapatinib-capecitabine combination therapy, and experienced 
an LVEF decrease event in each treatment group.58 
Among the 164 lapatinib subjects, 41 were participating in monotherapy studies and 123 received 
lapatinib in combination (capecitabine, cisplatin, letrozole, paclitaxel, paclitaxel+trastuzumab, 
trastuzumab or trastuzumab/docetaxel).   

 
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The majority (74%) of decreased LVEF events which occurred on lapatinib treatment were asymptomatic. 
The mean time to onset of decreased LVEF in the 122 asymptomatic lapatinib-treated subjects was 17.4 
weeks (range: 14 days to 2.6 years).  The mean LVEF decrease relative to baseline value was 29.5% 
(range: 20% to 69%).  This corresponded to a mean absolute LVEF decrease of 18.4% from baseline 
(range: 10% to 45%).89 Among the 122 subjects who experienced asymptomatic LVEF decreases, the 
majority (85%, 104/122) had pre-existing conditions and/or previous concurrent medications which may 
have contributed to their LVEF disease. Examples included: previous episodes of decreased LVEF, 
myocardial infarction, arrhythmia, left-chest radiation, and exposure to anthracyclines, trastuzumab, or 
paclitaxel, all of which have been associated with cardiac adverse events.89  
Overall, 92 of 122 asymptomatic subjects (75%) recovered or improved, 69 of these subjects after 
interruption/discontinuation of lapatinib (positive dechallenge).  Forty one of the subjects who recovered 
or improved continued to receive lapatinib.  Lapatinib had already been discontinued in twelve patients 
prior to detection of an LVEF decrease.  Seventeen asymptomatic events were ongoing, and thirteen 
LVEF decrease events were ongoing at the time of the subject’s death due to disease progression.89   
Forty-one lapatinib subjects experienced 46 symptomatic LVEF decreases while receiving lapatinib (8 
during monotherapy and 31 during combination therapy).  This gives an approximate incidence of 0.3% 
for symptomatic events (46/17,687).  The symptoms observed were dyspnea, chest pain, cardiac failure, 
and palpitations.  The majority (90%) pf these subjects had pre-existing conditions (e.g. pericardial 
effusion, pleural effusion, hypertension, diabetes) and/or previous/concurrent medications (e.g. exposure 
to anthracyclines, trastuzumab, or radiotherapy) which could have contributed to the event. 
Many of the subjects in the lapatinib trials had previously received treatment with either anthracyclines 
and/or trastuzumab, both of which have been associated with cardiotoxicity.  In addition some ongoing 
studies combine lapatinib with trastuzumab, paclitaxel, or capecitabine, which are associated with 
cardiotoxicity.  This therefore increases the risk of cardiotoxicity in the lapatinib patients irrespective of 
any cardiac toxicity attributed to lapatinib.  Decreased ejection fraction is included in the core safety 
information (CSI) for lapatinib.58  
These results are similar to results analyzed by Perez et al. in 3689 patients who had been in studies 
conducted between January 5, 2001, and September 30, 2006. Cardiac events (symptomatic or 
asymptomatic) were reported in 60 patients. Those patients who had prior treatment with anthracyclines 
had a 2.2% rate of cardiac events, prior treatment with trastuzumab was associated with a 1.7% rate of 
events, and those who had not had either previously had a 1.5% incidence of cardiac events. In most 
patients (53 patients, 83%), events were not preceded by symptoms.  The decrease in LVEF was rarely 
severe; the mean nadir was 43%. In 40 patients for whom outcome was determined, 35 (88%) had a 
partial or full recovery regardless of continuation or discontinuation of lapatinib. No cardiac deaths 
occurred among patients treated with lapatinib.95  
 
2.10 Other Important Safety Issues with Lapatinib 
The most extensive study of lapatinib toxicities was in combination with capecitabine.  Of note, many of 
these toxicities may be synergistic when given in combination, and the following two tables cannot serve 
as reliable predictors of toxicity with lapatinib monotherapy. 
 
 
 
 

 
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Table 3: Common Adverse Events in the Combination of Lapatinib with Capecitabine versus with 
Capecitabine Alone52 
 
 
Lapatinib 1,250 mg/day + 
Capecitabine 2,000 mg/m2/day 
Capecitabine 2,500 mg/m2/day  
(N = 198)  
(N = 191)  
 
All 
Grades* 
Grade 3 
Grade 4 
All 
Grades*  
Grade 3  
Grade 4  
Reactions  
%  
% 
%  
%  
%  
%  
Gastrointestinal disorders  
Diarrhea  
65  
13  
1  
40  
10  
0  
Nausea  
44  
2  
0  
43  
2  
0  
Vomiting  
26  
2  
0  
21  
2  
0  
Stomatitis  
14  
0  
0  
11  
<1  
0  
Dyspepsia  
11  
<1  
0  
3  
0  
0  
Skin and subcutaneous tissue disorders  
Palmar-plantar 
erythro-
dysesthesia  
53  
12  
0  
51  
14  
0  
Rash†  
28  
2  
0  
14  
1  
0  
Dry skin  
10  
0  
0  
6  
0  
0  
General disorders and administrative site conditions  
Mucosal 
inflammation  
15  
0  
0  
12  
2  
0  
Musculoskeletal and connective tissue disorders  
Pain in 
extremity  
12  
1  
0  
7  
<1  
0  
Back pain  
11  
1  
0  
6  
<1  
0  
Respiratory, thoracic, and mediastinal disorders  
Dyspnea  
12  
3  
0  
8  
2  
0  
Psychiatric disorders  
Insomnia  
10  
<1  
0  
6  
0  
0  
* National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.  
† Grade 3 dermatitis acneiform was reported in <1% of patients in lapatinib plus capecitabine group. 
 
 

 
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Table 4: Other Selected Laboratory Abnormalities in the Combination of Lapatinib with 
Capecitabine versus with Capecitabine Alone52 
 
Lapatinib 1,250 mg/day + Capecitabine 2,000 
mg/m2/day  
Capecitabine 2,500 mg/m2/day  
 
All 
Grades* 
 
Grade 
3  
Grade 4 
All Grades*  
Grade 3  
Grade 4 
Parameters  
%  
%  
% 
%  
%  
%  
Hematologic  
Hemoglobin  
56  
<1  
0  
53  
1  
0  
Platelets  
18  
<1  
0  
17  
<1  
<1  
Neutrophils  
22  
3  
<1  
31  
2  
1  
Hepatic  
Total Bilirubin  
45  
4  
0  
30  
3  
0  
AST  
49  
2  
<1  
43  
2  
0  
ALT  
37  
2  
0  
33  
1  
0  
 
* National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.  
 
2.10.1 Interstitial Pneumonitis 
Manufacturer-sponsored lapatinib protocols include specific requirements for reporting of signs or 
symptoms of pneumonitis. As of December 4, 2009, 55 pulmonary events have been reported suggestive 
of pneumonitis: 42 of these subjects received lapatinib, one subject remained blinded, 11 subjects 
received a comparator agent (trastuzumab, paclitaxel, cyclophosphamide, or radiotherapy), and one 
subject received placebo.  This gives an approximate incidence of 0.2% (42/17,687) for pulmonary events 
in lapatinib clinical trials.89 
Among the 42 lapatinib subjects, 11 were participating in monotherapy studies. Of these 11 subjects, four 
recovered, and two events were ongoing (one these subjects died due to disease progression while the 
event was ongoing.)  In four monotherapy subjects, the pulmonary event was associated with a fatal 
outcome: three subjects had evidence of disease progression (including lung metastases and esophageal 
carcinoma); the fourth subject developed interstitial lung disease and died approximately seven months 
after the last dose of lapatinib.  This subject had recently completed radiotherapy and the investigator felt 
that lapatinib may have affected the subject’s tolerance to radiotherapy.  In on subject the outcome of the 
event was unknown.89 
Thirty-one subjects experienced pulmonary events while receiving lapatinib in combination (irinotecan, 
paclitaxel, pazopanib, docetaxel, letrozole, trastuzumab, and radiation).  Eighteen of these combination 
therapy subjects recovered or improved. Five events were associated with a fatal outcome, however all 
five subjects had evidence of disease progression. Five subjects had not recovered by the time of GSK’s 
last safety evaluation. Outcome remained unknown for three events.89 
Post-marketing reports have revealed 16 pulmonary events suggestive of pneumonitis as of December 
2009.  This is based on patient exposure of 7,823 patient years, giving an estimated reporting rate of 
approximately 0.2% per patient year for pulmonary events. Seven events resolved, three events were 
ongoing at the time of reporting, four events reported outcome as unknown at the time of reporting, and 

 
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two events were reported as fatal as the patients died due either due to progression of disease or of other 
unknown causes.89 
2.10.2 Liver Chemistry 
As part of ongoing pharmacovigilance by GlaxoSmithKline, a review of all hepatobiliary events reported 
across the entire lapatinib clinical development program has been performed.  Two hundred sixteen 
reports of hepatic events were retrieved from the GSK safety database as of December 31, 2007 
regardless of source (clinical trials, spontaneous/marketed use data).  In 39 of the 216 cases, a causal 
association to lapatinib could not be ruled out: 38.5% (15/39) of these subjects received lapatinib 
monotherapy, 53.8% (21/39) of subjects received lapatinib in combination with other chemotherapies, 
such as capecitabine, and 3 cases were still blinded. 
The 216 cases noted were the overall number of events associated with hepatobiliary system organ class 
in the global safety database.  After further analysis, a total 177 reports were found to be confounded by 
factors such as underlying or concomitant diseases or the use of concomitant medications leading to 
hepatobiliary events.  There were 39 cases where a causal association to lapatinib was possible. 
Therefore, the number 39/8704= 0.4% accurately reflects the crude incidence for hepatobiliary events on 
the lapatinib program.  An incidence of 0.4% falls into the category of 'uncommon' (>/= 0.1% and <1%) 
per ICH guidelines. 
A total of 13 deaths were identified which contained hepatobiliary events.  In 3 of these cases, an 
association with lapatinib could not be excluded.  The remaining 10 cases were confounded by the 
patients underlying condition (progressive disease and/or progression of pre-existing liver metastases). 
Based on an additional sub-analysis, of 18 clinical studies of lapatinib in breast cancer, using Hy’s Law 
(defined as AST or ALT >3 x ULN, and total bilirubin >2 x ULN, with no initial findings of cholestasis 
i.e.: ALP <2 x ULN) as a predictor for potential drug induced liver injury, the liver injury associated with 
lapatinib seems to be the result of a prolonged exposure to the drug.  All the subjects whose events 
potentially met Hy’s Law received study medication for three months or longer.  The majority of these 
cases appeared reversible.  Most patients experienced a decline in liver enzymes with drug cessation. 
Based on the results of this review, GSK concluded a causal relationship between hepatobiliary disorders 
(specifically transaminase elevations) and lapatinib cannot be excluded.  As a consequence, 
hepatotoxicity was added to the core safety information (CSI) for lapatinib.  In addition, for ongoing 
clinical trials, the monitoring interval for hepatic function has been increased to every 4-6 weeks during 
treatment, and stopping rules have been added for severe hepatic events.  Lapatinib dosing should be 
discontinued if changes in liver function are severe and patients should not be retreated.58 
2.10.3 Diarrhea 
While cardiac, pulmonary, and hepatic toxicity may be the most concerning potential toxicities of 
lapatinib, diarrhea is by far the most common.  Most cases of diarrhea are Grade 1-2, however the rates of 
Grade 3 or higher diarrhea (using the definition in the NCI CTCAE v.3.0) have been shown to be 
relatively high (5-10%) on the lapatinib arm of all pivotal trials to date.  In the pivotal trial of capecitabine 
with or without lapatinib (given 1250mg daily), Geyer et al described diarrhea occurring in 60% of 
subjects in the combination arm (98/164) compared to only 39% in the capecitabine alone arm (60/152), 
and this difference was highly statistically significant.  The difference in Grade 3-4 diarrhea was not as 
pronounced.  Thirteen percent of those on the combination arm had grade 3 or higher diarrhea (Grade 
3=19, Grade 4=2) compared to eleven percent receiving capecitabine alone (Grade 3=17, Grade 4=0).52 
Johnston et al described a study in which 654 patients treated with letrozole combined with 1500mg daily 
of lapatinib were compared to 624 patients treated with letrozole plus placebo.  In this study diarrhea was 
also the most prevalent side effect in the lapatinib arm with rates of all grades of diarrhea similar to those 
reported in the paper by Geyer et al.  However, in this study, while less than 1% of those who received 

 
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letrozole alone had Grade 3 or higher diarrhea, 11% of those who received lapatinib plus letrozole had 
Grade 3 or higher diarrhea (Grade 3=58, Grade 4=2).53  This high rate of grade 3 or higher diarrhea may 
have been due to the higher dose of lapatinib given, or it may have been due to different demographics 
between the two studies.  The population described by Johnston et al had a much higher median age (62) 
than the population in the study by Geyer et al (median age 54).52-53 
 
More recently, Blackwell et al described the results of the combination of trastuzumab and lapatinib 
(given at 1000mg daily) with lapatinib alone (given at 1500mg daily).  In this study, both arms had a rate 
of grade 3 or higher diarrhea of 7%.  Median age in the study, though, was only 52 years.59 
 
Looking at this data in aggregate, it appears that higher doses of lapatinib as a single agent, or lapatinib in 
combination with other agents, whether chemotherapy, hormonal therapy, or targeted therapy, is 
associated with relatively high rates of grade 3 or higher diarrhea (7-13%).  It is possible that increased 
age may be associated with an increased risk of diarrhea as well as decompensation from the results of 
diarrhea (dehydration, electrolyte imbalances), and thus could lead to more severe clinical effects.  The 
rate of high-grade diarrhea in older adults versus younger adults receiving lapatinib has not yet been 
studied.  
 
2.11 Overview of Proposed Study 
We propose to study the tolerability of the combination of lapatinib and trastuzumab in older adults with 
advanced breast cancer who have previously received trastuzumab.  This will entail the administration of 
daily doses of 1000mg of oral lapatinib and either weekly doses of 2mg/kg of IV trastuzumab after an 
initial load of 4mg/kg, or 6mg/kg of IV trastuzumab every three weeks following an initial load of 
8mg/kg until disease progression, death, unacceptable side effects, or study withdrawal. 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the 
applicable regulatory requirements. 
 
2.11.1 Trastuzumab Dosing 
Two acceptable ways of dosing trastuzumab have been described in the literature.  While most major 
studies in the metastatic setting have used weekly dosing, many experts believe that every three week 
dosing of 6mg/kg (following an initial load of 8mg/kg) is adequate due to the drug’s low systemic 
clearance, low volume of distribution, and very long half-life.96 Post marketing studies of trastuzumab 
given in the every-three-week setting in metastatic cancer have been studied and found to be a good 
alternative to weekly dosing and tolerability seemed unaffected.97-100  Conventional wisdom thus 
concludes that every three week trastuzumab is substitutable for trastuzumab administered weekly.  We 
will thus allow either form of dosing, as per the discretion of the treating physician. 
   
2.11.2 Strict Rules for Cardiac Toxicity 
As cardiac toxicity is a serious adverse event reported with the combination of these agents59, we will 
have strict rules for holding lapatinib and trastuzumab in the event of asymptomatic drop in the left 
ventricular ejection fraction.  In some previous trials of lapatinib, dose reductions of lapatinib were 
recommended in asymptomatic decreases of LVEF only when the LVEF both fell by an absolute amount 
more than 20%, AND to a level below 50% (the lower limit of normal for most institutions).  These were 
the criteria that were used in the most recently reported lapatinib-trastuzumab combination study59 as well 
as the criteria that are being used in the ALLTO adjuvant trial which includes the combination of 
lapatinib and trastuzumab in one of the study arms.101  However, as detailed above, the trastuzumab 

 
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package insert recommends holding trastuzumab for a ≥16% absolute decrease in LVEF from pre-
treatment values OR an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in 
LVEF from pretreatment values.88 These criteria are clearly more conservative.  Because we are 
attempting use in a population who has a higher risk of trastuzumab cardiotoxicity than the average 
population35, we will use a stricter hold criteria defined as a drop of 10% OR a drop to below the lower 
limits of normal. 
We additionally plan to have study stopping rules in place (described in section 12 below), that will 
ensure that we do not continue to enroll patients on the study if the symptomatic cardiac toxicity (defined 
as NYHA Class III or IV heart failure) is higher than is seen in previous studies of trastuzumab (>4%).   
Finally, there will be safety assessments ongoing through the institutional oversight board. There will be 
two formal interim analyses; one following enrollment of 20 patients who have completed one cycle of 
treatment and a second following enrollment of 30 patients who have completed one cycle of treatment, 
to allow us to modify starting dose or close the protocol if the starting dose of lapatinib appears overly 
toxic.  We will especially be looking at gastrointestinal toxicity, as diarrhea is an oft-reported side effect 
of lapatinib, and the severity of diarrhea may be higher in older adults than in younger for a number of 
reasons described above. 
2.11.3 Secondary Objectives 
We plan to assess for efficacy of the combination.  CT or PET-CT (which contains a diagnostic CT 
component) will be performed every 4 cycles (12 weeks) to assess for response or progression. 
Progression-free and overall survival will also be evaluated. 
A Geriatric Assessment Survey (Appendix E) will be administered at baseline and every 4 cycles (12 
weeks) while on study. The Geriatric Assessment Survey measures various domains including functional 
status, comorbidity, cognition, psychological status, social functioning and support, and nutritional status. 
This information may allow us to form hypotheses regarding factors that influence toxicity or response in 
older adults on dual biologic therapy. 
Adherence to lapatinib therapy will be assessed utilizing drug diaries and pill counts.  Documentation of 
non-adherence both may serve as a descriptor of any dose-related toxicity determinations as well as a 
surrogate for unreported drug toxicities. 
As reported above, the pharmacokinetics of lapatinib are widely variable, with variable absorption that is 
influenced by food, concomitant medications, and potentially other unknown variables.  While multiple 
pharmacokinetic studies of lapatinib have been performed during drug development, only a very small 
number of these were done in older adults.  Steady-state lapatinib pharmacokinetic measures will be 
gathered.  Patients will have a single blood draw during each of week 3, 4, and 5 after starting treatments, 
immediately prior to their lapatinib dose. However, if the patient undergoes a dose reduction or a hold in 
treatment the pharmacokinetic samples will be rescheduled accordingly.  . 
3.0 Patient Eligibility 
3.1 Inclusion Criteria  
3.1.1 
Disease Status 
1. Locally advanced or metastatic Her2/Neu positive breast cancer (defined as IHC 3+ or a FISH ratio of 
> 2.0). This may be on either a primary tumor or a metastatic site, and there is no time limit from the time 
the specimen was obtained. Locally advanced breast cancer (LABC) includes breast cancers with 
advanced primary tumors, ie, large diameter (at least 5 cm) or those with skin and/or chest wall 
involvement, and advanced regional lymph node involvement. It also includes a rare subgroup, 
inflammatory breast cancer. 

 
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 In the 2010 American Joint Committee on Cancer and the International Union for Cancer Control 
(AJCC-UICC) TNM breast cancer staging system, locally advanced breast cancer (LABC) includes 
patients with stage III disease. This comprises: 
 
Advanced primary tumors [Tumors > 5 cm in greatest dimension (T3). direct extension to 
the chest wall and/or to the skin (T4): ulceration, skin nodules, and/or edema (including peau 
d'orange) confined to the same breast, Inflammatory breast cancer (IBC, T4d)]  
 
Advanced regional lymph nodes [Ipsilateral level I, II axillary lymph nodes that are 
clinically fixed or matted or clinically detected internal mammary lymph nodes in the 
absence of axillary lymph node metastases (N2), Ipsilateral infraclavicular (level III axillary) 
lymph nodes, ipsilateral internal mammary lymph node(s) with axillary lymph nodes, or 
ipsilateral supraclavicular lymph nodes (N3)] 
 
2. Both measurable and non-measurable disease are allowed 
 
3.1.2 
Age Criteria and Life Expectancy 
1.  Age 60 or older 
2.   Life expectancy of greater than 12 weeks 
 
3.1.3 
Child Bearing Potential 
The effects of lapatinib and trastuzumab on the developing fetus are unknown.  For this reason, women of 
child-bearing potential and sexually active men must agree to use adequate contraception prior to study 
entry and for six months following duration of study participation. 
3.1.4 
Protocol-Specific Criteria 
ECOG performance status <2 (Karnofsky performance status >60%) 
1.  (See Appendix A) 
2. Normal organ and marrow function as defined below: 
 
- 
hemoglobin  
 
 
>10 g/dL (after transfusion if necessary) 
 
- 
absolute neutrophil count 
 
>1,500/mcL 
 
- 
platelets  
 
 
 
>100,000/mcL 
 
- 
total bilirubin 
 
 
within normal institutional limits 
 
- 
AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal 
 - 
creatinine clearance 
 
>30 mL/min as measured using either the Cockroft-Gault 
method or 24-hour creatinine clearance 
 
- 
The above tests must be obtained within 14 days of study treatment 
3.  Cardiac ejection fraction >50% as measured by echocardiogram or MUGA scan.  
4. The ability to swallow and retain oral medication 
5.    Prior treatment with lapatinib or trastuzumab are allowed, provided that the agents have never been 
given in combination 

 
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6. Any number of prior cancer treatments, including investigational agents, chemotherapy, hormone 
therapy, or targeted therapy are allowed. 
3.1.5 
Informed Consent 
All patients must have the ability to understand and the willingness to sign a written informed consent. 
3.2 Exclusion Criteria 
3.2.1 
Study-Specific Exclusions 
1  Concurrent investigational treatment, chemotherapy, or targeted therapy. Prior chemotherapy, 
hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade ≥2 
must have resolved by the time of study commencement (except alopecia).   
2 
Unstable or symptomatic brain metastases (However, patients with stable or treated brain metastases 
who do not require steroids at doses above those permitted in Appendix C for control of symptoms 
may be enrolled) 
3 
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
lapatinib or trastuzumab. However, patients with a history of infusion reaction to trastuzumab which 
was controlled with premedication on subsequent infusions without a recurring infusion reaction are 
eligible. 
4 
Concomitant medications listed in Appendix C are prohibited. Inhibitors or inducers of CYP3A4 not 
listed in Appendix C can be used with caution. 
5 
Ongoing or active infection (including HIV) or psychiatric illness/social situations that would limit 
compliance with study requirements 
6   Inability to take oral medication 
7   Malabsorption syndrome, (prior surgical procedures affecting absorption), or inflammatory GI 
disease (e.g., Crohn’s, ulcerative colitis) which in the opinion of the study coordinator is likely to 
limit normal absorption of the drug  
8 
Current active hepatic or biliary disease (with the exception of patients with Gilbert’s syndrome, 
asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment) 
9 
Active cardiac disease, defined as (but not limited to): 
 
History of documented congestive heart failure (CHF) or systolic dysfunction (LVEF < 
50%) 
 
High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block, 
supraventricular tachycardias which are not adequately rate-controlled) 
 
Angina pectoris requiring antianginal medications 
 
Evidence of transmural infarction on ECG 
 
Clinically significant valvular heart disease 
 
Poorly controlled hypertension (e.g. systolic >180mmHG or diastolic >100mm Hg) 
 
Any other cardiac condition, which in the opinion of the treating physician would make 
this protocol unreasonably hazardous for the patient 
 
3.2.2 
Non-Compliance 
Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring 
requirements of the study are not eligible. 

 
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3.3 Inclusion of Women and Minorities 
This is a study of patients with locally advanced or metastatic breast cancer. Therefore, we anticipate the 
majority of participants will be female; however, accrual is open to both genders. The study is open to 
anyone regardless of gender or ethnicity.  Efforts will be made to extend the accrual to a representative 
population. 
4.0 Screening and Registration Procedures 
4.1 Screening Procedures 
4.1.1 
General Guidelines 
Eligible patients will be entered on study at the participating site and centrally at the City of Hope 
Comprehensive Cancer Center by the Study Coordinator. An Eligibility Screening Worksheet is 
attached as Appendix D. 
Following registration, patients should begin protocol treatment after receiving the oral medication 
and after being told to do so by the study team.  Issues that would cause treatment delays should be 
discussed with the Principal Investigator.  If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be canceled.  The Study Coordinator should 
be notified of cancellations as soon as possible. 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be 
done only after obtaining written informed consent.  Studies or procedures that were performed 
within 2 weeks for clinical indications (not exclusively to determine study eligibility) may be used 
for baseline values, even if the studies were done before informed consent was obtained. 
 
4.1.2 
Procedure for On-study and Treatment Deviations 
Any amendments to the study protocol need to be approved by the IRBs at both the study sponsor 
site as well as at all participating centers. All deviations or single subject exceptions to the study 
protocol must be reported to the primary IRB of the participating site, and to Dr. Arti Hurria, the 
study coordinator at the sponsoring institution. 
4.2 Informed Consent  
The investigational nature and objectives of the trial, the procedures and treatments involved and 
their attendant risks and discomforts, and potential alternative therapies will be carefully explained 
to the subject and a signed informed consent will be obtained.  Documentation of informed consent 
for screening will be maintained in the subject’s research chart and medical record.   
4.3 Registration Requirements/Process 
The participating clinicians who are approved at City of Hope may obtain informed consent: 
Confirm in the electronic medical record that the patient has received the Notice of Privacy 
Practice. This must be obtained before the eligibility confirmation and obtaining of the research 
informed consent. 
Confirm eligibility as defined in the section “Patient Eligibility” (3.0), and using the checklist in 
Appendix D. 
Obtain written informed consent by following procedures defined in the section entitled “Informed 
Consent Processes” (see section 14.7). 

 
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To register a City of Hope patient, the treating physician should contact the responsible Clinical 
Research Associate (CRA) in the Clinical Trials Office or the protocol nurse to determine whether 
the patient meets all of the eligibility criteria, and to assist with the informed consent process.  After 
verifying the eligibility and receiving the signed informed consent, the CRA will register the patient 
onto the study. 
4.3.1 
Registration Process (City of Hope patients) 
 
4.3.1.1  Registrations for protocols must be made through the CTO office  at the 
City of Hope between the hours of 8:30 a.m. to 4:30 p.m. PST, Monday through 
Friday (except holidays). 
4.3.1.2   Patients must be registered within 2 weeks prior to initiation of protocol 
therapy. 
4.3.1.3  A patient failing to meet all protocol requirements may not be registered.  
If you have any questions regarding eligibility, contact (626) 256-4673 ext. 
62468 and ask for the CRA in charge of this study. 
4.3.1.4   Prestudy laboratory tests, scans and x-rays must be completed prior to 
registration according to the study calendar. 
4.3.1.5  Patients must sign an informed consent prior to registration. 
4.3.1.6   Confirm that the patient meets all inclusion and exclusion eligibility 
criteria for a protocol. 
4.3.1.7   Complete the Eligibility Checklist. 
4.3.1.8   Verify that all required prestudy tests were performed. 
4.3.1.9   Fax the completed Eligibility Checklist and the signed, dated informed 
consent to CTO.  The FAX number is (626) 301-8393.  
4.3.1.10   Call CRA at (626) 256-4673 x 62468 to confirm the FAX arrival. If the 
Coordinator is not in the office, have her paged. 
4.3.1.11   If the patient qualifies, the City of Hope Coordinator will assign the 
patient's study ID number.   
4.3.1.12    Once a patient has been registered, CRA will confirm registration of 
the patient.  
 
The outside institution patient registration process will be handled by the Department of Clinical Research 
Information Support (CRIS) Data Coordinating Center (DCC) at City of Hope.  Documentation of current 
IRB approval must be on file with the DCC prior to registration of patients on this study for participating 
institutions.   
The steps below are to be taken when registering a patient at a participating institution: 
4.3.2 
Registration Process (Participating Institutions) 
 
4.3.2.1 The participating institution’s research staff must assure they have the 
most current and updated version of the protocol and informed consent prior to 
enrolling a patient.  If a question arises, please contact the Data Coordinating 
Center at 626-256-4673 extension 63968 or via pager at 626-423-6486. 
4.3.2.2   The participating institution must assure that all prestudy laboratory 
tests, scans and x-rays have been completed prior to registration according to the 
study calendar. 

 
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4.3.2.3   The participating institution must assure that the patient has signed an 
approved informed consent prior to registration, including Experimental Subject 
Bill of Rights (if applicable) and appropriate HIPAA authorization.   
4.3.2.4   The participating institution must confirm that the patient meets all 
inclusion and exclusion eligibility criteria for a protocol.  The eligibility checklist 
must be completed in its entirety.     
4.3.2.5    A patient failing to meet all protocol requirements may not be 
registered.  Patients must be registered within 2 weeks prior to initiation of 
protocol therapy. 
4.3.2.6   Once a patient is eligible, all the pre-study requirements have been 
fulfilled, and the informed consent obtained, the research nurse or the data 
manager (study coordinator) at the participating center will inform the Data 
Coordinating Center (626-256-4673, ext 63968; pager 626-423-6486) and FAX 
(fax number 626-301-8422) a copy of the signed informed consent, patients’ Bill 
of Rights, signed HIPPA consent, completed eligibility checklist and 
corresponding source documentation confirming eligibility (including pathology 
reports, lab reports, x-ray reports, etc.). 
4.3.2.7   The Data Coordinating Center will: 
 
 4.3.2.7.1   Review all materials received to ensure the patient is eligible. 
4.3.2.7.2   Ensure the consent form is valid and is signed correctly by all parties.  
If additional information is needed or should there be any questions, the 
Data Coordinating Center will immediately contact the participating 
institution and registration will not occur until all issues are resolved.  No 
exceptions will be granted. 
 
 4.3.2.7.3   The patient will be registered centrally at City of Hope. 
4.3.2.7.4   Confirmation of Registration will be emailed/faxed to the participating 
institution noting study number as well as assigning the dose (if 
applicable) within 24 hours via fax or email.   
4.3.2.7.5   The Data Coordinating Center will call the research nurse or data 
manager (study coordinator) at the participating site and verbally confirm 
registration. 
4.3.2.8   If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study may be cancelled.  The Data Coordinating 
Center should be notified of cancellations as soon as possible. 
 
4.4 Dose Assignment  
All study patients will receive the same initial dose of study agents (see section 5.0).  Dose reductions can 
occur as medically necessary as will be described below (see section 6.0). 
5.0 Treatment Program 
5.1 Treatment Overview 
Treatment will be administered in an outpatient setting.   
Lapatinib will be administered at 1000mg (Four 250mg tablets) orally daily. 

 
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Trastuzumab will be administered in one of the two following schedules (per preference of the treating 
physician): 
1. Trastuzumab loading dose of 4mg/kg IV during week 1, and 2mg/kg IV weekly thereafter (+ 1 
day) 
2. Trastuzumab loading dose of 8mg/kg IV during week 1, and 6mg/kg IV every 3 weeks 
thereafter (+ 3 days)  
Patients already receiving trastuzumab treatment do not need to receive the loading dose. 
Patients initially started on weekly trastuzumab can be changed to an every 3 week regimen at the 
discretion of the treating physician.  Likewise, patients initially started on trastuzumab every 3 
weeks can be changed to weekly trastuzumab at the discretion of the treating physician. 
Doses missed for toxicity will not be made up. 
Management and dose modification associated with adverse events are outlined in Section 6. 
5.2 Planned Duration of Therapy 
Treatment may continue until one of the following occurs: 
 
Disease progression 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) as defined in Section 6 below 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
5.3 Criteria for Removal from Treatment 
Any subject who is removed from treatment prior to obtaining the first doses of both lapatinib and 
trastuzumab may be replaced.  Reason for removal should be documented and noted in the patient’s case 
report form. 
5.3.1 
Criteria for Removal 
 
Adverse Events 
 
Intercurrent illness that prevents further administration of treatment 
 
General or specific changes in the patient's condition which render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
Clinical disease progression confirmed by imaging 
 
Withdrawal of Consent 
5.3.2 
Subject Follow-Up 
Subjects will be followed for toxicity outcomes for an additional 30 days after stopping the drug 
and until resolution of all grade >2 toxicities.   Patients removed from study for unacceptable 

 
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adverse events will be followed until resolution or stabilization of the adverse event even if after 
disease progression is noted.  All patients will be passively followed until death, though active 
follow-up will cease upon removal from study. 
5.4 Supportive Care and Other Concomitant Therapy 
All concomitant medications taken during the study treatment will be recorded in the Case Report 
Form. The minimum requirements are that drug name and the dates of administration are to be 
recorded. All prescription and over-the-counter medications that have been taken within 1 month 
prior to the first dose of investigational treatment should also be reported in the Case Report Form. 
Patients should receive full supportive care during the study, including treatment with antibiotics, 
antiemetics, blood transfusions, antidiarrheals, and analgesics as appropriate, with the exception of 
drugs listed in Appendix C. 
5.4.1 
Medications Prohibited in Combination with Lapatinib 
Lapatinib is predominantly metabolized by CYP3A4.  Medications listed in Appendix C that are 
either inducers or inhibitors of CYP3A4 are prohibited throughout the study period until two weeks 
after the last dose of lapatinib. The following are additional points of interest. 
 
Washout period: The period of time between the last dose of a prohibited medication and the 
first allowed dose of lapatinib is dependent on the prohibited medication and is listed in 
column 3 of Appendix C. 
 
Medications that are inducers or inhibitors of CYP3A4 and are not listed in Appendix C may 
be used with caution 
 
Though use of intravenous and oral steroids is prohibited in Appendix C at doses above 10mg 
of prednisone daily or its equivalent, short term oral or intravenous steroid use of up to two 
weeks is allowed as treatment for any acute reaction or for prevention of an anticipated 
reaction for which in the opinion of the treating physician steroids are warranted. 
 
Lapatinib must be taken on an empty stomach. Patients must avoid use of grapefruit or 
grapefruit juice while on lapatinib.  Other prohibited food items are listed in Appendix C. 
 
Warfarin may be used together with lapatinib with caution.  Lapatinib potentially interacts 
with warfarin and quinazoline derivatives to increase INR and bleeding. While these 
medications are permitted to be taken during the study, it is recommended that INR and PT 
determinations should be collected at least weekly for the first month after starting lapatinib, 
and weekly for the first month after discontinuing lapatinib. 
NOTE: Lapatinib should NOT be taken with grapefruit or grapefruit juice. 
5.4.2 
Medications Prohibited in Combination with Trastuzumab 
There have been no formal drug interaction studies performed with trastuzumab in humans.  
Administration of paclitaxel in combination with trastuzumab resulted in a two-fold decrease in 
trastuzumab clearance in a non-human primate study and a 1.5-fold increase in trastuzumab clearance in 
clinical studies.  There are no formal recommendations prohibiting any medication in combination with 
trastuzumab.  However, clinical studies have shown that the administration of trastuzumab in combination 
with anthracyclines likely increase the risk of both clinical and subclinical risk of decreased cardiac 
ejection fraction, and therefore concurrent use is discouraged.  This is of minimal concern in this study as 
patients will not receive concurrent chemotherapy. 

 
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5.5 Laboratory/Monitoring Studies 
5.5.1 
Required Clinical, Laboratory and Disease Evaluation at Baseline 
Complete blood count and differential, comprehensive metabolic panel (including sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, ALT, AST, alkaline phosphatase, 
total bilirubin, total protein, and albumin), must be performed within 14 days of enrolling on trial.  
Laboratory tests within this time period may be accepted from third-party sites as long as an official 
laboratory report (or photocopy thereof) is provided. 
A full history and physical exam including demographics, medical history, concurrent medications, vital 
signs, height measurement, weight measurement, and performance status analysis must be done within 
one week of enrolling on trial. 
Radiologic evaluation including computed tomography (CT) of the chest, abdomen, and pelvis; or 
combined PET-CT with a diagnostic CT component, must have been performed within 30 days of the 
start of treatment. If measurable disease is present, tumor measurements must be performed and reported 
from this scan. Central review is not required for treatment decisions in individual subjects. 
The patient must complete a Geriatric Assessment prior to starting therapy (see Appendix E). 
Cardiac imaging (either by echocardiogram or MUGA scan) with a reported left ventricular ejection 
fraction must have been obtained within 30 days of the start of treatment, or since the most recent dose of 
prior trastuzumab, whichever is later.  Regardless of where the baseline evaluation is performed, future 
cardiac evaluation must be performed using only the same modality as the baseline evaluation. A baseline 
EKG before starting treatment is also required. 
5.5.2 
Studies Obtained During the Trial 
5.5.2.1 Disease evaluation 
CT scan of the chest, abdomen, and pelvis; or PET-CT with a diagnostic CT component must be 
performed every 12 weeks (±1 week) in the absence of symptoms to document disease response or 
progression.  In the presence of symptoms, these tests may be performed at the discretion of the treating 
physician.    
5.5.2.2 Cardiac evaluation 
Echocardiogram or MUGA scan must also be performed every 12 weeks (±1 week) in the absence of 
symptoms.  The modality must be the same as the modality used in the baseline cardiac evaluation.  In the 
presence of symptoms, or in the setting in which a prior study showed an abnormality requiring 
confirmation, echocardiogram or MUGA will be done either at the discretion of the treating physician, or 
according to the algorithm described below in section 6.1. 
5.5.2.3 Blood evaluation 
Complete blood count with differential and complete metabolic panel must be performed every three 
weeks (+/- 1 wk). If screening laboratories are performed within 14 days of the first study treatment, 
repeat laboratory tests will not be required before week 1, day 1. 
5.5.2.4 Pharmacokinetics 
One blood sample for lapatinib trough pharmacokinetics will be drawn on each of the following dates: 
cycle 1 day 15; cycle 2, day 1; and cycle 2, day 8 (±1 day for each) immediately prior to taking the 
lapatinib dose for that day.  Patients must not have taken anything by mouth other than water for 8 hours 
prior to the drawing of the pharmacokinetic sample.  The sample will be drawn at week 3, 4, and 5, only, 

 
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provided that the patient has taken lapatinib at the same dose level for each of the seven days prior to this 
study.  If lapatinib has not been taken at the same dose level according to schedule for seven days 
prior to the pharmacokinetic lab draw, the draw will be rescheduled accordingly for the 
pharmacokinetic analysis. 
At each of the required timepoints, 2 mL venous blood will be collected into a tube containing EDTA (to 
be provided by GSK).  Samples will be inverted several times and kept on ice until processing can begin. 
Plasma will be separated from whole blood by centrifugation at 1,500 x g for 10 minutes at 4° C and 
transferred to appropriately-labeled polypropylene tubes (to be provided by GSK) and frozen at < -20°C 
until shipping. Specimens will be batched at each participating site and stored in freezers at each site. At 
City of Hope, the specimens will be stored in a freezer accessible only to members of the City of Hope 
pharmacokinetic staff working under the auspices of Tim Synold, PharmD. 
Each tube will be labeled with the study number, patient registration number, time point, and the date and 
time the sample was drawn.  
Frozen serum samples at each site will be packed in the shipping container (provided by GSK) in 
sufficient dry ice to last at least 3 days (typically 6-8 kg), this shipment will occur yearly. The container 
will be sealed and shipped along with the packing worksheet via courier to: 
PharmaNet Canada, Inc 
Sample Controller 
2500 rue Einstein 
Quebec (Quebec), Canada G1P 0A2 
Phone: 1-418-527-40000 
Fax:  1-418-688-5242 
E-mail : vcholette@anapharm.com 
 
5.5.3 
Monitoring Studies 
5.5.3.1 Toxicity Evaluation 
Monitoring will take place every three weeks (± 1 week) consisting of a physician visit and assessment 
As early toxicity may be common with lapatinib, during cycles 1 and 2, during each week that the patient 
is not seeing an MD, patients will have a focused visit with a registered nurse to evaluate for new 
toxicities. (Week 2, Week 3, Week 5). A complete case report form does not need to be filled out for 
these short visits, which are rather designed to ensure that interventions may occur should toxicity be 
apparent. 
5.5.3.2 Adherence evaluation 
Adherence to trastuzumab will be measured by proportion of doses given in the infusion center as 
compared to number of doses scheduled.  Adherence to lapatinib will be measured by pill count every 
three weeks during the first five cycles during the investigator assessment, and every twelve weeks 
thereafter, as well as by patient self-report in dedicated patient diaries evaluated at the same time as pill 
count. In the event of discrepancy in these two measures of adherence, we will follow whichever indicates 
the lower measure of adherence (i.e. If patient states they took 26 of 28 doses, but only 20 doses are 
missing, we will count the patient as having taken only 20 days.  Alternatively, if 26 doses are missing, 
but the patient stated she only took 20 doses, we will count the patient as having taken only 20 doses.) All 
toxicity related dose interruptions or reductions, hospitalizations, and adverse events will be noted. 
Subjects will be followed for toxicity outcomes for an additional 30 days after stopping the drug and until 
resolution of all grade >3 toxicities. 

 
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5.5.3.3 Geriatric Assessment 
Geriatric assessment surveys will be administered at baseline, after every four cycles, and at the end of 
the study if it had not been performed in the previous 1 month (see Appendix E for Geriatric Assessment 
Survey). 
5.5.3.4 Survival Status 
Patients will be followed indefinitely to establish overall survival. All participants enrolled on the study 
will be informed that their medical condition will be followed indefinitely. In order to obtain survival 
status on the enrolled patients we will need the patient's first and last name, middle initial, social security 
number, date of birth, and gender.  This information will be securely transferred to the primary 
coordinating institution (City of Hope) and will be kept in a separate password protected file, which will 
only be linked for the purpose of establishing survivor status. The investigators will utilize the Social 
Security Death Index and the National Death Index to establish survival status.  Survival analysis will be 
conducted once a year. 
 
6.0 Dose Delays/Modifications for Adverse Events 
Patients will be treated per protocol or until disease progression or withdrawal from treatment due to 
unacceptable adverse events or treatment consent withdrawal. At each study assessment, subjects are to 
be evaluated for evidence of drug-related adverse events. 
In all cases where the subject is withdrawn due to unusual or unusually severe adverse event considered 
related to lapatinib or trastuzumab, the investigator must report the withdrawal as a Serious Adverse 
Event. 
Treatment may be delayed for up to 4 weeks, to allow for resolution of toxicity except in the event of 
those toxicities described below in which cases treatment must be discontinued permanently (see Table 
6).  
If one full cycle or more of trastuzumab is missed due to toxicity, on resumption of trastuzumab, an 
additional loading dose should be given (8mg/kg if q3wk schedule, 4mg/kg if q1wk schedule). 
Table 5: Dose reduction schema 
Dose Level 
Dose of lapatinib 
Dose of trastuzumab 
 
Level 0 
 
1000mg orally daily
2mg/kg IV weekly 
or 
6mg/kg q3wks 
 
Level -1 
 
750mg orally daily 
2mg/kg IV weekly 
or 
6mg/kg q3wks 
 
Level -2 
 
500mg orally daily 
2mg/kg IV weekly 
or 
6mg/kg q3wks 
Lapatinib may not be used at doses below 500mg in combination with trastuzumab. 
 

 
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6.1 Non-hematological adverse events 
The below discussion outlines situations in which lapatinib and trastuzumab must be either permanently 
discontinued, interrupted, or dose-reduced. In general, when dose interruption is indicated, administration 
of lapatinib may be interrupted for up to 4 weeks to allow the adverse event to resolve or decrease in 
severity  
At a minimum, reassessment of adverse events will be done every three weeks and more frequently if 
clinically indicated.  
If toxicities are ≥ grade 3, except for anemia, or related to a pre-existing comorbidity, or any toxicity 
deemed unrelated to cancer or cancer treatment (such as hypertension, hyperglycemia, decreased 
lymphocyte count, non-cancer related pain, fracture or orthopedic surgery) using NCI CTCAE v.4.0, 
treatment should be withheld until resolution to ≤ grade 1 or to baseline levels, then reinstituted, if 
medically appropriate, at the next lower dose level (see Table 5).  Patients who present with grade 1 or 2 
toxicities may have their treatment held, continued with dose-reduction, or continued at current dose with 
increased supportive care measures at the discretion of the treating physician unless meeting other 
stopping criteria below (see specifically section 6.2, 6.3, and 6.5.2). Treatments skipped due to toxicity 
will be omitted and total cycle length remains the same.  If toxicity is attributable to lapatinib (ie, rash, 
diarrhea, nausea) then dose modification should be initiated as detailed in section 6. Treatment with 
trastuzumab may continue 
For a summary of dose modifications required for adverse events, see Table 6 in section 6.7 below. 
 
6.2 Cardiac toxicity 
Cardiac toxicity with trastuzumab or lapatinib is most often manifested as Congestive Heart Failure.  The 
grading of CHF will follow the system developed by the New York Heart Association.  The following is a 
summary of the grading system: 
Class 
Patient Symptoms
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, or dyspnea 
(shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, 
but ordinary physical activity results in fatigue, palpitation, 
or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, 
but less than ordinary activity causes fatigue, palpitation, or 
dyspnea. 
Class IV 
(Severe) 
Unable to carry out any physical activity without 
discomfort. Symptoms of cardiac insufficiency at rest. If 
any physical activity is undertaken, discomfort is increased.
Source: Heart failure society of America. http://www.abouthf.org/questions_stages.htm. Accessed on November 22, 
2010. 
Treatment with lapatinib and trastuzumab must be permanently stopped for each of the following 
events:  
 
Cardiac arrest defined as either 

 
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o Cardiac death due to heart failure, myocardial infarction or arrhythmia 
o Probable cardiac death defined as sudden unexpected cardiac arrest within 24 hours 
of a definite or probable cardiac event. 
 
Severe symptomatic congestive heart failure defined as NYHA Class III or IV (Class III 
defined as being not capable of climbing one flight of stairs and Class IV defined as having 
symptoms at rest) 
 
A significant drop in LVEF, (confirmed by a second LVEF assessment after 21 days of 
holding the study drug also showing a significant drop). A significant LVEF drop is defined 
as an absolute decrease of more than 10 points below the baseline LVEF or to below 50%. 
See Figure 2 for an algorithm for dose interruptions and discontinuations for lapatinib and 
trastuzumab related cardiac toxicity manifesting as Class I or II Heart Failure. 
 

 
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Figure 2: Algorithm for continuation and discontinuation of lapatinib and trastuzumab based on 
interval LVEF assessments, for patients with NYHA Class I or II congestive heart failure 
 
 
6.3 Hepatic toxicity 
For grade 1 ALT or bilirubin increases (ALT>ULN - 3x ULN; bilirubin >ULN - 1.5x ULN), no dose 
modification is necessary. 
For grade 2 increases in ALT or bilirubin (ALT > 3x ULN - 5x ULN; bilirubin >1.5x ULN - 3x ULN, see 
Figure 3 below. 
For grade 3 or higher increases of ALT or bilirubin (ALT >5x ULN; bilirubin >3x ULN), lapatinib must 
be permanently discontinued. 
In any instance of hepatic toxicity in which lapatinib requires permanent discontinuation, the following 
actions should be taken as soon as possible for the purposes of patient safety and attribution of adverse 
events: 
o Liver imaging should be performed to rule out the potential of disease progression. 
o Other blood tests should be performed including direct (fractionated) bilirubin, Hepatitis 
A IgM antibody, Hepatitis B surface antigen, Hepatitis B Core Antibody (IgM), Hepatitis 
C RNA, Cytomegalovirus IgM antibody, Epstein-Barr viral capsid antigen IgM antibody 
(or heterophile antibody or monospot testing), and Hepatitis E IgM antibody. 
RESUME Treatment
LVEF < 50% 
LVEF  > 50% 
LVEF drop 10 points
HOLD treatment 
repeat
LVEF in 3 weeks
LVEF drop CONFIRMED
(LVEFdrop >10%  
or LVEF <50%) 
Not confirmed
(LVEF drop < 10% 
and LVEF > 50%)
STOP Treatment 
LVEF drop 10 points 
CONTINUE treatment
NYHA Class I (asymptomatic) or II (minimally 
symptomatic) LVEF drop from baseline 

 
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o Re-testing of LFTs every 2 weeks until improvement to Grade 1 or lower if alternative 
cause is not found 
Of note, lapatinib may not be restarted following the toxicities described above regardless of the results of 
imaging and laboratory tests, or other attributable cause. 
Dose interruptions and dose reductions may also be appropriate following other abnormal liver function 
tests.  For NCI CTCAE v.4.0 Grade 1 abnormal liver function tests, no change is necessary but may be 
undertaken at the discretion of the treating physician. See Figure 3 for management of NCI CTCAE 
Grade 2 abnormal liver function tests.  
 
6.4 Dermatologic toxicity 
 
Grade 2 EITHER 
ALT >3x ULN – 5x ULN
OR
Bilirubin >1.5x ULN – 3x ULN
Grade 2 BOTH
ALT >3x ULN – 5x ULN
AND
Bilirubin >1.5x ULN – 3x ULN
Hold lapatinib and re-test
every 2 weeks for 4 weeks
Signs and symptoms which in the opinion 
of the investigator is/are caused 
by lapatinib induced liver injury
No
Yes
Stop lapatinib
c
Improved to grade <1
by 4 weeks
Dose reduction of 250mg to 
a minimum dose of 500mg per day
Persistent Grade 2 or higher
Grade 2 liver abnormalities
Figure 3: Algorithm for management of Grade 2 abnormal liver function tests with lapatinib
Permanently

 
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For NCI-CTCAE v.4.0 Grade 4 rash manifested as toxic epidermal necrolysis (i.e. Stevens-Johnson 
Syndrome), lapatinib must be permanently discontinued. 
 
Subjects with poorly tolerated skin adverse events may undergo a brief (up to 14 day) therapy 
interruption at the discretion of the patient and investigator.  The daily dose of lapatinib should then 
be reinstated.  However, this is not mandated, as the rash may improve without the need for 
interrupting therapy, and is left up to the discretion of the treating physician. 
 
Of note in current studies, many subjects were able to resume lapatinib therapy at the same dose 
after resolution of rash, and they then had less extensive and/or less severe rashes. A variety of 
agents can be used to manage skin rashes. These include mild-to-moderate strength steroid creams, 
topical or systemic antibiotics, or topical or systemic antihistamines. 
There is no standard, known, or established treatment proven effective for drug-related skin rashes 
or changes due to lapatinib. If the rash is severe (1-3%) then most commonly, a papular/pustular 
rash has been observed, which frequently improves even though the same dose of lapatinib therapy 
is continued uninterrupted. The need for oral or topical antibiotics is a clinical decision of the 
investigator and should be preceded by a culture of affected areas and, if indicated, a dermatology 
consultation. Oral retinoids should not be given because of theoretical concerns about negatively 
affecting the lapatinib mechanism of action. Oral steroids are also strongly discouraged. Other 
options for treatment of significant rashes may be determined upon consultation with dermatologist. 
 
6.5 Gastrointestinal Toxicity 
If GI events are not appropriately managed, they may be associated with the development of 
dehydration. Management of gastrointestinal adverse events is discussed in detail below. 
 
6.5.1 
Nausea, Vomiting, or Both 
 
In subjects who have emesis and are unable to retain lapatinib, every attempt should be made to 
obtain control of nausea and vomiting. If a subject vomits after administration of lapatinib, the 
subject should be instructed not to retake the dose. Subjects should take the next scheduled dose. If 
vomiting persists, then the subject should contact the investigator. 
 
6.5.2 
Diarrhea 
 
These broad general management principles are recommended to proactively try and avoid more 
serious complications by active management of diarrhea syndrome. Guidelines such as these should 
never replace sound clinical judgment. Experience thus far suggests that when lapatinib is used as 
monotherapy, uncomplicated Grade 1 or 2 diarrhea is most prevalent. These general management 
principles do not address comprehensive management of more serious or protracted diarrhea 
syndromes. 
 

 
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Common clinical sense with the onset of uncomplicated Grade 1-2 diarrhea: stop all lactose 
containing products: drink 8-10 large glasses of clear liquids a day; eat frequent small meals;  
 
For Grade 1 or 2 diarrhea; administer standard doses of loperamide: initial dose 4 mg followed by 2 
mg every 4 hours or after every unformed stool. It is suggested to continue loperamide until the 
subject is free from diarrhea for 12 hours. 
 
For Grade 2-4 diarrhea or Grade 1 diarrhea with complicating features (severe cramping, severe 
nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, frank 
bleeding, dehydration) hold lapatinib until diarrhea resolved.  Use intravenous fluids as appropriate, 
consider hospital administration. Use prophylactic antibiotics as needed (example: 
fluoroquinolones) especially if diarrhea is persistent beyond 24 hours or there is a fever or Grade 3-
4 neutropenia. 
See figure 4 for an algorithm for managing diarrhea with lapatinib. 
 
Figure 4: Dose modifications for lapatinib GI toxicity 
 
 
Grade 4 
life-threatening  
consequences; 

 
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*Note: A patient may only resume lapatinib at a 500mg dose reduction if he/she had been on the full dose 
prior to the episode (1000mg daily).  If a patient on 750mg daily of lapatinib experiences Grade 4 
diarrhea, lapatinib must be permanently discontinued. Doses of lapatinib less than 500mg daily are not 
permitted. 
 
6.6 Pulmonary Toxicity 
 
If a patient develops symptoms suggestive of interstitial pneumonitis, adult respiratory distress 
syndrome (ARDS), or non-cardiogenic pulmonary edema, lapatinib and trastuzumab therapy should 
be interrupted and a thorough evaluation performed.  
 
If NCI-CTCAE v4.02 Grade 3 or 4 pneumonitis/fibrosis or pulmonary infiltrate is confirmed (and 
the relationship to lapatinib and/or trastuzumab cannot be excluded), lapatinib and trastuzumab 
must be permanently discontinued. All incidences of interstitial lung disease/ interstitial 
pneumonitis regardless of grade must be reported as serious adverse events (SAEs). 
 
6.7 Summary of Modifications due to Toxicity 
A summary of dose holding, delays, and dose reduction recommendations for lapatinib and 
trastuzumab is described in Table 4. 
 
Table 6:  Summary of dose holding and dose de-escalation recommendations for lapatinib in 
case of lapatinib related adverse events 
Adverse events 
Action 
Cardiotoxicity (↓ 
LVEF) 
 
NYHA Class I or II and/or asymptomatic LVEF drop: see algorithm 
(Figure 2) 
NYHA Class III or IV: Permanently discontinue both lapatinib and 
trastuzumab 
Hepatotoxicity (↑ 
LFTs) 
Grade 1 abnormal LFTs: Adjust per MD discretion 
Grade 2 abnormal LFTs: See specific algorithm (Figure 3) 
Grade 3 abnormal LFTs: Permanently discontinue lapatinib 
Diarrhea 
See specific algorithm (Figure 4) 
Other Non-heme 
Grade 1 
Continue lapatinib therapy at full dose prescribed. Apply maximum 
supportive care recommendations. 
Other Non-heme 
Grade 2 
MD discretion as to whether to continue lapatinib, interrupt therapy until 
resolution, or continue with dose reduction. Continue trastuzumab. 
Continue maximum supportive care recommendations. 

 
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Other Non-heme 
Grade >3 
Hold lapatinib and trastuzumab. If toxicity resolves to grade 1 or less 
within 4 weeks, dose reduce lapatinib by one dose level before resuming 
(max 2 dose reductions of lapatinib allowed). If toxicity does not resolve 
within 4 weeks, permanently discontinue both drugs. If more than one 
full cycle of trastuzumab is missed, reloading of trastuzumab is 
required upon resuming the drug. For grade 3 toxicities deemed 
unrelated to cancer or cancer treatment (such as hypertension, 
hyperglycemia, decrease lymphocyte count, non-cancer related pain, 
fractures, or orthopedic surgery) treatment may be continued at the 
current dose at the discretion of the treating physician unless meeting 
other stopping criteria (see specifically section 6.2, 6.3, 6.5.2). 
Hematologic toxicity 
No required dose modification.  Treatment discontinuation or dose 
adjustment at the discretion of treating MD. 
 
7.0 Data and Safety Monitoring  
    7.1 
Definition of Risk Level  
This is a Risk Level 3 study, as defined in the “City of Hope Data 
and Safety Monitoring Plan”, 
http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx because 
it is a Phase II clinical trial where the risks are at least balanced by 
the potential benefit to subjects and the importance of the knowledge 
that may result. 
7.2 
Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, CRA, protocol nurse, and statistician is responsible for 
monitoring the data and safety of this study, including implementation of 
any stopping rules for safety and efficacy. 
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
Risk Level 
Phase 
Standard Reporting Requirement 
RL 1, RL2, and  
Expanded Access Studies 
No reports required 
3 
I 
Every 3 months from activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from activation date, as 
indicated in MIDAS 

 
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4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from activation date, as 
indicated in MIDAS 
 
 
 
 
 
Data and safety will be reported to the COH DSMC using the PMT report and submitted according to the 
timelines in Table 1 above.  Protocol specific data collection will include the following items:  After 30 
patients have completed one full cycle of therapy, the study team will review the data and assess the 
toxicity profile and rates of dose reduction, delays, interruptions and hospitalization related to the 
combination of agents.  Within this interim analysis a specific review will be made of the data for the 
patients over 75 years of age.  Additional guidelines and will be used to flag an unexpected number of 
patients that experience symptomatic cardiac toxicity (NYHA Class III or IV if cardiac failure, or Grade 3 
or higher by NCI NCTAE v4.0 for other cardiac events)safety of lapatinib given in combination with 
trastuzumab in older adults (using CRFs based on CTCAE v.4.02), efficacy of lapatinib plus trastuzumab 
in older adults (based on imaging using RECIST 1.1 criteria), geriatric assessment of older adults, 
adherence of the population to the oral medication, cardiac safety in the study population (using cardiac 
imaging).  Reporting of data and safety to the DSMC will occur at the time of enrollment of 20 subjects, 
or after an unexpected number of severe adverse cardiac events (see section 13) using the PMT report. 
7.3 Definitions 
Adverse event (AE) - An adverse event is any untoward medical experience or change 
of an existing condition that occurs during or after treatment, whether or not it is 
considered to be related to the protocol intervention.  
 
 Unexpected Adverse Event [21 CFR 312.32 (a)] - An adverse event is unexpected if 
it is not listed in the investigator’s brochure and/or package insert; is not listed at the 
specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any 
underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected 
event OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
 
 
7.1.1.1 Serious Adverse Event (SAE) [21 CFR 312.32] - defined as any expected or unexpected 
adverse event that results in any of the following outcomes: 
 Death 

 
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 Is life-threatening experience (places the subject at immediate risk of death from 
the event as it occurred) 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasias of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
 
 
Unanticipated problem (UP) – Any incident, experience, or outcome that meets all 
three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may have 
been caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
 
7.4 Reporting of Unanticipated Problems and Adverse Events 
Unanticipated Problems - Most unanticipated problems must be reported to the COH 
DSMC and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/policy/Policies%20and%20Procedures/REVIEWING_AND_REP
ORTING_UNANTICIPATED_PROBLEMS.pdf.  Any unanticipated problem that 
occurs during the study conduct will be reported to the DSMC and IRB by submitting 
electronically in iRIS (http://iris.coh.org). 
 
7.1.1.2 Serious Adverse Events - All SAEs occurring during this study, whether observed 
by the physician, nurse, or reported by the patient, will be reported according to 
definitions and guidelines at 
http://www.coh.org/policy/Policies%20and%20Procedures/REVIEWING_AND_
REPORTING_UNANTICIPATED_PROBLEMS.pdf and Table 2 below.  Those 
SAEs that require expedited reporting will be submitted electronically in iRIS 
(http://iris.coh.org). 

 
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Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that 
do not meet the criteria of serious OR are not unanticipated problems will be reported 
only in the protocol continuation reports and PMT report (see Table 2 below). 
 
 
 
 
 
 
 
 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
 
 
DSMC Risk Level 3 and Risk Level 4 Protocol Reporting Timelines 
 
Required Reporting Timeframe to the DSMC 
Attribution 
Unexpected 
Expected 
Death while on active treatment or within 30 days of last day of treatment 
Possibly, Probably, Definitely 
5 calendar days 
Unlikely, Unrelated 
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
Within 30 days of last active treatment/therapy 
  
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
 
Grades 1 and 2 AND resulting in “hospitalization” 

 
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Required Reporting Timeframe to the DSMC 
Attribution 
Unexpected 
Expected 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
After 30 days of last active treatment/therapy 
 
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 

 
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 DSMC Risk Level 1 and Risk Level 2 Protocol Reporting Timelines 
 
Required Reporting Timeframe to DSMC 
Attribution 
Unexpected 
Expected 
  
Death while on active treatment or within 30 days of last day 
of treatment 
Possibly, Probably, Definitely 
5 calendar days 
5 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
 
COH IRB Adverse Event Reporting Timelines  
 

 
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Required Reporting Timeframe to COH IRB  
Attribution 
Unexpected 
Expected 
 
Death while on active treatment/therapy or within 30 days 
of the last day of active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days1 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 
Possibly, Probably, Definitely 
5 calendar days1 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 
Possibly, Probably, Definitely 
5 calendar days1 
Annual2 
Unlikely, Unrelated 
Annual2 
Annual2 
1 These events must be reported in the time frame if they meet the definition of an unanticipated problem. 
2 For studies that are not first in human, Phase I and first in pediatric trials, only grades 3-5 must be reported at annual review.  
 
PLEASE NOTE: If additional reporting guidelines are required due to a sponsor’s 
requirement or for any other reasons, please add those reporting requirements here, below 
the City of Hope reporting requirements. 
 
Additional SAE Reporting Requirements:  
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 

 
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 is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, 
and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E) (For patients 
taking Lapatinib / Novartis drugs). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).  
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 after the patient has provided informed consent and until atleast 30 days after the patient has 
stopped study treatment/participation 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind 
treatment, etc.) and 30 days after the patient has stopped study treatment 
 after the start of any period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g., treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication) and until 30 days after the patient has 
stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence  Information about all 
SAEs is collected and recorded on a Serious Adverse Event Report Form; all applicable sections 
of the form must be completed in order to provide a clinically thorough report. The investigator 
must assess and record the relationship of each SAE to each specific study treatment (if there is 
more than one study treatment), complete the SAE Report Form in English, and send the 
completed, signed form by fax to (fax: 877-778-9739) within 24 hours to the oncology 
Novartis DS&E department with the provided FAX cover sheets. 
This includes serious, related, labeled (expected) and serious, related, unlabeled (unexpected) 
adverse experiences. All deaths during treatment or within 30 days following completion of 
active protocol therapy must be reported within 5 working days. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, 
or progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. A SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one should 
be reported separately as a new event.  The end date of the first event must be provided. 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the 
Trial Master File at the study site. 
Follow-up information is sent to the same fax number as the original SAE Report Form was sent, 
using a new fax cover sheet, stating that this is a follow-up to the previously reported SAE, and 
giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information should describe whether the event has resolved or continues, if and how it 

 
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was treated, whether the blind was broken or not (if applicable), and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Lapatinib Investigator Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study drug, a DS&E 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. 
 
 
7.5 
Reporting Adverse Events (Occurring at Participating Institutions) 
The guideline is to provide a procedure for accurate and timely reporting of 
serious adverse events (SAEs) from the participating institution to the Principal 
Investigator (PI) at City of Hope (COH).  The participating institution, 
participating PI and/or study coordinators are responsible for reporting all serious 
adverse events immediately (within 24 hours after learning of the event) to their 
local IRB, the PI at City of Hope, the Data Coordinating Center at COH as well 
as follow the protocol specific SAE reporting requirements (per Section 7.2.9, 
7.2.10 and 7.2.11 below).   The participating investigator must report each 
serious adverse event, regardless of attribution, to the Principal Investigator 
within 24 hours of learning of the occurrence. In the event that the participating 
investigator does not become aware of the serious adverse event immediately 
(e.g., participant sought treatment elsewhere), the participating investigator is to 
report the event within 24 hours after learning of it and document the time of his 
or her first awareness of the adverse event..    
Report serious adverse events by telephone and facsimile to: 
 
 
 
       Dr. Arti Hurria 
Phone: 626-471-9200  
Fax: 626-301-8233  
 
The participating institution will notify the Data Coordinating Center of 
any serious adverse event (defined in Section 7.2.13) via a telephone call 
to (626) 256-4673 ext. 63968.   
 
The participating institution will notify their local IRB as per their local 
established guidelines.   
 
As this study will not involve an IND, reporting to FDA is voluntary.  
Guidelines can be found at http://www.fda.gov/cder/aers/fr07oc97.htm 
and http:///www.fda.gov/medwatch/index/html.  All relevant events may 
be voluntarily reported to the FDA using the MedWatch system.   
 
In addition to being reported to the participating institutions’ local IRB 
and to the FDA (voluntary reporting), the Data Coordinating Center will 

 
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need to send a copy of the participating institutions serious adverse event 
report to GSK Oncology MDC.   
 
A copy of the participating institutions serious adverse event report 
submitted to their local IRB, as well as a copy of the MedWatch form (if 
applicable) must be sent to the Data Coordinating Center in the 
Department of Clinical Research Information Support at City of Hope by 
fax to (626) 301-8422 within 24 hours.  The Notification of Toxicity 
Form (see Appendix F) should also be sent to the Data Coordinating 
Center within 24 hours.  Any supporting documentation to the reports 
(i.e., laboratory, pathology, progress notes, discharge summary, autopsy, 
etc.) explaining the adverse event should also be submitted to the Data 
Coordinating Center at City of Hope.  The Data Coordinating Center will 
then submit to our COH IRB as well as submit to the Novartis Drug 
Safety and Epidemiology Safety Desk in a timely manner. 
 
7.5.1 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.02. In addition, NYHA 
Class III and IV heart failure will be captured. Any suspected or confirmed dose-limiting 
toxicity should be reported immediately (within 24 hours) to the Principal Investigator. 
 
Definitions 
 
Adverse Event:  Any untoward medical experience or change of an existing 
condition that occurs during or after treatment, whether or not it is considered to 
be related to the protocol intervention. 
 
Serious Adverse Event:  Any expected or unexpected adverse event that is related 
or unrelated to either the intervention or the study agents(s) that results in any of 
the following outcomes: 
o Death 
o A life-threatening event 
o Inpatient hospitalization (not required as part of the treatment) or 
prolongation of existing hospitalization 
o A persistent or significant disability/incapacity 
o A congenital anomaly/birth defect 
o Causes cancer 
o Is an overdose 
Certain medical events that may not result in death, be life-threatening, or require 
hospitalization, may also be considered a serious adverse event when appropriate medical or 
surgical intervention is necessary to prevent one of the outcomes listed above. 
 
Unexpected Adverse Event:  Any event in which the severity or specificity is not 
consistent with the risk information described in the protocol, and the event is not 
anticipated from the subject's disease history or status. 

 
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 
Expected Adverse Event:  Any event in which the severity or specificity is 
consistent with the risk information described in the protocol, or is consistent 
with the subject's medical history. 
 
Follow-up to Adverse Event:  Any new information obtained following the initial 
report of the event (e.g. lab result(s) for pending test(s)). 
 
Attribution:  For reporting purposes, attribution is the assessment of the 
likelihood that an AE is caused by the research agent or protocol intervention.  
The attribution is assigned by the Principal Investigator (PI) after considering the 
clinical information, the medical history of the subject, and past experience with 
the research agent/intervention.  This is recorded electronically in iRIS 
(http://iris.coh.org/) in one of five categories scored as the following: 5=related, 
4=probably related, 3=possibly related, 2=unlikely related, and 1=unrelated.  The 
attribution is subject to change as follow-up information becomes available, and 
can be changed by the DSMB or by the IRB during the process of review. 
 
8.0 Agent Information 
8.1 Drug Information for Lapatinib (Tykerb®) 
 
Other Names: NSC # 727989, Tyverb® 
Mode of Action: Dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 
tyrosine kinases. 
Availability: Lapatinib is commercially available 
 
8.1.1 
Risks and Contraindications 
 
Table 7:  Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for lapatinib 
alone 
 
Metabolism and nutrition disorders 
 
Common (>10%) 
Anorexia 
Cardiac disorders 
 
Less common (>1%) 
Decreased left ventricular 
ejection fraction 
Gastrointestinal disorders 
 
Common (>10%) 
Diarrhea, which may lead to 
dehydration 
 

 
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Nausea 
 
Vomiting 
Skin and Subcutaneous Tissue Disorders 
 
Common (>10%) 
Rash 
General disorders 
 
Common (>10%) 
Fatigue 
 
Serious Adverse Events:  
Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) 
inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases 
were defined as signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3or 
a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the 
institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine combination 
treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3.0).  
Hepatotoxicity: Lapatinib has been associated with hepatotoxicity though very rarely 
Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and 
pneumonitis in monotherapy or in combination with other chemotherapies, but also very rarely. 
 
8.1.2 
Supplier 
Study drug is being provided by the drug manufacturer, GlaxoSmithKline. 
8.1.3 
Concomitant Medications/Precautions 
See section 5.5 and Appendix A 
8.1.4 
Dose and Administration 
Dose: 1000mg (4 tablets) 
Route of Administration: Orally on an empty stomach (either 1 hour before or 1 hour after meals). 
8.1.5 
Storage 
Storage: The intact bottles should be stored at controlled room temperature (15°C-30°C). 

 
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8.1.6 
Structure and Molecular Weight 
The structural formula is: 
 
Molecular formula: C29H26CIFN4O4S(C7H8O3S)2H2O 
Molecular weight: 581.05 g/mol  
Chemical Name: N-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl)-6-[5-(([2-
(methylsulfonyl)ethyl]amino}methyl)-2 furyl]-4-quinazolinamine 
8.1.7 
Formulation/Agent Preparation 
How Supplied: lapatinib is supplied as 250 mg oval, biconvex, orange film-coated tablets with one 
side plain and the opposite side debossed with FG HLS.  The tablets contain 410 mg of lapatinib 
Ditosylate Monohydrate, equivalent to 250 mg lapatinib free base per tablet.  The tablets are packaged 
into HDPE bottles with child-resistant closures. 
Excipients present in the tablet include: Microcrystalline cellulose, povidone, sodium starch 
glycolate, and magnesium stearate. 
The film-coat contains: Hydroxypropyl methylcellulose, titanium dioxide, triacetin/glycerol 
triacetate, and yellow iron oxide. 
Kool-Aid Flavored Suspension 
Prepare Lemonade or Tropical Punch Kool-Aid as directed on the package.  Place 2 or 4 oz of 
Kool-Aid (room temperature or refrigerated) in a glass container, then add four 250 mg lapatinib 
tablets to the container.  Cover the container, let it stand for 5 minutes, and then stir the mixture 
intermittently for 10-20 minutes or until the tablets are completely broken up.  Stir the container for 
5 seconds then administer.  Rinse the container with a 2 oz aliquot of water and administer (total of 
4-6 oz of liquid is dispensed). 
Suspension in Water 
Place 4 oz of water in a glass container, then add four 250 mg lapatinib tablets to the container.  
Cover the container, let it stand for 5 minutes, and then stir the mixture intermittently for 10-20 
minutes or until it is fully dispersed.  Stir the container for 5 seconds then administer.  Rinse the 
container with a 2 oz aliquot of water and administer (total of 6 oz of liquid is dispensed). 
8.1.8 
Stability 
Stability: Shelf life surveillance studies of the intact bottle are on-going.  Current data indicates 
lapatinib is stable for at least 2 years at controlled room temperature (15°C - 30°C). 

 
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8.1.9 
Agent Accountability 
The Investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of all agents received from Novartis. 
8.1.10 Agent Ordering 
Lapatinib will be ordered directly from the manufacturer, Novartis. 
8.2 Drug Information for Trastuzumab (Herceptin©) 
The below information is largely duplicated from the Herceptin package insert.94  Relevant points are 
summarized as follows. 
Other names: none 
Mode of Action: recombinant DNA-derived humanized monoclonal antibody that selectively binds with 
high affinity in a cell-based assay to the extracellular domain of the human epidermal growth factor 
receptor 2 protein, HER2.  
Availability: Trastuzumab is commercially available 
 
8.2.1 
Risks and Contraindications 
Cardiotoxicity:  
Signs and symptoms of cardiac dysfunction, such as dyspnea, increased cough, paroxysmal nocturnal 
dyspnea, peripheral edema, S3 gallop, or reduced ejection fraction, have been observed in patients treated 
with trastuzumab. Congestive heart failure associated with trastuzumab therapy may be severe and has 
been associated with disabling cardiac failure, death, and mural thrombosis leading to stroke. The clinical 
status of patients in the trials who developed congestive heart failure was classified for severity using the 
New York Heart Association classification system (I-IV, where IV is the most severe level of cardiac 
failure). (See Table 8)  
Table 8: Incidence and Severity of Cardiac Dysfunction  
  
Trastuzumab  
alone38 
n = 213 
Trastuzumab
+ 
Paclitaxel28
n = 91 
Paclitaxel28
n = 95 
Trastuzumab + 
Anthracycline+ 
cyclophosphamide28
n = 143 
Anthracycline+ 
cyclophosphamide28
n = 135 
Any 
Cardiac 
Dysfunction 
7% 
11% 
1% 
28% 
7% 
Class III-IV 
5% 
4% 
1% 
19% 
3% 
38 (see reference): Open-label, single-agent Phase II study (94% received prior anthracyclines). 
28 (see reference): Randomized Phase III study comparing chemotherapy plus trastuzumab to chemotherapy 
alone, where chemotherapy is either anthracycline/cyclophosphamide or paclitaxel.  
Candidates for treatment with trastuzumab should undergo thorough baseline cardiac assessment 
including history and physical exam and one or more of the following: echocardiogram, and MUGA scan. 
There are no data regarding the most appropriate method of evaluation for the identification of patients at 

 
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risk for developing cardiotoxicity. Monitoring may not identify all patients who will develop cardiac 
dysfunction.  
Extreme caution should be exercised in treating patients with pre-existing cardiac dysfunction.  
Patients receiving trastuzumab should undergo frequent monitoring for deteriorating cardiac function.  
The probability of cardiac dysfunction was highest in patients who received trastuzumab concurrently 
with anthracyclines. The data suggest that advanced age may increase the probability of cardiac 
dysfunction.  
Pre-existing cardiac disease or prior cardiotoxic therapy (e.g., anthracycline or radiation therapy to the 
chest) may decrease the ability to tolerate trastuzumab therapy; however, the data are not adequate to 
evaluate the correlation between trastuzumab-induced cardiotoxicity and these factors.  
Discontinuation of trastuzumab therapy should be strongly considered in patients who develop clinically 
significant congestive heart failure. In the clinical trials, most patients with cardiac dysfunction responded 
to appropriate medical therapy often including discontinuation of trastuzumab. The safety of continuation 
or resumption of trastuzumab in patients who have previously experienced cardiac toxicity has not been 
studied. There are insufficient data regarding discontinuation of trastuzumab therapy in patients with 
asymptomatic decreases in ejection fraction; such patients should be closely monitored for evidence of 
clinical deterioration.  
Precautions  
General: Trastuzumab therapy should be used with caution in patients with known hypersensitivity to 
trastuzumab, Chinese Hamster Ovary cell proteins, or any component of this product.  
Drug Interactions: There have been no formal drug interaction studies performed with trastuzumab in 
humans. Administration of paclitaxel in combination with trastuzumab resulted in a two-fold decrease in 
trastuzumab clearance in a non-human primate study and in a 1.5-fold increase in trastuzumab serum 
levels in clinical studies.  
Benzyl Alcohol: For patients with a known hypersensitivity to benzyl alcohol (the preservative in 
Bacteriostatic Water for Injection) reconstitute trastuzumab with Sterile Water for Injection (SWFI), USP. 
DISCARD THE SWFI-RECONSTITUTED TRASTUZUMAB VIAL FOLLOWING A SINGLE USE.  
Immunogenicity: Of 903 patients who have been evaluated, human anti-human antibody (HAHA) to 
trastuzumab was detected in one patient, who had no allergic manifestations.  
Carcinogenesis, Mutagenesis, Impairment of Fertility:  
Carcinogenesis: Trastuzumab has not been tested for its carcinogenic potential.  
Mutagenesis: No evidence of mutagenic activity was observed in Ames tests using six different test 
strains of bacteria, with and without metabolic activation, at concentrations of up to 5000 µg/mL 
trastuzumab. Human peripheral blood lymphocytes treated in vitro at concentrations of up to 5000 
µg/plate trastuzumab, with and without metabolic activation, revealed no evidence of mutagenic potential. 

 
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In an in vivo mutagenic assay (the micronucleus assay), no evidence of chromosomal damage to mouse 
bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg trastuzumab.  
Geriatric Use: Trastuzumab has specifically evaluated in 133 patients who were 65 years of age or over. 
The risk of cardiac dysfunction may be increased in geriatric patients. The reported clinical experience is 
not adequate to determine whether older patients respond differently from younger patients. 
Adverse Reactions 
Cardiac Failure/Dysfunction: For a description of cardiac toxicities, see above.  
Anemia and Leukopenia: An increased incidence of anemia and leukopenia was observed in treatment 
groups receiving trastuzumab and chemotherapy, especially in those receiving trastuzumab with AC The 
majority of these cytopenic events were mild or moderate in intensity and reversible 
Hematologic toxicity is infrequent following the administration of trastuzumab as a single agent, with an 
incidence of Grade III toxicities for WBC, platelets, hemoglobin all <1%.  
Diarrhea: Of patients treated with trastuzumab as a single agent in various studies, 25% experienced 
diarrhea. An increased incidence of diarrhea, primarily mild to moderate in severity, was observed in 
patients receiving trastuzumab in combination with chemotherapy.  
Infection: An increased incidence of infections, primarily mild upper respiratory infections of minor 
clinical significance or catheter infections, has been observed in patients receiving trastuzumab in 
combination with chemotherapy.  
Infusion Reactions: During the first infusion with trastuzumab, a symptom complex most commonly 
consisting of chills and/or fever was observed in about 40% of patients in clinical trials. The symptoms 
were usually mild to moderate in severity and were treated with acetaminophen, diphenhydramine, and 
meperidine (with or without reduction in the rate of trastuzumab infusion). Trastuzumab discontinuation 
is rarely necessary. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at 
tumor sites), rigors, headache, dizziness, dyspnea, hypotension, rash and asthenia. The symptoms occur 
infrequently with subsequent trastuzumab infusions.  
Table 9: Adverse Events Occurring in > 5% of Patients or at 
Increased Incidence in the Trastuzumab Arms of Various Randomized Studies 
(Percent of Patients)94  
  
Single
Agent
n = 352
Trastuzumab
+ Paclitaxel
n = 91 
Paclitaxel
Alone 
n = 95 
Trastuzumab 
+ AC 
n = 143 
AC 
Alone
n = 135
Body as a Whole 
Pain 
47 
61 
62 
57 
42 
Asthenia 
42 
62 
57 
54 
55 
Fever 
36 
49 
23 
56 
34 

 
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Chills 
32 
41 
4 
35 
11 
Headache 
26 
36 
28 
44 
31 
Abdominal pain 
22 
34 
22 
23 
18 
Back pain 
22 
34 
30 
27 
15 
Infection 
20 
47 
27 
47 
31 
Flu syndrome 
10 
12 
5 
12 
6 
Accidental injury 
6 
13 
3 
9 
4 
Allergic Reaction 
3 
8 
2 
4 
2 
Cardiovascular 
Tachycardia 
5 
12 
4 
10 
5 
Congestive heart failure 
7 
11 
1 
28 
7 
Digestive 
Nausea 
33 
51 
9 
76 
77 
Diarrhea 
25 
45 
29 
45 
26 
Vomiting 
23 
37 
28 
53 
49 
Nausea and vomiting 
8 
14 
11 
18 
9 
Anorexia 
14 
24 
16 
31 
26 
Heme & Lymphatic 
Anemia 
4 
14 
9 
36 
26 
Leukopenia 
3 
24 
17 
52 
34 
Metabolic 
Peripheral edema 
10 
22 
20 
20 
17 
Edema 
8 
10 
8 
11 
5 
Musculoskeletal 
Bone pain 
7 
24 
18 
7 
7 
Arthralgia 
6 
37 
21 
8 
9 
Nervous 
Insomnia 
14 
25 
13 
29 
15 
Dizziness 
13 
22 
24 
24 
18 
Paresthesia 
9 
48 
39 
17 
11 
Depression 
6 
12 
13 
20 
12 
Peripheral neuritis 
2 
23 
16 
2 
2 

 
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Neuropathy 
1 
13 
5 
4 
4 
Respiratory 
Cough increased 
26 
41 
22 
43 
29 
Dyspnea 
22 
27 
26 
42 
25 
Rhinitis 
14 
22 
5 
22 
16 
Pharyngitis 
12 
22 
14 
30 
18 
Sinusitis 
9 
21 
7 
13 
6 
Skin 
Rash 
18 
38 
18 
27 
17 
Herpes simplex 
2 
12 
3 
7 
9 
Acne 
2 
11 
3 
3 
<1 
Urogenital 
Urinary tract infection 
5 
18 
14 
13 
7 
   
Other serious adverse events  
The following other serious adverse events occurred in at least one patient on trastuzumab being treated in 
clinical trials: 
Body as a Whole: cellulitis, anaphylactoid reaction, ascites, hydrocephalus, radiation injury, deafness, 
amblyopia  
Cardiovascular: vascular thrombosis, pericardial effusion, heart arrest, hypotension, syncope, 
hemorrhage, shock, arrhythmia  
Digestive: hepatic failure, gastroenteritis, hematemesis, ileus, intestinal obstruction, colitis, esophageal 
ulcer, stomatitis, pancreatitis, hepatitis  
Endocrine: hypothyroidism  
Hematological: pancytopenia, acute leukemia, coagulation disorder, lymphangitis  
Metabolic: hypercalcemia, hypomagnesemia, hyponatremia, hypoglycemia, growth retardation, weight 
loss  
Musculoskeletal: pathological fractures, bone necrosis, myopathy  
Nervous: convulsion, ataxia, confusion, manic reaction  

 
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Respiratory: apnea, pneumothorax, asthma, hypoxia, laryngitis  
Skin: herpes zoster, skin ulceration  
Urogenital: hydronephrosis, kidney failure, cervical cancer, hematuria, hemorrhagic cystitis, 
pyelonephritis  
8.2.2 
Supplier 
Trastuzumab will be ordered from the individual study site’s pharmacy. 
8.2.3 
Concomitant Medications/Precautions 
See section 5.5.2 
8.2.4 
Dose and Administration 
Usual Dose  
The recommended initial loading dose is either 4 mg/kg trastuzumab administered as a 90-minute 
infusion (if planning weekly dosing) or 8 mg/kg trastuzumab administered as a 90-minute infusion (if 
planning every three week dosing). The recommended weekly maintenance dose is 2 mg/kg trastuzumab 
and can be administered as a 30-minute infusion if the initial loading dose was well tolerated. The 
recommended every three week maintenance dose is 6mg/kg trastuzumab and can be administered as a 30 
minute infusion if the loading dose was well tolerated. Trastuzumab may be administered in an outpatient 
setting. Trastuzumab is to be diluted in saline for IV infusion. DO NOT ADMINISTER AS AN IV 
PUSH OR BOLUS (see Administration).  There is no change in dosage for obese patients. 
Administration  
Treatment may be administered in an outpatient setting by administration of either a 4 mg/kg trastuzumab 
loading dose by intravenous (IV) infusion over 90 minutes or 8mg/kg trastuzumab loading dose by 
intravenous infusion. DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. Patients should be 
observed for fever and chills or other infusion-associated symptoms (see ADVERSE REACTIONS). If 
prior infusions are well tolerated, subsequent weekly doses of 2 mg/kg trastuzumab may be administered 
over 30 minutes, or subsequent doses of 6mg/kg trastuzumab may be administered every three weeks.  
Trastuzumab should not be mixed or diluted with other drugs. Trastuzumab infusions should not 
be administered or mixed with Dextrose solutions.  
8.2.5 
Storage 
Vials of trastuzumab are stable at 2-8°C (36-46°F) prior to reconstitution. Do not use beyond the 
expiration date stamped on the vial. Discard any remaining multi-dose reconstituted solution after 28 
days. If unpreserved SWFI (not supplied) is used, the reconstituted trastuzumab solution should be used 
immediately and any unused portion must be discarded. DO NOT FREEZE TRASTUZUMAB THAT 
HAS BEEN RECONSTITUTED.  
The solution of trastuzumab for infusion diluted in polyvinylchloride or polyethylene bags containing 
0.9% Sodium Chloride Injection, USP, may be stored at 2-8°C (36-46°F) for up to 24 hours prior to use. 
Diluted trastuzumab has been shown to be stable for up to 24 hours at room temperature (2-25°C). 

 
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However, since diluted trastuzumab contains no effective preservative, the reconstituted and diluted 
solution should be stored refrigerated (2-8°C). 
8.2.6 
Structure and Molecular Weight 
Formula: 
C6470H10012N1726O2013S42 
Molecular Mass: 14531.5 g/mol 
Herceptin (Trastuzumab) is a recombinant DNA-derived humanized monoclonal antibody that selectively 
binds with high affinity in a cell-based assay (Kd = 5 nM) to the extracellular domain of the human 
epidermal growth factor receptor 2 protein, HER2. The antibody is an IgG1 kappa that contains human 
framework regions with the complementarity-determining regions of a murine antibody (4D5) that binds 
to HER2.  
The humanized antibody against HER2 is produced by a mammalian cell (Chinese Hamster Ovary) 
suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not 
detectable in the final product.  
8.2.7 
Formulation/Agent Preparation 
Herceptin is a sterile, white to pale yellow, preservative-free lyophilized powder for intravenous (IV) 
administration. The nominal content of each Herceptin vial is 440 mg trastuzumab, 9.9 mg L-histidine 
HCl, 6.4 mg L-histidine, 400 mg trehalose dihydrate, and 1.8 mg polysorbate 20, USP. Reconstitution 
with only 20 mL of the supplied Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% 
benzyl alcohol as a preservative, yields a multi-dose solution containing 21 mg/mL trastuzumab, at a pH 
of approximately 6.  
Preparation  
The diluent provided has been formulated to maintain the stability and sterility of HERCEPTIN for up to 
28 days. Other diluents have not been shown to contain effective preservatives for HERCEPTIN. Each 
vial of Herceptin should be reconstituted with ONLY 20 mL of BWFI, USP, 1.1% benzyl alcohol 
preserved, as supplied, to yield a multi-dose solution containing 21 mg/mL trastuzumab. Use of all 30 
mL of diluent results in a lower-than-intended dose of HERCEPTIN. THE REMAINDER (approximately 
10 mL) OF THE DILUENT SHOULD BE DISCARDED. Immediately upon reconstitution with BWFI, 
the vial of Herceptin must be labeled in the area marked "Do not use after:" with the future date that is 28 
days from the date of reconstitution.  
If the patient has known hypersensitivity to benzyl alcohol, Herceptin must be reconstituted with Sterile 
Water for Injection (see PRECAUTIONS). HERCEPTIN WHICH HAS BEEN RECONSTITUTED 
WITH SWFI MUST BE USED IMMEDIATELY AND ANY UNUSED PORTION DISCARDED. USE 
OF OTHER RECONSTITUTION DILUENTS SHOULD BE AVOIDED.  
Shaking the reconstituted Herceptin or causing excessive foaming during the addition of diluent may 
result in problems with dissolution and the amount of Herceptin that can be withdrawn from the vial.  
Use appropriate aseptic technique when performing the following reconstitution steps:  

 
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a. Using a sterile syringe, slowly inject 20 mL of the diluent into the vial containing the lyophilized cake 
of trastuzumab. The stream of diluent should be directed into the lyophilized cake.  
b. Swirl the vial gently to aid reconstitution. Trastuzumab may be sensitive to shear-induced stress, e.g., 
agitation or rapid expulsion from a syringe. DO NOT SHAKE.  
c. Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed 
for approximately 5 minutes. The solution should be essentially free of visible particulates, clear to 
slightly opalescent, and colorless to pale yellow.  
Determine the number in mg of trastuzumab needed, based on a loading dose of 4 mg trastuzumab/kg 
body weight or a maintenance dose of 2 mg trastuzumab/kg body weight. Calculate the volume of 21 
mg/mL trastuzumab solution and withdraw this amount from the vial and add it to an infusion bag 
containing 250 mL of 0.9% Sodium Chloride Injection, USP. DEXTROSE (5%) SOLUTION 
SHOULD NOT BE USED. Gently invert the bag to mix the solution. The reconstituted preparation 
results in a colorless to pale yellow transparent solution. Parenteral drug products should be inspected 
visually for particulates and discoloration prior to administration.  
No incompatibilities between Herceptin and polyvinylchloride or polyethylene bags have been observed.  
8.2.8 
Stability 
A vial of Herceptin reconstituted with BWFI, as supplied, is stable for 28 days after reconstitution when 
stored refrigerated at 2-8°C (36-46°F), and the solution is preserved for multiple use. 
 
9.0 Correlative/Special Studies 
One blood sample for lapatinib trough pharmacokinetics will be drawn on the day of trastuzumab 
administration immediately prior to taking the lapatinib dose for that day.  This sample will be drawn 
weeks 3, 4, and 5 only, provided that the patient has taken lapatinib at the same dose level for each of the 
seven days prior to this study.  In the event that the  lapatinib dose is held or the dose level is changed, 
pharmacokinetic sample will be rescheduled accordingly. 
At each of the required timepoints (Days 15/22/29), 2 mL venous blood will be collected into a tube 
containing EDTA (to be provided by GSK).  Samples will be inverted several times and kept on ice until 
processing can begin. Plasma will be separated from whole blood by centrifugation at 1,500 x g for 10 
minutes at 4° C and transferred to appropriately-labeled polypropylene tubes (to be provided by GSK) 
and frozen at < -20°C until shipping. Specimens will be batched at each participating site and stored in 
freezers at each site.  If sites do not have sufficient storage space to keep these samples, sites not at City 
of Hope can ship frozen plasmasamples to City of Hope/Beckman Research Institute, Shapiro Building 
Room 1043, 1500 E. Duarte Rd, Duarte Ca. 91010. At City of Hope, the specimens will be stored in this 
same freezer accessible only to members of the City of Hope pharmacokinetic staff working under the 
auspices of Tim Synold, PharmD. 
Each tube will be labeled with the study number, patient registration number, time point, and the date and 
time the sample was drawn.  

 
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 Frozen plasmasamples at each site will be packed in the shipping container (provided by GSK) in 
sufficient dry ice to last at least 3 days (typically 6-8 kg), this shipment will occur yearly. The container 
will be sealed and shipped along with the packing worksheet via courier to: 
PharmaNet Canada, Inc 
Sample Controller 
2500 rue Einstein 
Quebec (Quebec), Canada G1P 0A2 
Phone: 1-418-527-40000 
Fax:  1-418-688-5242 
E-mail : vcholette@anapharm.com 
 
Analytical Methods 
Lapatinib concentrations will be determined in all samples by GSK using a validated LC/MS/MS assay.  
Assay methodologies are based on previously reported methods, and the limits of detection for lapatinib 
is 1 ng/ml. 
Pharmacokinetic Data Analysis 
Lapatinib trough levels will be calculated by GSK using standard noncompartmental methods and 
WinNonlin software. 
 

 
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10.0 Study Calendar 
 
Pre-Study 
(up to 14 days 
prior to 
enrolling)j 
Cycl 1 
Day 1 
(21 day 
cycle) 
Cycl 1 
Day 
8 
Cycl 1 
Day 
15 
Cycl 2 
Day 1
Cycl 2 
Day 8
Cycl 3 
Day 1
Cycl 4 
Day 1 
Cycl 5 
Day 1 
Every 
cycle 
There- 
after 
Every 
4 
cycles
 
Off 
Studyi
Lapatinib (day 1-7 of each 
wk)a 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Trastuzumab (±1 day if qwk, 
±3 days if q3wk)a,b  
 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Physical exam (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
Vital signs (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight (± 1 wk) 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
Performance Status (± 1 wk) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
CBC w/diff, plts (± 1 wk) 
X 
Xc 
 
 
X 
 
X 
X 
X 
X 
 
X 
Complete Metabolic Paneld (± 
1 wk) 
X 
Xc 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Nurse brief toxicity evaluation 
 
 
X 
X 
 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic samples (± 1 
days)k 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Adherence evaluation (pill 
count, diaries) (± 1 wk) 
 
 
 
 
X 
 
X 
X 
X 
 
X 
 
Adverse event evaluation (± 1 
wk) 
 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
Tumor measurements using 
CT or PET-CT (± 1 wk) 
Xe 
 
 
 
 
 
 
 
X 
 
Xf 
Xg 
LVEF Assessment 
Xe 
 
 
 
 
 
 
 
X 
 
Xf 
Xg 
Geriatric Assessment Survey 
(±1 wk) 
X 
 
 
 
 
 
 
 
X 
 
X 
Xh 
a:    Dose as assigned; lapatinib 1000mg orally daily; trastuzumab 4mg/kg IV cycle one day 1, 2mg/kg IV every week thereafter; OR 
trastuzumab 8mg/kg cycle 1, day 1, 6mg/kg each cycle (3 wks) thereafter. Doses held due to toxicity will not be made up. 
b:    X in schema for trastuzumab applies to q3 week schedule. 
c: If baseline laboratory tests are done within 14 days of start of treatment, these labs do not need to be repeated prior to day 1. 
d:    Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, 
SGOT[AST], SGPT[ALT], sodium. 
e: Baseline radiologic imaging may be done up to 30 days prior to start of treatment 
f:    Tumor measurements and LVEF assessment are repeated every 4 cycles ± 1 wk until patient comes off study.  Documentation 
(radiologic or clinical) must be provided for patients removed from study for progressive disease. 
g: Off-study radiologic evaluation will only be done if clinically indicated 
h:    Geriatric assessment should be repeated off study ONLY if it had not been administered within the previous month 
i:    Patients will be followed for 30 days following discontinuation of therapy in order to capture toxicity attributable to therapy 

 
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j.    Chart review data must be within 14 days to determine if patient meets study criteria.  Once patient is deemed to meet study criteria, then
      all criteria must be within window specified in protocol from Day1 as indicated in column one in the schema above. 
k:   Phamacokinetic samples will be drawn after the patient has been taking lapatinib at the same dose level for a period of at least 7 days. 

 
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11.0 Evaluation Criteria/Measurement of Effect 
For the purposes of this study, patients should be reevaluated for response every 12 weeks.   
Response and progression will be evaluated in this study using the new updated international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee version 1.1.102  Per the new RECIST 
criteria, as disease response is not the primary endpoint of this trial, confirmatory scans following documentation 
of progression or response will not be required. Rather, progression/response will be determined based on results 
of the single scan. 
 
11.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first treatment with 
lapatinib. 
Evaluable for objective response.  Only those patients who have measurable disease present at baseline, 
have received at least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
 
11.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter in the plane of measurement to be recorded) with a minimum size of 
10mm with conventional techniques (CT, MRI, or caliper measurement) or >20mm by chest X-ray (if 
clearly defined and surrounded by aerated lung.) To be considered pathologically enlarged and 
measurable, lymph nodes must be greater than 15mm on short axis and considered measureable can be 
used as target lesions when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5mm). All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest diameter 
<20 mm by chest X-ray or <10 mm using CT, MRI or caliper measurement), are considered non-
measurable disease. Leptomeningeal disease, blastic bone lesions, 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 are 
all non-measurable. Lymph nodes measuring between 10 to <15mm are also considered non-measurable. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and measured at 
baseline. Lymph nodes less than 15mm in the short axis can not be used as target lesions.  Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) and their suitability for 
accurate repeated measurements (either by imaging techniques or clinically).  A sum of the longest axis of 
non-lymph target lesion and the shortest axis of target lymph nodes will be calculated and reported as the 
baseline sum longest diameter (LD).  The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
 

 
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Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and above 
the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence or absence of each should be noted 
throughout follow-up.  
11.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 
30 days before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by 
clinical examination when both methods have been used to assess the antitumor effect of a treatment. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and neck tumors and those of 
extremities usually require specific protocols. 
 
Ultrasound (US):  When the primary endpoint of the study is objective response evaluation, US should not 
be used to measure tumor lesions.  It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US might also be useful to 
confirm the complete disappearance of superficial lesions usually assessed by clinical examination. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation has not yet 
been fully and widely validated.  Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers.  Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation purposes in reference centers. 
However, such techniques may be useful to confirm complete pathological response when biopsies are 
obtained. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete clinical response.  
 

 
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Cytology, Histology:  These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 
11.4 Response Criteria 
 
11.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  
Disappearance of all target lesions. Lymph node CR is when the lymph 
node has decreased to less than 10mm in the short axis. 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD):  
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started 
(including the baseline scan if that is the smallest), and at least a 5mm 
increase or the appearance of new lesions. 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment 
started 
 
11.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  
Disappearance of all non-target lesions and normalization of tumor marker 
level 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Incomplete Response/Stable Disease (SD): 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 

 
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Progressive Disease (PD):  
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. However, unequivocal progression should not 
normally trump target disease status.  It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances. 
 
11.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the achievement of 
measurement criteria, but confirmation is not necessary. 
 
Table 10: Assessment of Best Overall Response Using Target and Non-Target Lesions 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at 
that time should be reported as “symptomatic deterioration”.  Every effort 
should be made to document the objective progression even after discontinuation 
of treatment. 
 

 
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11.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started.  
 
11.6 Progression-Free Survival 
Progression-free survival is defined as the length of time between the start of treatment and when objective 
evidence of disease progression is documented. 
11.7 Overall Survival 
Overall survival is defined as the length of time between the start of treatment and death. 
12.0 Data Reporting/Protocol Deviations 
12.1 Data Reporting 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements). 
 
12.1.1 Method 
This study will be monitored by the City of Hope.  Reports are due quarterly on the 15th of each month.  
Note:  All adverse events that have occurred on the study must be reported to the study sponsor.  
Reporting will conform to the COH policy on reporting of AEs 
(http://www.infosci.coh.org/ocrqa/forms/guidance.doc) and to all FDA requirements.  As 
this study will not involve an IND, voluntary reporting requirements will conform to policies as 
described at http://www.fda.gov/cder/aers/fr07oc97.htm and 
http:///www.fda.gov/medwatch/index/html, and all relevant events will also be voluntarily 
reported to the FDA using the MedWatch system.   
 
12.1.2 Responsibility for Data Submission 
Study participants are responsible for submitting data and/or data forms to the Study Sponsor quarterly by 
the 15th day of the month. The Principal Investigator will then review, and timely submit data to the IRB.  
 

 
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The City of Hope PI is responsible for compiling and submitting data to all data review authorities for all 
participants and for providing the data to each Principal Investigator for review.   
 
12.1.3 Confidentiality of  and Storage of Records 
The original data collection forms will be stored in password protected databases. Hard copy forms will be 
stored in locked cabinets.  When results of this study are reported in medical journals or at meetings, 
identification of those taking part will not be disclosed.  Medical records of subjects will be securely 
maintained in the strictest confidence, according to current legal requirements.  They will be made 
available for review, as required by the FDA, HHS, or other authorized users such as the NCI, under the 
guidelines established by the Federal Privacy Act and rules for the protection of human subjects. 
The original data collection forms will be submitted into Medidata Electronic Data Collection (EDC).  
Data will be stored in encrypted, password protected, secure computers that meet all HIPAA 
requirements.  When results of this study are reported in medical journals or at meetings, identification of 
those taking part will not be disclosed.  Medical records of subjects will be securely maintained in the 
strictest confidence, according to current legal requirements.  They will be made available for review, as 
required by the FDA, HHS, or other authorized users such as the NCI, under the guidelines established by 
the Federal Privacy Act and rules for the protection of human subjects. 
 
12.1.4 Subject Consent Form 
At the time of registration, the original signed and dated Informed Consent form, HIPAA research 
authorization form, and the California Experimental Subject’s Bill of Rights (for the medical record) and 
three copies (for the subject, the research record, and the Coordinating Center) must be available.  All 
Institutional, NCI, Federal, and State of California requirements will be fulfilled. 
12.1.5 Data Collection Forms and Submission Schedule (for COH Patients)  
All data will be collected in a timely manner using Case Report Forms (Paper or via Medidata Electronic 
Data Collection (EDC). , Geriatric Assessment Surveys, medication adherence forms, Adverse/Serious 
Event logs, Pharmacokinetics Worksheet, and Tumor Measurement Logs.  Data will be sent to the Primary 
Investigator and stored in a secure location.   
12.1.5.1 Eligibility Checklist 
The Eligibility Checklist (see Appendix D) must be completed by a protocol nurse or clinical research 
associate and signed by an authorized investigator prior to registering the subject.  See Section 4.3 for the 
registration procedure. 
12.1.5.2 Prior Therapy and On-Study Forms 
Before the first dose of study agents are given, the clinical research associate must submit the Eligibility 
Checklist, the baseline Geriatric Assessment Form, baseline report of cardiac ejection fraction form, and 
baseline tumor measurement form. 
 
12.1.6 Data Collection Forms and Submission Schedule (for Participating 
Institutions)  
All data will be collected in a timely manner using Case Report Forms (Paper or via Medidata Electronic 
Data Collection (EDC).   Other forms that may be used include:  Geriatric Assessment Surveys (Paper or 

 
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touchscreen computer survey), medication adherence forms, Adverse/Serious Event logs, 
Pharmacokinetics Worksheet, and Tumor Measurement Logs.   
The participating institutions will be provided with a complete forms set specific to this protocol, along 
with forms instructions and the timepoints when data is to be collected and submitted to the Data 
Coordinating Center at City of Hope.   
12.1.6.1  The participating institution will complete the Eligibility Checklist Worksheet at the time of 
registration.   
12.1.6.2 Patient Consent Form:  The original consent form will reside with the participating institution 
and a copy will be kept at the Data Coordinating 
12.1.6.3 Center at City of Hope.  
12.1.6.4 Data collection forms will be submitted to the Data Coordinating Center via FAX at (626) 
301-8422 or online (if applicable), along with all corresponding source documentation.  All 
forms will remain in a secure location in the Department of Clinical Research Information 
Support (CRIS).   
 
12.2 Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the Study Sponsor’s Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Study Sponsor (Coordinating Center) and 
the procedures for auditing are presented in Appendix B. 
 
 
The Principal Investigator/Study Sponsor is responsible for distributing all IND Action Letters 
or Safety Reports received from the study sponsor to all participating institutions for submission 
to their individual IRBs for action as required. 
 
 
Except in very unusual circumstances, each participating institution will order the investigational 
agent lapatinib directly from the manufacturer.  Agents may be ordered by a participating site 
only after the initial IRB approval for the site has been forwarded by the City of Hope to GSK. 
 
12.3 Protocol Deviations 
12.3.1 Deviation Policy 
In accordance with the COH Policy on Clinical Research Protocol Deviation, there will be a “no deviations” rule 
for this protocol.  However, for subject safety or unforeseen scheduling problems, planned deviations may be 
permitted following IRB approval.  These planned deviations, considered Single Subject Exception, are 
considered an Amendment to the Protocol.  In addition, if contractually obligated, the sponsor must also approve 
any planned deviations. 
12.3.2 Reporting of Unplanned Deviations 
All unplanned deviations will be reported to the COH DSMB who will forward to the IRB following review. 

 
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12.3.3 Resolving Disputes 
If there is a dispute among the persons involved in the provision of research treatment, in regard to whether a 
treatment deviates from the protocol, the facts of the case will be reported to the DSMB which will serve as the 
arbiter of whether a deviation exists. 
 
13.0 Statistical Considerations 
13.1 Study Design 
The primary objective of this study is to determine the safety & tolerability of lapatinib (1000mg orally 
daily) in combination with trastuzumab given either weekly (first as a loading dose of 4mg/kg 
intravenously during week 1, and then at a maintenance dose of 2mg/kg intravenously weekly), or every 
three weeks (loading dose of 8mg/kg intravenously during week 1, then at a maintenance dose of 6mg/kg 
every three weeks thereafter) for patients 60 years of age and older.   
13.1.1 Primary Endpoints 
Grade 3 or higher non-hematological toxicities in patients taking the combination of lapatinib and 
trastuzumab, and symptomatic congestive heart failure 
13.1.2 Secondary Endpoints 
1. All toxicities associated with the combinations as measured by NCI CTCAE v.4.0 
2. Dose reductions, interruptions, and discontinuations 
3. Pharmacokinetic parameters 
4. Response as determined by RECIST criteria 
5. Progression-free survival 
6. Overall survival 
13.1.3 Methods for Stratification and Randomization  
             None. 
13.2 Sample Size and Accrual Rate 
Given a sample size of 40 subjects the widest half-width of the 95% confidence limits for the rate of grade 
3 or higher toxicities will be less than or equal to 0.16. For example if we saw a toxicity rate of 0.2 (8 
subjects/40) the 95% lower and upper confidence limits would be .09 and .36, respectively. As of 
December 2014, the accrual for this study has been approximately 8 participants per year.  Given the 
current sample size of 27 evaluable participants, we should reach our accrual goal of 40 patients within 24 
additional months making the full accrual period 72 months. 
 
13.3 Interim Analyses and Stopping Rules 
Interim Analyses: After 20 patients have completed one full cycle of therapy, the study team will review 
the data and assess the toxicity profile and rates of dose reduction, delays, interruptions and hospitalization 
related to the combination of agents.  Within this interim analysis a specific review will be made of the data 
for the patients over 75 years of age. In response to the DSMB review of the planned interim analysis 
results, we are adding a second interim analysis after 30 patients have completed one full cycle of therapy. 

 
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Stopping Rules: As cardiac toxicity has been seen with this combination, we have established additional 
guidelines and criteria which will be used to flag an unexpected number of patients that experience 
symptomatic cardiac toxicity (NYHA Class III or IV if cardiac failure, or Grade 3 or higher by NCI 
NCTAE v4.0 for other cardiac events).  
The risk set to be used in the safety monitoring decision (to trigger a review of the protocol) will include all 
patients that have received the combination of lapatinib and trastuzumab. 
Every time a patient experiences a symptomatic cardiac toxicity, we will look at the column for the total 
number of patients that have experienced symptomatic cardiac toxicity (X), and compare the number of 
patients, N, who are in the risk set to NX.  If the number of patients, N, is greater than NX, the number given 
in the bottom row of the table below, then accrual will continue.   If N is less than or equal to NX, then the 
monitoring boundary will have been crossed and a careful review of the trial data will be mandated. 
 
Table 11: Criteria for Suspending Accrual to Evaluate Safety 
X: # pts who experience a 
symptomatic cardiac toxicity 
2 
3 
4 
Nx: safety boundary crossed 
if # patients in risk set  (N) is 
less than or equal to Nx  (if N 
 Nx) 
≤10 
≤ 33 
≤ 40 
 
These rules were selected to ensure a low probability that the safety boundary would be crossed, indicating 
excessive cardiac toxicity, if the true chance of symptomatic cardiac toxicity were less than 2% and a high 
probability that the boundary would be crossed if the true chance of symptomatic cardiac toxicity reached 
8%. Criteria for flagging an excessive number of patients that have symptomatic  cardiac toxicity are based 
on the sequential probability ratio test with =0.10, =0.05, po=0.02 and pa=0.08. The table below 
summarizes these probabilities.  The values in the table below are based on 10,000 simulations.  
 

 
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Table 12: Probability of Crossing the Safety 
Boundary 
(i.e. too many patients have TOX) 
True Chance of 
Experiencing 
Symptomatic Cardiac 
Toxicities 
2% 
4% 
8% 
 
 
12% 
 
 
16% 
Probability of 
Crossing the Safety 
Boundary 
0.04 
0.18 
0.54 
 
.81 
 
0.94 
 
 
 
 
 
 
 
 
13.4 Analysis of Toxicity Data:  
Tables will be created to summarize the toxicities and side effects for each dose schedule by dose, course, 
organ and severity for all patients.  We will describe all serious adverse events and other serious toxicities 
on a patient by patient basis.  Numbers of cycles received and dose reductions will be tabulated by dose.  
Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for 1) 
grade 3 or higher toxicities, 2) all grade nausea, diarrhea and vomiting, 3) all grade cardiac events including 
SAEs and otherwise, 4) dose reductions, delays, interruptions and hospitalizations.  Descriptive statistics 
will be provided for study patient demographics.   
The primary analysis will be on all patients who receive the first dose of the combination of lapatinib and 
trastuzumab.  Sub-analyses will then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these sub analyses will not serve as 
the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients 
from the analysis will be clearly reported.   
 
13.5 Secondary analyses: 
13.5.1 Evaluation of response 
All patients included in the study must be assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible.  Each patient will be assigned one of the following categories:  
1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the “unknown” 
status of any type of data in a clinical database.] Response rate (CR + PR) and clinical benefit rate 
(CR+PR+SD) and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated. . 
All of the patients who met the eligibility criteria (with the possible exception of those who received no 
study medication) will be included in the main analysis of the response rate.  Patients in response categories 

 
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4-9 should be considered to have a treatment failure (disease progression).  Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
Primary analysis will be on all patients who are evaluable for toxicity.  Sub analyses will then be performed 
on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified 
(e.g., early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.).  
However, these subanalyses will not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis will be clearly reported.   
13.5.2 Pharmacokinetic parameters: 
We will measure trough levels of lapatinib in each patient who is eligible for such measure (has been on a 
stable dose of lapatinib for at least 7 days) at three different time periods as described earlier.  Each sample 
will be processed at the participating study site, and will be batched and sent to GSK for assay.  AUC will be 
calculated and reported using standard descriptive statistics. 
13.5.3 Factors other than chronologic age that can affect outcomes: 
We will perform a geriatric assessment analysis on all patients enrolling in the study. This assessment will be 
given at baseline, at the end of every four cycles, and once the study is over. A comprehensive cancer-
specific geriatric assessment includes an evaluation of functional status, comorbidity, cognition, 
psychological status, social functioning and support, and nutritional status.1 This assessment has been piloted 
in the CALGB. We will also collect data on the subjects regarding number at type of prior treatments, and 
collect baseline laboratory values, baseline tumor burden, and baseline ejection fraction.  General linear 
models and graphical methods will be used to explore factors other than chronologic age that can predict 
toxicity, efficacy and/or pharmacokinetic parameters of interest. 
 
14.0 Human Subject Issues 
14.1 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the federal 
regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 17,  must 
review and approve this protocol and the informed consent form prior to initiation of the study.  All institutional, 
NCI, Federal, and State of California regulations must be fulfilled. 
14.2 Recruitment of Subjects 
Potential research subjects will be identified by a member of the patient’s treatment team, the protocol 
investigator, or research team, from the pool of patients seen by the study center with locally advanced or 
metastatic breast cancer.  Potential subjects will be contacted by their treating physician and will be 
referred to the investigator/research staff of the study at their institution. 
 
During the initial conversation between the investigator/research staff and the patient, the patient may be 
asked to provide certain health information that is necessary to the recruitment and enrollment process. 
The investigator/research staff may also review portions of their medical records at the participating 
institution, provided that the investigator/research team is only reviewing records at their home institution, 
in order to further assess eligibility.  They will use the information provided by the patient and/or medical 
record to confirm that the patient is eligible and to contact the patients regarding study enrollment.  If the 
patient turns out to be ineligible for the research study, the research staff will destroy all information 

 
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collected on the patient during the initial conversation and medical records review, except for any 
information that must be maintained for screening log purposes. 
 
In most cases, the initial contact with the prospective subject will be conducted by the treatment team, 
investigator, or the research staff working in conjunction with the treatment team.  The recruitment process 
outlined presents no more than minimal risk to the privacy of the patients who are screened and minimal 
PHI will be maintained as part of a screening log. For these reasons we seek a limited waiver of 
authorization for the purposes of (1) reviewing medical records to identify potential research subjects and 
obtain information relevant to the enrollment process; (2) conversing with patients regarding possible 
enrollment; (3) handling of PHI contained within those records and provided by the potential subjects; and 
(4) maintaining information in a screening log of patients approached (if applicable). Treating physicians 
will be contacted regarding potentially eligible patients, and may then choose whether to offer eligible 
patients the opportunity to participate in the study. The goals of the study will be described and the patient 
will be given a copy of the informed consent to review.  The interested patient will sign the consent form 
and retain a copy. 
 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Blood tests that were performed within 14 days and 
radiologic tests performed within 28 days for clinical indications (not exclusively to determine study 
eligibility) may be used for baseline values, even if the studies were done before informed consent was 
obtained. 
14.3 Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, etc., will be 
reviewed and approved by the IRB prior to their use to recruit potential study subjects.   
14.4  Study location and Performance Sites 
This study will be performed at COH.  Other sites may enroll patients onto the research protocol provided that 
this protocol, with site-specific changes only, is approved by each site IRB.  All data analysis will be performed 
at City of Hope. 
14.5 Confidentiality  
This research will be conducted in compliance with federal and state of California requirements relating to 
protected health information (PHI).  The study will record individual response to the study drugs and any 
side effects, and this will be linked to the subject’s identity using a coded study number.  The principal 
investigator, co-investigators, and laboratory technicians will have access to this information, but all 
information will be treated confidentially.  No identifiers will be used in any subsequent publication of 
these results. 
14.6 Financial Obligations and Compensation 
The study drug lapatinib will be provided by the manufacturer free of charge to patients on this study. 
*Note: For patients enrolling at Roswell Park Cancer Institute, lapatinib will be provided as Standard of 
Care and this drug will be billed to the insurance. (It is anticipated that lapatinib related costs will be 
covered wholly or in part by most insurances due to the fact that lapatinib is FDA approved in HER2 
overexpressing breast cancer.) Pharmacokinetic lab draws, processing, and results will also be free of 
charge as a part of research. Routine standard of care clinic visits, laboratory tests, and tumor imaging will 
be billed to the patient and/or the patient’s insurance.  Cardiac imaging will be provided free of charge. The 
study drug trastuzumab, infusion center time, and routine nursing care involved in administering 

 
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trastuzumab and supportive medications during infusion will be billed to the patient and/or the patient’s 
insurance.  It is anticipated that trastuzumab related costs will likely be covered wholly or in part by most 
insurances due to the fact that trastuzumab is FDA approved in HER2 overexpressing breast cancer.  
Medication and/or treatment needed for side effects of either study drug will be billed to the patient and/or 
the patient’s insurance. 
If there is a serious medical complication of the research, treatment will be available at City of Hope, but 
there will be no compensation to the subject for this injury.   
14.7 Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Research subjects will be informed that they may withdraw from the 
study at any time and for any reason without prejudice, including as applicable, their current or future care 
or employment at City of Hope or any relationship they have with City of Hope.   
Should sufficient doubt be raised regarding the adequacy of comprehension, further clarifications will be 
made and the questionnaire repeated until a satisfactory result is obtained.  Prospective research subjects 
who cannot adequately comprehend the fundamental aspects of the research study with a reasonable 
amount of discussion, education and proctoring will be ineligible for enrollment.  For those subjects who do 
comprehend the fundamental aspects of the study, the research team will review the results of eligibility 
testing and determine if the subject is a candidate for study enrollment.  

 
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15.0 References 
1. 
Hurria A, Gupta S, Zauderer M, et al. Developing a cancer-specific geriatric assessment. Cancer 
2005;104:1998-2005. 
2. 
Hurria A, Balducci L, Naeim A, et al. Mentoring Junior Faculty in Geriatric Oncology: Report From the 
Cancer and Aging Research Group. J Clin Oncol 2008;26:3125-7. 
3. 
Baudard M, Marie J, Cadiou M, Viguie F, Zittoun R. Acute myelogenous leukaemia in the elderly: 
retrospective study of 235 consecutive patients. Br J Haematol 1994;86:82-91. 
4. 
Stein B, Petrelli N, Douglass H, et al. Age and sex are independent predictors of 5-fluorouracil toxicity. 
Cancer 1995;75:11-7. 
5. 
Allen A. The cardiotoxicity of chemotherapeutic drugs. Semin Oncol 1992;19:529-42. 
6. 
Balducci L, Corcoran M. Antineoplastic chemotherapy of the older cancer patient. Hematol Oncol Clin 
N Am 2000;14:193-212. 
7. 
Hurria A, Lichtman SM. Pharmacokinetics of Chemotherapy in the Older Patient. Cancer Control 
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APPENDIX A: 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair.
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 

 
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APPENDIX B: 
Multicenter Guidelines 
 
Responsibility of the Protocol Chair  
 
The Protocol Chair will be the single liaison with sponsoring organization.  The Protocol Chair is 
responsible for the coordination, development, submission, and approval of the protocol as well as its 
subsequent amendments.  The protocol must not be rewritten or modified by anyone other than the 
Protocol Chair.  There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating institutions are using 
the correct version of the protocol. 
 
The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and 
for monitoring its progress.  All reporting requirements to the FDA and Novartis are the responsibility of 
the Protocol Chair.  
 
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the 
patients. 
 
The Protocol Chair will be responsible for the review of and timely submission of data for study 
analysis. 
 
Responsibilities of the Data Coordinating Center 
 
Each participating institution will have an appropriate assurance on file with the Office for Human 
Research Protection (OHRP), NIH.  The Data Coordinating Center is responsible for assuring that each 
participating institution has an OHRP assurance and must maintain copies of IRB approvals from each 
participating site.  
 
The Data Coordinating Center is responsible for central patient registration of patient’s from 
participating institutions.  The Data Coordinating Center is responsible for assuring that IRB approval 
has been obtained at each participating site prior to the first patient registration from that site. 
 
The Data Coordinating Center is responsible for the preparation of all submitted data for review by the 
Protocol Chair that has been received by the participating institutions. 
 
The Data Coordinating Center will maintain documentation of AE reports.  There are two options for AE 
reporting: (1) participating institutions may report directly to the FDA and Novartis with a copy to the 
Coordinating Center, or (2) participating institutions report to the Coordinating Center who in turn report 
to Novartis and the FDA.  The Data Coordinating Center will submit AE reports to the Protocol Chair 
for timely review. 
 
Routine monitoring of data quality will take place for all data received from participating institutions.  
The participating institution will be asked to provide the Data Coordinating Center source documentation 
pertaining to the data collected.  This information should be de-identified by the participating institution 
prior to faxing to the Data Coordinating Center. 
 
Audits may be accomplished in one of two ways:  (1) source documents and research records for 
selected patients are sent from participating sites to the Data Coordinating Center for audit, or (2) 
selected patient records may be audited on-site at participating sites.  If the study sponsor chooses to 
have an audit at the Data Coordinating Center, then the Data Coordinating Center is responsible for 
having all source documents, research records, all IRB approval documents, NCI Drug Accountability 
Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the audit. 

 
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Inclusion of Multicenter Guidelines in the Protocol 
 
The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and the name, 
telephone number and e-mail address of the responsible investigator at each participating institution. 
 The Data Coordinating Center must be designated on the title page. 
 Central registration of patients is required.  The procedures for registration must be stated in the 
protocol. 
 Data collection forms should be of a common format.  Sample forms should be submitted with the 
protocol.  The frequency and timing of data submission forms to the Data Coordinating Center 
should be stated. 
 Describe how AEs will be reported from the participating institutions through the Data Coordinating 
Center. 
 
 
Agent Ordering 
 
Except in very unusual circumstances, each participating institution will order lapatinib directly from 
Novartis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX C: 
Lapatinib Prohibited Medication List 
 
Lapatinib is a substrate for CYP3A4.  Inducers and inhibitors of CYP3A4 may alter the metabolism of lapatinib.  
The following list of CYP3A4 inducers and inhibitors are prohibited from screening through discontinuation 
from study. 
 
 
 
Drug Class 
Agent
Wash-out1
CYP3A4 Inducers 
Antibiotics 
all rifamycin class agents (e.g., rifampicin, rifabutin, 
rifapentine)
14 days
Anticonvulsants 
phenytoin, carbamezepine, barbiturates (e.g.,  
phenobarbital)
Antiretrovirals 
efavirenz, nevirapine, tipranivir, etravirine
Glucocorticoids (oral) 
cortisone (>50 mg), hydrocortisone (>40 mg), prednisone or 
prednisolone (>10 mg), methylprednisolone or 
triamcinolone (>8 mg), betamethasone or dexamethasone2 
(>1.5 mg)
Other 
St. John’s Wort, modafinil
CYP3A4 Inhibitors 
Antibiotics 
clarithromycin, erythromycin, troleandomycin, flucloxacillin 
7 days
Antifungals 
itraconazole, ketoconazole, fluconazole (>150 mg daily), 
voriconazole
Antiretrovirals, Protease Inhibitors 
delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, 
saquinavir, lopinivir, atazanivir
Calcium channel blockers 
verapamil, diltiazem
Antidepressants 
nefazodone, fluvoxamine
 
GI Agents 
cimetidine, aprepitant3
Other 
red wine, Seville oranges, grapefruit or grapefruit juice 
and/or kumquats, pomegranate or pomegranate juice, 
pomelos, exotic citrus fruit (i.e., star fruit, bitter melon), 
grapefruit hybrids or fruit juices, or other foods and juices 
known to inhibit CYP3A4
amiodarone
6 months
Miscellaneous 
H2 blockers 
cimetidine
7 days
Antacids 
Mylanta, Maalox, TUMS™, Rennies
1 hour before and after 
dosing
Herbal supplements4  
ginkgo biloba, kava, grape seed, valerian, ginseng, 
echinacea, evening primrose oil
14 days
Study Specific Medications 
Potent Pgp inhibitors 
resperine
14 days
tacrolimus
3 days
cyclosporine
5 days

 
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1. At baseline, if a subject is receiving any of the above listed medications/substances, the medication or substance must be 
discontinued (if clinically appropriate) for the period of time specified prior to administration of the first dose of study drug and 
throughout the study period in order for the subject to be eligible to participate in the study. 
2. Glucocorticoid daily doses (oral) 1.5 mg dexamethasone (or equivalent) are allowed. Glucocorticoid conversions are provided in 
parentheses. 
3. Emetogenic chemotherapy may require 3-4 daily doses of aprepitant.  CYP3A4 inhibition by oral (not IV) aprepitant may require a 
concurrent dose reduction of 1-2 lapatinib tablets. 
4. This list is not all-inclusive; therefore, for herbal supplements not listed, please contact a GSK medical monitor. 
NOTE: If future changes are made to the list of prohibited medications, formal documentation will be 
created and stored with the study file.  Any changes will be communicated to the investigative sites in the 
form of a letter. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX D: 
Eligibility Checklist 
 
 
Question 
Yes 
No 
Does this patient have locally advanced or metastatic breast 
cancer? 
 
 
Does this patient have documented HER2 positive disease 
(defined as IHC 3+ or FISH ratio >2.0)? 
 
 
IHC: 
FISH ratio: 
Is the patient age 60 or older? 
 
 
Does the patient have a life expectancy of >12 weeks? 
 
 
Is the patient’s ECOG Performance Status < 2? 
 
PS: 
 
Has the patient had resolution of all grade 2 or higher 
toxicities from previous treatments? 
 
 
Can the patient understand and sign a written informed 
consent document? 
 
 
Is the absolute neutrophil count > 1,500/mm3? 
 
 
ANC: 
Date: 
Is the platelet count > 100,000/ mm3? 
 
 
Plts: 
Date: 
Is the hemoglobin > 10g/dL? 
 
 
 
 
 
 
 
Hgb: 
Date: 

 
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Question 
Yes 
No 
Is the total bilirubin within the normal institutional limits 
(or does the patient have known chronic but stable liver 
disease such as Gilbert’s syndrome)? 
 
 
Bilirubin: 
Date: 
Are the ALT and AST < 2.5 times the institution’s upper 
limit of normal? (Or does the patient have known chronic 
but stable liver disease?) 
 
 
ALT/AST: 
 
Date: 
Is the creatinine clearance > 30ml/min? 
 
 
Cr clearance: 
Were the above tests performed within 14 days of study 
enrollment? 
 
 
Does the patient have the ability to swallow and retain oral 
medication? 
 
 
Will the patient be receiving any other investigational 
agents? 
 
 
Has the patient ever received trastuzumab and lapatinib 
concurrently? 
 
 
Does the patient have untreated CNS metastases or 
symptomatic CNS metastases requiring doses of 
corticosteroids? 
 
 
History of allergic reactions attributed to compounds of 
similar chemical or biologic composition to lapatinib or 
trastuzumab. However patients with a history of infusion 
reaction to trastuzumab which was controlled with 
premedication on subsequent infusions without a recurring 
infusion reaction are eligible. 
 
 
Does the patient have the presence of any serious or 
uncontrolled infection (including HIV)? 
 
 
Does the patient have psychiatric illness or a social 
situation that would limit compliance with study 
medications? 
 
 
 
 

 
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Question 
Yes 
No 
Is the patient currently taking any of the medicines listed in 
Appendix C? 
 
 
If the patient is sexually active and not post-menopausal, 
does he/she agree to use appropriate contraception during 
the trial? 
 
 
Does the patient have a left ventricular ejection fraction 
greater than 50%? 
 
 
 
EF: 
Date: 
Does the patient have problems with GI absorption that 
may limit her ability to retain the drug? 
 
 
Does the patient have active hepatic or biliary disease? 
 
 
Has the patient had a documented myocardial infarction in 
the past six months? 
 
 
Does the patient have angina pectoris requiring anti-anginal 
medication? 
 
 
Does the patient have clinically significant valvular heart 
disease? 
 
 
Does the patient have a history of congestive heart failure 
or decreased left ventricular ejection fraction <50%? 
 
 
Does the patient have evidence of transmural infarction, 
ventricular tachycardia, high-grade AV-block, and/or 
supraventricular tachycardia which is not adequately rate-
controlled on EKG? 
 
 
Does the patient have poorly controlled hypertension 
(systolic BP >180mm Hg or diastolic BP >100mm Hg? 
 
 
BP: 
 
Signatures: 
 
Consenting MD:_________________________________________  
Date:____________ 
 
Protocol RN:____________________________________________ 
Date:____________      
 
*Shaded boxes must be checked for patient to be eligible 

 
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APPENDIX E:  
Geriatric Assessment Survey 
 
Completed via touchscreen computer survey (preferable) or paper assessment forms (Attached) 

 
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APPENDIX  F 
Data Coordinating Center 
Department of Clinical Research Information Support 
City of Hope 
NOTIFICATION OF TOXICITY 
THIS FORM ALONG WITH A COPY OF LOCAL IRB REPORT, NOVARTIS SAE NOTIFICATION AND 
MEDWATCH (IF APPLICABLE) FORM MUST BE FAX'D (626-301-8422) TO THE DATA 
COORDINATING CNETER WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF ADVERSE EVENT 
 
COH IRB #10112 
INSTITUTIONAL IRB # ___________ 
TOLERABILITY OF THE COMBINATION OF LAPATINIB AND TRASTUZUMAB IN ADULTS AGED 
60 OR OLDER WITH HER2 POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST CANCER  
Participating/Treating Institution:  __________________________________________________________ 
Reporter:  ___________________________________          Phone #:________________________________ 
Email:   ________________________________ 
 
PATIENT INFORMATION 
Patient Name________________________________________     Pt Study ID:  _____________________ 
 
ADVERSE EVENT INFORMATION 
 
Adverse Event:  _______________________________  
Start Date of AE: ____/____/____ 
 
 
REPORTING INFORMATION 
Has the event been reported to the following? 
Via Phone/Fax to Dr. Arti Hurria? 
 
 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
 
Phone:  626-471-9200/Fax:  626-301-8233 
Institutional IRB?  
 
 
 
 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
FDA (if applicable)? 
 
 
 
 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
Novartis? 
  
 
 
 
 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
Report sent to Data Coordinating Center (COH)? 
__ No    __ Yes   Date: __ __ / __ __  / __ __ 
Fax:  626-301-8422