Conditions: HER2-Positive Early Stage Breast Cancer
Keywords: Paclitaxel Trastuzumab Lapatinib HER2 13-002
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this study is to study a new treatment for HER2-positive breast cancer.

Detailed description:

Arms:
arm 1: Paclitaxel (T) at 175 mg/m2 q 2 weeks x 4 with filgrastim/pegfilgrastim + trastuzumab (H) + daily oral lapatinib (L), followed by trastuzumab q 3 weeks x 15 doses + daily oral lapatinib (HL). Pegfilgrastim 6mg will be given subcutaneously (SQ) on day # 2 of each paclitaxel administration. Filgrastim may be used in lieu of pegfilgrastim at physician's discretion. Trastuzumab will be administered weekly (4 mg/kg bolus followed by 2 mg/kg weekly) starting with paclitaxel treatment cycle # 1. After 4 cycles of paclitaxel, pts will receive trastuzumab on a q 3 weeks x 15 doses (to complete about one year). The q 3 week trastuzumab may be started from 1-3 weeks after the last dose of paclitaxel. A total of 15 infusions of trastuzumab will be given q 3 weeks after the completion of paclitaxel during the HL phase. Lapatinib will be given orally at 1000 mg daily, starting with paclitaxel during the THL phase \& continued for the remaining year during the HL phase for about a year.

Interventions: intervention 1: Paclitaxel intervention 2: Trastuzumab intervention 3: Lapatinib intervention 4: Pegfilgrastim
Intervention descriptions: intervention 1: None intervention 2: The q 3 week trastuzumab may be started at the last dose of paclitaxel infusion or from 1-3 weeks after the last dose of paclitaxel. Trastuzumab may also be administered at a dose of 6mg/kg during the last dose of paclitaxel in the THL phase. intervention 3: None intervention 4: Pegfilgrastim SQ is given on day # 2 of each paclitaxel cycle and may be dropped at the last paclitaxel infusion. Filgrastim may be used in lieu of pegfilgrastim at the physician's discretion.

Protocol document:
Prot_SAP_000.pdf: 
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The Feasibility of Paclitaxel with Trastuzumab and Lapatinib in HER2-Positive Early Stage 
Breast Cancer 
 
Principal Investigator/Department: 
Chau Dang, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Devika Gajria, MD 
Medicine 
Investigator(s)/Department: 
Jose Baselga, MD,PhD 
Shanu Modi, MD 
Maura Dickler, MD 
Jacqueline Bromberg, MD, PhD 
Teresa Gilewski, MD 
Larry Norton, MD Mark 
Robson, MD Gabriela 
D’Andrea, MD 
Diana Lake, MD 
Andrew Seidman, MD 
Nancy Sklarin, MD 
Mary Ellen Moynahan, MD 
Tiffany A. Traina, MD 
Shari Goldfarb, MD 
Elizabeth Comen, MD 
Sarat Chandarlapaty, MD, PhD 
Victoria Blinder, MD 
Monica Fornier, MD 
Ayca Gucalp, MD 
Neil Iyengar, MD 
Richard Steingart, MD 
Jennifer Liu, MD 
Ting Bao, MD, MS 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Roseann Caruso, NP 
Leslie Matthews, NP 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Tiffany Troso-Sandoval, MD 
Sujata Patil, PhD 
Martin Fleisher, PhD 
Medicine 
Medicine/Cardiology 
Medicine/Integrative Medicine 
Medicine (Commack) 
Medicine (Basking Ridge) 
Medicine (Rockville Centre) 
Biostatistics 
Laboratory Medicine 
Consenting 
Jose Baselga, MD,PhD 
Medicine 


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Professional(s)/Department: 
Chau Dang, MD 
Shanu Modi, MD 
Maura Dickler, MD 
Jacqueline Bromberg, MD, PhD 
Teresa Gilewski, MD 
Larry Norton, MD Mark 
Robson, MD Gabriela 
D’Andrea, MD 
Diana Lake, MD 
Andrew Seidman, MD 
Nancy Sklarin, MD 
Mary Ellen Moynahan, MD 
Tiffany A. Traina, MD 
Shari Goldfarb, MD 
Devika Gajria, MD 
Elizabeth Comen, MD 
Sarat Chandarlapaty, MD, PhD 
Victoria Blinder, MD 
Monica Fornier, MD 
Ayca Gucalp, MD 
 
Ting Bao, MD, MS 
 
Stuart Lichtman, MD 
Steven Sugarman, MD 
  
 
Audrey Hamilton, MD 
Mila Gorsky, MD 
 
 
 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Tiffany Troso-Sandoval, MD 
Medicine/Integrative Medicine 
 
Medicine (Commack) 
Medicine (Basking Ridge) 
Medicine (Rockville Centre) 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
Participating Institutions 
PI's Name 
Site's Role 
University of Pennsylvania 
Bonnie Ky, PhD 
Specimen Analysis 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA..................................................................... 4 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS.............................................................................. 5 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 6 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ......................................................... 15 
 
4.1 
Design .......................................................................................................................... 15 
 
4.2 
Intervention ................................................................................................................... 16 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 16 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 22 
 
6.1 
Subject Inclusion Criteria .............................................................................................. 22 
 
6.2 
Subject Exclusion Criteria ............................................................................................. 23 
 
7.0 
RECRUITMENT PLAN..................................................................................................... 24 
 
8.0 
PRETREATMENT EVALUATION .................................................................................... 24 
 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................. 25 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 32 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 38 
 
Information on pregnancy ........................................................................................................... 39 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 43 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 43 
 
14.0 BIOSTATISTICS .............................................................................................................. 44 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
46 
 
15.1 Research Participant Registration ................................................................................. 46 
 
16.0 DATA MANAGEMENT ISSUES....................................................................................... 46 
 
16.1 Quality Assurance......................................................................................................... 47 
 
16.2 Data and Safety Monitoring........................................................................................... 47 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 48 
 
17.1 Privacy.......................................................................................................................... 48 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 48 
 
17.2.1................................................................................................................................... 49 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 50 
 
19.0 REFERENCES ................................................................................................................. 50 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a feasibility trial of dose-dense adjuvant chemotherapy for patients with node-negative, 
HER-2/neu-overexpressed/amplified breast cancer. The regimen consists of paclitaxel (T) at 175 
mg/m2 q 2 weeks x 4 with filgrastim/pegfilgrastim + trastuzumab (H) + daily oral lapatinib (L), 
followed by trastuzumab q 3 weeks x 15 doses + daily oral lapatinib (HL). Pegfilgrastim 6mg will 
be given subcutaneously (SQ) on day # 2 of each paclitaxel administration.  Filgrastim may be 
used in lieu of pegfilgrastim at the physician’s discretion. Trastuzumab will be administered 
weekly (4 mg/kg bolus followed by 2 mg/kg weekly) starting with paclitaxel treatment cycle # 1. 
After completion of 4 cycles of paclitaxel, patients will receive trastuzumab on a q 3 week 
schedule x 15 doses.  A total of 15 infusions of trastuzumab will be given q 3 weeks after the 
completion of paclitaxel (during the HL phase). Lapatinib will be given orally at 1000 mg daily, 
starting with paclitaxel during the THL phase and continued for the remaining year during the HL 
phase for about a year. 
 
Study blood will be collected serially for cardiac biomarker analysis [troponin I (cTnI), brain type 
natriuretic peptide (BNP), neuregulin-1ß (NRG-1ß)]. We will also assess the left ventricular 
ejection fraction (LVEF) at baseline and at months 2, 6, 9, 12 and 18 of treatment with an 
echocardiogram (ECHO) with a strain imaging analysis (+/- 4 weeks). When an ECHO cannot be 
done, a multi-gated acquisition scan (MUGA) may be done. 
 
The primary objective is to determine the feasibility of a dose-dense adjuvant paclitaxel with HL in 
patients with node-negative, HER-2/neu-overexpressed/amplified breast cancer. 
 
The regimen is considered feasible if patients are able to complete the paclitaxel, trastuzumab, 
and lapatinib (THL) portion of the regimen without a dose delay or reduction or grade 3 or greater 
QTc prolongation.  An early stopping rule that terminates the trial if the overall cardiac event (CE) 
rate is greater than 4% or if there is excessive grade 3 gastrointestinal toxicity has been 
incorporated. The incidence of cardiac events will be closely monitored.  A CE is defined as 1) 
cardiac death or 2) symptomatic congestive heart failure (CHF) defined as dyspnea with normal 
activity or at rest and “absolute” decline in LVEF by > 10% to < 50 % by echocardiogram or 
MUGA.  A cardiac event will result in discontinuation of trastuzumab and lapatinib. 
 
The secondary objectives are to evaluate the toxicities of this regimen, to explore the use of 
cardiac biomarkers as predictors of cardiac toxicity and to explore the use of single-nucleotide 
polymorphism (SNP) genotyping in evaluation of pharmacogenetic determinates of 
gastrointestinal toxicity. 
 
We plan to accrue 55 evaluable patients with HER-2/neu overexpressed/amplified breast cancer 
(node-negative, tumor size < 3 cm) to this trial within 12 months.  Endpoints for removal from the 
study are unacceptable toxicity, progression of disease while on study drugs, death, major 
protocol violation, and patient withdrawal from study. 


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Schema 
 
Accrual Goal = 55 pts 
 
 
 
 
 
Radiation as needed given 
concurrently w/ HL 
 
.……………x 15 doses (Rx=1 year) 
 
Lapatinib……………………………………………………………………….........x1 year 
 
 
@  mo  0 
2 
6……………….....9……………12…………………….18 
 
Paclitaxel (T) = 175mg/m2 every 2 wks x 4 (with pegfilgrastim or filgrastim) 
Trastuzumab (H) = 2 mg/kg every wk x 8 → 6 mg/kg every 3 wks x 15 
Lapatinib (L) = 1000 mg daily x 1 year 
ECHO/EKG 
Blood-pharmacogenomics 
Blood-cardiac biomarkers 
 
 
 
 
 
 
Research bloods (TnI, BNP, NRG-1ß) every cycle (pre- and post-infusion of cycles 1-4 during 
THL pre- and post-infusion during months 6 and 9 (cycles )(+/- a cycle) and month 18 (after 
completeion of HL). 
 
Post-Chemotherapy 
 
Hormonal therapy such as tamoxifen or an aromatase inhibitor will be given to patients with 
hormone receptor positive disease at the physician’s discretion. Radiation therapy to the breast or 
chest is recommended to patients as appropriate. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective 
  
To determine the feasibility of a dose-dense adjuvant paclitaxel in patients with node-negative, 
HER2-positive breast cancer using dual anti-HER2 inhibition with trastuzumab and lapatinib (1000 
mg). 
The regimen is considered feasible if patients are able to complete the paclitaxel, 
trastuzumab, and lapatinib (THL) portion of the regimen without a dose delay or reduction 
or grade 3 or greater QTc prolongation.  We have incorporated an early stopping rule that 
terminates the trial if the overall cardiac event (CE) rate is greater than 4% or if there is 
excessive grade 3 gastrointestinal toxicity. 
 
 
 
Secondary Objectives 


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- Safety 
- To explore certain allele frequencies of CYP3A4, CYP3A5, CYP2C8, CYP2C19, ABCB1, and 
ABCG2 (genes known to be involved in taxane and lapatinib metabolism) and their association 
relative to gastrointestinal toxicity 
-To explore the use of serial troponin I, and B-type natriuretic peptide, as potential predictors of 
cardiac toxicity of this regimen 
-To explore serial ECHOs with strain imaging 
 
3.0 
BACKGROUND AND RATIONALE 
 
Background 
 
 
Adjuvant Chemotherapy 
 
 
Adjuvant chemotherapy with combinations of cytotoxic agents reduces the risk of recurrence and 
has an important role in the treatment of early breast cancer.  The 2005 Early Breast Cancer 
Trialists’ Collaborative Group (EBCTCG) meta-analysis demonstrated a survival advantage for 
anthracycline-based  adjuvant  regimens  compared  with  non-anthracycline  based  therapies.1 
Given the rare but serious long-term effects of anthracycline exposure including congestive heart 
failure and secondary hematologic malignancies, tailoring adjuvant regimens to minimize the 
cumulative exposure to anthracyclines and optimize efficacy has been a focus for medical 
oncologists.  Over the past 25 years, taxanes have been studied in the treatment of breast cancer 
and are well established agents in the metastatic setting.   Paclitaxel and docetaxel, when 
administered as single agents have similar efficacy to anthracyclines in chemotherapy naïve 
patients.2-3    Several randomized controlled trials have evaluated the benefit of a taxane to an 
anthracycline-based regimen in the treatment of early breast cancer.  A recent meta-analysis 
demonstrated that taxane-based regimens provide both a disease free survival (DFS) and overall 
survival benefit (OS) with an absolute 5-year risk reduction of 5% for DFS and 3% for OS when 
compared to standard anthracycline regimens.   The benefit risk reduction for recurrence was 
seen irrespective of estrogen receptor (ER) status, lymph node status, and age with a magnitude 
of benefit that remained nearly constant across subgroups of patients.4 
 
Dose Dense Therapy 
 
In an attempt to optimize taxane delivery in the adjuvant setting, the Cancer and Leukemia Group 
B (CALGB) 9741 trial explored the concept of dose density or the administration of chemotherapy 
with shortened inter-treatment intervals.5    This strategy was developed from the Norton-Simon 
mathematical model of tumor cell growth which shows that a given dose of chemotherapy kills a 
certain fraction rather than a certain number of cancer cells.  Additionally, breast cancer cells 
demonstrate non-exponential Gompertzian kinetics, and regrowth of cancer cells between cycles 
of therapy is more rapid in these cancer models than exponential models.6-7   Thus, the fixed cell 
kill achieved with each cycle of therapy may be optimized by delivering each subsequent cycle in 
quick succession.  The limitation of dose-dense therapy is the impact on rapidly proliferating cells, 
including bone marrow progenitor cells though this is mitigated by the administration of G-CSF. 
The CALGB 9741 trial randomized 2,005 patients to one of four treatment arms: 1) sequential 
doxorubicin (A) x 4 cycles, paclitaxel (T) x 4 cycles, cyclophosphamide (C) x 4 cycles (A-T-C) 
delivered three weeks apart; 2) sequential A-T-C delivered every two weeks with G-CSF; 3) 


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concurrent AC x 4 cycles followed by 4 cycles of T (AC-T) delivered every three weeks; 4) 
concurrent AC-T delivered every two weeks with G-CSF.   At a median 6.5 years of follow-up, 
there  is  a  statistically  significant  improvement  in  DFS  and  OS  in  favor  of  dose-dense 
chemotherapy administration.8. 
 
Anti-HER2 Therapies 
 
 
Trastuzumab 
 
In an effort to improve upon these outcomes, biologic therapeutics have been incorporated into 
adjuvant regimens.  Amplification of the human epidermal growth factor receptor 2 (HER2/neu) 
gene is observed in 20% to 30% of invasive breast carcinomas and portends a poor prognosis 
with increased risk of disease progression and decreased overall survival.9    Given that HER2 
overexpression mediates the transformed phenotype, therapeutic strategies targeting HER2 
activation are a logical approach. Trastuzumab (Herceptin®), a humanized, recombinant 
monoclonal antibody, binds to the extracellular domain of HER2 inhibiting kinase activity and 
leading to cell cycle arrest and apoptosis.10    The pivotal phase III clinical trial, which led to FDA 
approval of trastuzumab for the treatment of metastatic HER2-positive breast cancer, randomized 
469  women  who  had  not  received  chemotherapy  for  metastatic  HER2-amplified  disease  to 
receive chemotherapy plus trastuzumab or chemotherapy alone. Women were treated with an 
anthracycline- or taxane-based regimen based on their prior exposures. The addition of 
trastuzumab to chemotherapy led to statistically significant improvements in time to progression, 
duration of response, objective response rate, and overall survival. These results were tempered 
by cardiac toxicity documented with trastuzumab especially in combination with anthracycline 
therapy   (27%   incidence   with   anthracycline   and   trastuzumab,   13%   with   paclitaxel   and 
trastuzumab, and 8% with anthracycline therapy alone).11 
 
Motivated by the proven benefits of trastuzumab in the metastatic setting, four international 
studies initiated in 2000-2001 with over 13,000 women examined the safety and efficacy of 
adjuvant trastuzumab: the Herceptin Adjuvant (HERA)12-13 trial, the National Surgical Adjuvant 
Breast and Bowel Project B-31 (NSABP B-31) trial, the North Central Cancer Treatment Group 
9831 (N9831)14 trial, and the Breast Cancer International Research Group 006 (BCIRG 006)15-16 
trial. Two smaller trials, the Finland Herceptin (FinHER)17 trial and the Protocole Adjuvant dans le 
Cancer du Sein 04 (PACS 04)18  trial followed soon after (Table 1). With the exception of PACS 
04, the adjuvant trials collectively demonstrated trastuzumab reduced the risk of breast cancer 
recurrence by approximately 40-50% despite differences in patient population and trial design. 
Although trastuzumab has been widely accepted in the adjuvant setting, there remain several 
uncertainties regarding administration including possible cardiac toxicity. 
 
Cardiac Toxicity 
 
Reports of trastuzumab-related cardiac toxicity during pivotal trials of data collected from seven 
phase II and III clinical trials for trastuzumab are available.19-20   The analysis performed 
independently by the Cardiac Review and Evaluation Committee, evaluated the risk and severity 
of cardiac dysfunction, baseline risk factors, and the role of cumulative doses of anthracyclines 
and trastuzumab relative to the development of cardiac dysfunction. The severity of these events 
was categorized using the New York Heart Association functional classification system. The 


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incidence of class III or IV cardiac dysfunction was 2% for those receiving first-line trastuzumab, 
4% for those receiving trastuzumab in the refractory setting, 2% for those receiving concurrent 
paclitaxel plus trastuzumab, 1% for those receiving paclitaxel alone, 16% for those receiving 
concurrent AC and trastuzumab, and 4% for those receiving AC alone. The incidence and 
severity of cardiac dysfunction was greatest among patients receiving concurrent AC and 
trastuzumab. The risk of cardiac toxicity was lower in those receiving concurrent paclitaxel and 
trastuzumab or paclitaxel alone, despite prior anthracycline exposure in most of these patients. 
The four large adjuvant trials have shown that the incidence of cardiac toxicity attributable to 
treatment with anthracycline-taxane based regimen followed by trastuzumab is acceptable with 
rates of congestive heart failure below 4% and very rare cardiac deaths.13, 16, 21-24 
 
Given the superiority of dose-dense AC-T over conventionally scheduled AC-T in terms of DFS 
and OS, and the benefit and safety of trastuzumab with conventionally scheduled AC-T, our group 
examined the feasibility of dose-dense AC followed by T and trastuzumab in HER2-amplified 
breast cancer. The primary end point of the study was cardiac safety. In our study, the addition 
of trastuzumab to dose-dense AC-T was well tolerated with only 1/70 patients (1.4%) 
experiencing symptomatic LVEF decline with congestive heart failure; there were no cardiac 
deaths.25 
 
Lapatinib 
 
Having shown the safety of dose-dense AC-T plus trastuzumab, our attention turned to further 
improving adjuvant regimens and their outcomes for patients with HER2-overexpressing breast 
cancer.  Lapatinib, a dual inhibitor of epidermal growth factor and HER2/neu kinase activity has 
demonstrated activity as a single agent, combined with trastuzumab, as well as with capecitabine 
in patients with progression after prior anthracycline, taxane, and trastuzumab therapy.26-28   This 
motivated the inclusion of lapatinib into adjuvant regimens including the large multicenter phase III 
ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial. We conducted a 
phase II study to establish safety data for one arm of ALTTO: dose-dense AC followed by 
paclitaxel, weekly trastuzumab, and lapatinib, followed by trastuzumab and lapatinib. The dose of 
lapatinib selected was 1,000 mg daily based on phase I studies that established the feasibility of 
the combination of trastuzumab and lapatinib (EGF10023) and weekly paclitaxel and lapatinib 
(EGF10009/EGF105764).27, 29 
 
Our phase II study of dose-dense AC followed by paclitaxel, trastuzumab, and lapatinib (THL) 
followed by trastuzumab, lapatinib was not feasible at a lapatinib dose of 1000 mg given 
excessive diarrhea.  Diarrhea was experienced by 84 (88%) patients and 27 (29%) patients had 
grade 3 diarrhea. The study was closed early as 43% of patients required a lapatinib dose 
reduction due to grade 3 or unacceptable grade 2 or less diarrhea.30   Two trials with similar 
designs demonstrated high rates of diarrhea for the combination of weekly paclitaxel, 
trastuzumab, and lapatinib dosed at 1,000 mg daily.  Johnson and colleagues reporting the Mayo 
Clinic experience found that 43% of patients had grade 3 or greater diarrhea.31   The neoadjuvant 
CHERLOB (Chemotherapy Plus Trastuzumab, Lapatinib, or Both in HER2-Positive Operable 
Breast Cancer) reports 41% of patients experienced grade 3 or greater diarrhea in the arm 
receiving weekly paclitaxel, trastuzumab, and lapatinib.32Institution of proactive diarrhea 
management in our study could explain the lower rate of grade 3 diarrhea reported in our phase II 
study. 


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Diarrhea 
 
Diarrhea is a known side-effect of lapatinib therapy; a pooled analysis of eleven studies with 
lapatinib monotherapy or in combination with capecitabine or taxanes demonstrated a less than 
10% rate of grade 3 or 4 diarrhea. Diarrhea rates in the two phase I studies examining 
combination lapatinib with taxane therapy were higher than that for lapatinib monotherapy. In 
EGF10009 (lapatinib 1,250 or 1,500 mg with paclitaxel at 135 to 225 mg/m2 every 3 weeks or 80 
mg/m2 weekly) and in EGF10021 (lapatinib 1,000 or 1,500 mg with docetaxel at 50 to 75 mg/m2 
every 3 weeks) incidence of all grade diarrhea were 82% and 71%, respectively.33 
Pharmacokinetic studies for EGF10009 demonstrated a greater than 20% increase in systemic 
exposure for both lapatinib and paclitaxel when paclitaxel was administered every three weeks. 
Diarrhea rates were higher for patients who received lapatinib with weekly paclitaxel than those 
on every three week paclitaxel, 50% versus 7%, respectively.29 
 
There are several possible explanations for the excessive diarrhea seen in our phase II safety trial 
of dose-dense AC followed by paclitaxel, trastuzumab, lapatinib, followed by trastuzumab and 
paclitaxel.  First, paclitaxel, trastuzumab, and lapatinib can all individually lead to diarrhea 
although this is usually grade 1 or 2.34-36   Second, paclitaxel therapy may affect the intestinal crypt 
cells and lead to a loss of absorption leading to worsening diarrhea with lapatinib and trastuzumab 
therapy.37   Third, the schedule of paclitaxel administration influences diarrhea rates. There is a 
higher incidence of grade 3 diarrhea reported with weekly than every three week paclitaxel 
administration.35   Examination of every two week versus every three week dosing of paclitaxel 
(CALGB 9741) showed no significant difference in diarrhea rates.5   The findings of our phase II 
safety trial of dose-dense AC followed by paclitaxel, trastuzumab and lapatinib followed by 
trastuzumab and lapatinib influenced the design of the ALTTO trial. The dose of lapatinib was 
adjusted from 1000 mg to 750 mg daily when combined with paclitaxel and lapatinib. In terms of 
cardiac toxicity, three patients (3%) had symptomatic congestive heart failure and there were no 
cardiac deaths on study.30   The rate of cardiac toxicity is similar to the Mayo Clinic experience 
with paclitaxel, trastuzumab, and lapatinib.31   A recent review of the cardiac safety data from 
3,689 patients on lapatinib determined a symptomatic CHF rate of 0.2% and an asymptomatic 
cardiac event rate of 1.4%.38   Although our study reported higher rates of cardiac toxicity, this may 
be explained by enhanced cardiac toxicity with concurrent administration of lapatinib and 
trastuzumab. In support of this hypothesis, the phase III study comparing lapatinib and 
trastuzumab with lapatinib monotherapy, more cardiac events were reported for combination 
illustrating the potential of greater cardiac toxicity for lapatinib and trastuzumab in combination.39 
 
Adjuvant Therapy for Node Negative HER2 Positive Patients 
 
There is much less data on the treatment of patients with node-negative HER2-positive breast 
cancer than those with node-positive disease. We have recently completed accrual of a single- 
arm phase II efficacy trial designed to evaluate the role of 12 doses of adjuvant weekly paclitaxel 
and trastuzumab followed by trastuzumab monotherapy for an additional 40 weeks in about 400 
patients with node-negative HER2-positive breast cancers measuring < 3cm. The DFS and OS 
outcomes of this study are forthcoming. There are now data showing that dual anti-HER2 therapy 
is more effective than single anti-HER2 treatment. In the metastatic setting, Blackwell et al 
showed that in a heavily pre-treated population, lapatinib combined with trastuzumab led to a 
improvement in progression-free survival over just lapatinib alone.39   In the neoadjuvant setting, 
the Neo-ALTTO trial showed that the pathologic complete response (pCR) rate was higher in the 


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group that received THL (51.3%) at the time of surgery when compared to those who received TH 
(29.5%) or TL (24.7%).40 One of the major side effects was a higher grade > 3 diarrhea in those 
receiving lapatinib containing arms, with 23% in TL arm and 21% in THL group, but only 2 % in 
TH arm. Of note, paclitaxel in this study was given weekly and the diarrhea toxicity data is 
consistent with our findings when weekly paclitaxel is used with lapatinib and trastuzumab.30 
However, the DFS and OS results for both Neo-ALTTO and ALTTO are pending. 
 
 
It is possible that dual anti-HER2 therapy (ie: THL) may lead to improved DFS and/or OS over 
time. However, the limitation with the THL combination with weekly paclitaxel is the occurrence of 
significant > G 3 diarrhea. Thus, it is important to establish an optimal THL schedule with a 
different paclitaxel schedule (dose-dense) and study it in a lower risk, node negative population. 
 
Pharmacogenomics Studies of Drug Toxicity 
 
Chemotherapy associated toxicity differs greatly between patients. Genetic variation may 
contribute to the differences in severity and frequency with which chemotherapy associated 
toxicities occur.  A genetic polymorphism is defined as a minor allelic variant present in >1% of 
the population.41 Genetic polymorphisms can occur as single nucleotide polymorphism in coding, 
non-coding and promoter regions, deletions, insertions, or gene copy number variant, all of which 
can result in altered functional pharmacokinetic and pharmacodynamic activity of the affected 
protein.42   Functional polymorphisms resulting in altered drug metabolism of chemotherapeutic 
agents have been identified and may contribute to the variability of toxicities observed. Table 1 
lists the candidate genes and the partial rationale for inclusion in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1. Candidate SNPs for Toxicity Association Assessment 
 
 
Gene 
Polymorphism 
Allele 
Freq43 
Partial Rationale For Inclusion 


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CYP2C8 
*2, rs11572103 
0.16 
Result in lower metabolism of paclitaxel44-48 
CYP2C19 
*2, rs4244285 
0.20 
Leads to “slow metabolizer” phenotype49-51 
CYP3A4 
*1B, rs2740574 
0.22 
Involved in taxane metabolism/clearance52-55 
CYP3A5 
*3, rs776746 
0.34 
Results in a splicing defect that reduces CYP enzyme 
activity56-57 
ABCG2 
421(C>A) rs2231142 
0.14 
Gastrointestinal toxicity with TKI 58-59 
ABCB1 
3435 (C>T) rs1045642 
0.39 
Multi-Drug resistance transporter60 
1236 (C>T) rs1128503 
0.41 
2677(G>T/A) 
rs2032582 
0.34 
 
 
Polymorphisms in ATP-binding cassette (ABC) transporters have been shown to result in altered 
toxicity in those receiving tyrosine-kinase inhibitors (TKI) and taxanes.  ATP-binding cassette 
transporter B1 (ABCB1, Multidrug resistance-1) polymorphism may change the function of P- 
glycoprotein, by which taxanes can be extruded through the cell membranes. The prevalence 
and severity of mucosal inflammation and dermatologic toxicity has been shown to be higher in 
patients with variant haplotypes of ABCB1 efflux transporter genes receiving tyrosine kinase 
inhibitors. The ABCB1 haplotype P-gp*2 includes 3435(C>T), 1236(C>T), 2677(G>T/A); and has 
been associated with grade 3 diarrhea in those treated with taxanes.60 Another relevant 
polymorphism for this study is ABCG2 at position 421(C>A), which has been associated with 
diarrhea in those treated with TKIs.59 
 
Functional polymorphism in genes encoding for the enzymes responsible for paclitaxel and 
lapatinib metabolism have also been identified within the hepatic CYP450 family.  For instance, 
paclitaxel is converted to p-3′-hydroxypaclitaxel by CYP3A4 and CYP2C8 catalyzes the formation 
of 6  -hydroxypaclitaxel.62   We will evaluate these and other CYP genes involved in paclitaxel and 
lapatinib metabolism including CYP2C19 and CYP3A5 for the presence of previously identified 
polymorphisms. 
 
Determining of the extent to which functional polymorphism in drug metabolism results in altered 
toxicity has the potential to be applicable in multiple regimens and malignancies and in the future 
may allow us to identify a sub-population that is at increased for toxicity, thus helping to inform 
treatment decisions. 
 
Cardiac Biomarkers 
Cardiac toxicity is a potentially grave toxicity of certain cytotoxic chemotherapy agents, particularly 
the anthracycline drugs. In the adjuvant setting where cure is the goal, potential long- term cardiac 
sequelae of treatment are particularly relevant.  Early detection of evolving cardiac damage and 
the institution of medical management may help to decrease the morbidity associated with cardiac 
toxicity.  The use of angiotensin converting enzyme (ACE) inhibitors has been shown in studies to 
reduce the risk of developing symptomatic heart failure or cardiac death in patients with 
asymptomatic left ventricular dysfunction.62 Research has focused on the development and 
validation of cardiac biomarkers that might identify subclinical cardiac damage 


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and patients who may benefit from cardioprotective measures.  Preliminary data suggests that the 
use of ACE inhibitors may prevent cardiac toxicity in patients receiving high-dose chemotherapy 
identified as increased risk on the basis of cardiac biomarkers.63 To date, the majority of 
experience with cardiac biomarkers has been in the setting of anthracycline chemotherapy.64 
 
 
Cardiac Troponins 
The incidence of elevation of cardiac troponins I or T (cTnI or cTnT) with each chemotherapy cycle 
may be as high as 30-34% in patients treated with potentially cardiotoxic (primarily anthracycline) 
chemotherapy across studies. The etiology of the troponin rise appears to be non- ischemic as it is 
not associated with symptoms or classical EKG changes, and it predates LV dysfunction rather 
than accompanying it. Troponin determination in breast cancer patients has been found to predict 
the occurrence of clinically significant LV dysfunction as well as the degree and severity of future 
LV dysfunction. Cardinale and colleagues studied 211 patients receiving high dose therapy for 
breast cancer (mean age 46) using cardiac troponin I (cTnI) measurements at six time points 
before and after each chemotherapy cycle (up to 72 hours after) and correlated these to ECHO 
findings at 1,2,3,4,7 and 12 months.65 A close relationship was found between the maximal cTnI 
value obtained and maximum LVEF decrement seen in follow up. In addition, there was a 
significant correlation between the number of positive cTnI values and the LVEF maximal 
decrement. The presence of normal cTnI levels after therapy was associated with no significant 
decline in LVEF in follow-up. A study in 79 patients with leukemia measured cTnI at various 
intervals during induction therapy, and found elevated cTnI levels at day 7-14 correlated with 
reversible decreases in LVEF.66 Reports of smaller patient cohorts ranging from 15 to 31 patients 
showed more variable levels of cTnI detection after anthracycline therapy.67-69 There are now 
emerging data on the utility of cardiac biomarkers in patients treated with anti-HER2 agents after 
an anthracycline based treatment, and the data are mixed. 70-71At MSKCC, we recently showed 
that 67% of patients had an elevated cTNI during the THL phase (after dd AC) but these patients 
were asymptomatic. This may reflect a subtle cardiac injury related to the treatment.70 Cardinale 
et al, on the other hand, reported in their group of patients, treated with trastuzumab after an 
anthracycline-based treatment, that those with elevated TNIs are at risk for trastuzumab induced 
cardiac toxicity.71 
 
 
B-type natriuretic peptide (BNP) 
Natriuretic peptides are rapidly produced by the heart in response to hemodynamic stress.  Both 
BNP and NT-proBNP are widely tested in heart failure as markers of heart failure diagnosis, 
prognosis, and overall risk assessment.64 Several studies examined BNP levels at prolonged 
intervals from chemotherapy. A Dutch study evaluated BNP and NT-BNP levels at two time points 
after anthracycline chemotherapy: a median of 2.7 years later, and a median of 6.5 years 
afterwards.72   Elevated BNP levels were found in 14 out of 54 patients 6.5 years after 
chemotherapy. The BNP levels were significantly higher in patients receiving 450 mg/m2 
epirubicin than those who received 360 mg/m2. Cardiac function was not assessed. However, a 
similar study evaluating BNP levels in 63 patients at least 1 year from anthracycline therapy found 
cardiac dysfunction in 41% and significantly higher mean BNPs in this group.73 Similar results of 
elevated BNP levels in association with reduced left ventricular function have been documented in 
the pediatric literature after anthracycline exposure. 
 
 
 
Cardiac biomarkers with trastuzumab 


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Limited data exist regarding the use of cardiac biomarkers as predictors of cardiac toxicity in 
patients treated with trastuzumab. Plasma cTnI and NT-proBNP levels were assayed in 15 
patients taking part in a study of an imaging modality (indium-111 labeled trastuzumab 
scintigraphy) as a predictor of cardiac toxicity.74 Patients received trastuzumab as part of a non- 
anthracycline containing regimen. While the imaging test was not shown to be of value, pre- 
treatment plasma NT-proBNP levels were found to be higher in patients who developed cardiac 
toxicity. A pilot study examined and established novel measures of metabolic and vascular risk 
factors for cardiovascular disease (including BNP) in a small subset of patients participating in the 
BCIRG 006 adjuvant trastuzumab study.75 Patients entered the study a median of 20 months after 
the completion of chemotherapy and trastuzumab.  In this study, 38.4% of patients had an LVEF 
value 10% or more below their baseline assessment; BNP was significantly elevated in 40% of 
patients and was a predictor of LVEF on univariate analysis. In N9831, an adjuvant study of 
anthracycline and taxane-based chemotherapy with trastuzumab vs chemotherapy alone, a study 
correlating cardiac biomarkers including BNP, C-reactive peptide (CRP), and troponin T and I with 
LVEF was conducted.  Elevations in BNP and cTnI at baseline and doubling of BNP during trial 
were seen as possibly predictive of cardiac toxicity in a small subset of patients.76 
 
Neuregulin 
Neuregulin-1 (NRG-1) is a cardioprotective, paracrine growth factor released by microvascular 
endothelial cells.  This pathway, which is necessary for the maintenance of cardiac function and 
survival during states of increased stress, is believed to be an important mediator of heart failure 
and chemotherapy-induced cardiac dysfunction.77  In vitro studies demonstrate that NRG-1 
administration protects doxorubicin-treated cardiomyocytes from myofibrillar disarray and death, 
and NRG-1 or ErbB2 deficient mice have dramatically worse survival with anthracycline 
exposure.78-80 Trastuzumab, and pertuzumab, specifically target the ErbB2 receptor, a mediator of 
NRG-1 activity, and its association with clinical cardiac dysfunction may be related to effects on 
this signaling pathway.80 
 
In order to define the mechanistic and translational significance of NRG-1 signaling in humans, Ky 
and colleagues recently quantified serum NRG-1ß levels in a large cohort (N=899) of patients with 
chronic heart failure in the Penn Heart Failure Study.81 Elevated NRG-1ß levels were significantly 
associated with more advanced heart failure (NYHA Class IV median 6.2 ng/ml versus those with 
Class I CHF 4.4 ng/ml, p=0.002). Furthermore, NRG-1ß was independently associated with an 
elevated risk of all-cause death or cardiac transplantation over a median follow-up of 2.4 years 
(adjusted HR 1.58, 95% C.I of 1.04-2.3, p=0.003), comparing the 4th vs the 1st quartile of NRG-1ß. 
Associations differed according to heart failure cause and severity, with stronger relationships 
observed in those with ischemic heart failure (interaction p=0.008) and advanced NYHA Class 
III/IV symptoms (interaction p=0.01).  In addition, patients with chemotherapy-induced cardiac 
dysfunction had significant alterations in their circulating NRG-1 ß levels compared to all other 
etiologies (p=0.02). 
 
Our goal is to extend these findings and provide further insight of the potential clinical relevance 
of cTnI, BNP and NRG-1ß  on chemotherapy-induced cardiac dysfunction. We will quantify the 
relationship of these cardiac biomarkers with incident cardiac dysfunction by serial 
echocardiogram imaging. We hope to develop an understanding of the predictive utility of these 
biomarkers. 


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As of A(6), we will no longer be quantifying the relationship between NRG-1ß cardiac biomarkers 
and incident cardiac dysfunction by serial echocardiogram imaging since the incidence of cardiac 
dysfunction based on the LVEF data has been minimal. 
 
Echocardiograms (and Strain Imaging Analysis for research purposes): 
 
Echocardiograms will be performed at months 2, 6, 9, 12 and 18 of treatment as defined in the 
study.  Strain imaging will be analyzed off-line using 2D image loops from the routine 
echocardiographic examination. The ECHO machine for the strain imaging analysis should be 
the Vivid 7 or E9 machine (GE healthcare, Milwaukee, WI). In addition to being stored in the main 
ECHO PACS system, these studies will also be stored in an external GE workstation which 
contains the software needed to perform the strain imaging analysis. To calculate strain and strain 
rate, the LV myocardium is traced in a click-to-point approach.  Subsequently, the software 
automatically defines an epicardial and myocardial line and processes all frames of the loop. The 
myocardium in each of the 3 standard apical views is divided into 6 segments.  The software will 
automatically calculate strain and strain rate for each of the 18 segments plus a global value for 
the entire myocardium. These measurements will be made by a designated investigator (Dr. 
Jennifer Liu) blinded to patient identification, demographics and clinical characteristics at the end 
of the study. When possible any ECHOs done outside of MSKCC are requested to be done on 
the GE Vivid 7 or E9 machine (GE healthcare, Milwaukee, WI),  and the disc to be sent to Dr. 
Jennifer Liu for the strain imaging analysis. 
 
Rationale 
 
With great advances made with chemotherapy combinations in breast cancer outcomes and 
trastuzumab in HER2-positive breast cancer cells, there is always room for improvement.  Most 
patients enrolled onto clinical trials for the treatment of HER2-positive breast cancer had node- 
positive disease, and the majority received an anthracycline and taxane-based treatment with 
trastuzumab. This led to a significant improvement in DFS and OS with an acceptable 2-4% risk 
of cardiac events. The optimal treatment for a lower risk group, such as those with node-negative 
HER2-positive disease, needs to be studied further. With emerging data demonstrating better 
outcomes with dual anti-HER2 therapy in metastatic breast cancer and improved pCR rates in the 
neoadjuvant setting ,39, 40 it is important to study a dual anti-HER2 treatment with a taxane in this 
lower risk group, but omit the anthracycline (such as AC) to avoid the added risk of cardiac 
toxicity. 
 
Lapatinib is one of the most exciting targeted drugs and the simultaneous inhibition of HER2 with 
lapatinib and trastuzumab has shown to be effective in the metastatic setting39 and may allow for 
more potent inhibition of cell growth than one line of anti-HER2 therapy.  Previous studies showed 
that the rate of G 3 diarrhea was only 7 % when lapatinib (1250-1500mg) was given with 
paclitaxel (135-225 mg/m2) every 3 weeks, but it was 50% when given with weekly paclitaxel  (80 
m/m2).39 Citron et al showed that the incidence of G 3 diarrhea was extremely low at 2 % versus 
1% with paclitaxel (175 mg/m2) given every 3 versus 2 weeks (dose dense), respectively.5   It 
remains unanswered if lapatinib at 1,000 mg with trastuzumab, as established by Storniolo27, can 
be better administered with dose-dense paclitaxel as part of adjuvant therapy for early HER2- 
amplified breast cancer.  Based on previous data, we hypothesize that dose-dense paclitaxel may 
be better tolerated when combined with lapatinib (1000 mg) and trastuzumab. 


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We seek to address this in a phase II trial of adjuvant chemotherapy with dose-dense paclitaxel 
every two weeks with weekly trastuzumab and daily lapatinib (1,000 mg) followed by the 
completion of a year of trastuzumab (administered every three weeks) and lapatinib therapy. We 
choose paclitaxel every two weeks as it is may be the more optimal taxane schedule to combine 
with a full dose of lapatinib (1000 mg) and trastuzumab, with possibly a lower diarrhea toxicity risk 
than what has been reported with weekly paclitaxel.  However, we may still uncover significant 
G3-4 diarrhea with this new THL combination. There may be an interaction between paclitaxel 
and lapatinib and both drugs are metabolized by CYP3A4, CYP3A5, and CYP2C8, and lapatinib 
is additionally metabolized by CYP2C19.  Toxicities of these 2 drugs may also be influenced by 
variants of drug transporter genes, such as ABCB1 and ABCG2. Thus, we will perform 
exploratory analyses on allele frequencies of these candidate genes. 
 
Since the incidence of G3-4 cardiac events of a previous adjuvant taxane and trastuzumab study 
(BCIRG 006)16 was reported as < 1%, we anticipate that we will observe a low cardiac event 
(symptomatic CHF or cardiac death) rate with this study regimen as an anthracycline is omitted. 
However, it is still unknown the long-term cardiac event rate as well as the implication of 
asymptomatic LVEF declines over time. Thus, it will be important to explore cardiac biomarkers 
and correlate them with LVEF declines (both symptomatic and significant asymptomatic drops as 
defined by our study). Thus, as a correlative study we will evaluate potential cardiac biomarkers 
(cardiac troponin I, and B-type natriuretic peptide (BNP)) to assess if there is a correlation 
between elevated markers and decline in left ventricular ejection fraction (LVEF) on 
echocardiogram (ECHO) imaging.  Additionally, for research purposes cardiac strain imaging will 
be done with each ECHO when possible. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a phase II trial of dose-dense adjuvant chemotherapy for patients with node-negativeHER- 
2/neu overexpressed/amplified breast cancer. The regimen consists of paclitaxel (T) at 175 
mg/m2 q 2 weeks x 4 with filgrastim/pegfilgrastim + trastuzumab (H) + daily oral lapatinib (L), 
followed by trastuzumab q 3 weeks x 15 doses + daily oral lapatinib (HL). Pegfilgrastim 6mg will 
be given subcutaneously (SQ) on day # 2 of each paclitaxel administration.  Filgrastim may be 
used in lieu of pegfilgrastim at the physician’s discretion. Trastuzumab will be administered 
weekly (4 mg/kg bolus followed by 2 mg/kg weekly) starting with paclitaxel treatment cycle # 1. 
After completion of 4 cycles of paclitaxel, patients will receive trastuzumab on a q 3 weeks x 15 
doses (to complete about one year). The q 3 week trastuzumab may be started at the last dose 
of paclitaxel infusion or from 1-3 weeks after the last dose of paclitaxel. A total of 15 infusions of 
trastuzumab will be given q 3 weeks after the completion of paclitaxel during the HL phase. 
Lapatinib will be given orally at 1000 mg daily, starting with paclitaxel during the THL phase and 
continued for the remaining year during the HL phase for about a year. 
 
We plan to accrue 55 evaluable patients with HER2-amplified breast cancer to this trial within 12 
months.  Endpoints for removal from the study are unacceptable toxicity, progression of disease 
while of study drugs, death, and patient withdrawal from study. 
 
One sample of blood (10 ml in EDTA) will be collected for pharmacogenomics analysis. This may 
be done at any point during the study regimen, but preferably at the beginning of the treatment. 


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Cardiac biomarkers (troponin I, B-type natriuretic peptide, neuregulin-1ß) will be serially followed 
throughout the study period.  Baseline values will be obtained and biomarker testing will occur 
pre- and post-infusion of each paclitaxel and trastuzumab administration every 2 weeks x 4 
(during THL phase).  Biomarkers will then be drawn pre- and post- infusion of trastuzumab at 
every other cycle (approximately every 6 weeks) x 7 draws (during HL phase). 
 
Echocardiograms (with strain) and EKGs will be obtained at baseline and at months 2, 6, 9, 12, 
18 (+/- 4 weeks) following the start of chemotherapy. 
 
4.2 
Intervention 
 
T (175mg/m2) q 2 week x 4 + trastuzumab + lapatinib (THL) → HL 
 
↑ECHO/EKG 
↑ECHO/EKG 
↑ECHO/EKG 
 
(0 mo) 
(2 mo) 
(6 mo, 9 mo, 12 mo,18mo) 
 
↑Bloods for pharmacogenetic analysis 
 
(0 mo) 
 
Bloods for cardiac biomarkers will be collected pre-and post- each paclitaxel/trastuzumab infusion 
(q 2 weeks) X 4, then every other cycle (q 6 weeks) during trastuxumab monotherapy X 7. 
 
This is a phase II study of lapatinib in combination with trastuzumab and paclitaxel for the 
treatment of patients with early-stage node negative HER2 (+) breast cancer.  Based on 
promising results of the combination of lapatinib and trastuzumab in a metastatic population and 
better responses seen in the neoadjuvant setting39-40 it makes sense to test this combination with 
paclitaxel given in a dose-dense every 2 week regimen in the treatment of patients with low-risk 
node negative HER2-positive breast cancer. With the superiority of every 2 week over every 3 
week schedule of paclitaxel5, 8 and since there are less toxicities seen with every 3 week 
paclitaxel than weekly paclitaxel,29 it is worthwhile to combine dose-dense every 2 week paclitaxel 
with trastuzumab and lapatinib. 
 
The regimen will consist of paclitaxel (175 mg/m2) every 2 weeks x 4 + trastuzumab weekly (4 
mg/kg loading dose → 2 mg/kg ) both given intravenously (IV) + lapatinib 1000mg orally daily. 
After the completion of paclitaxel, trastuzumab (6 mg/kg IV q 3 weeks) x 15 and lapatinib (1000 
mg daily) will be given to complete the year’s duration.  Pegfilgrastim SQ is given on day # 2 of 
each paclitaxel cycle and may be dropped at the last paclitaxel infusion. Filgrastim may be used 
in lieu of pegfilgrastim at the physician’s discretion. 
 
 
 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Paclitaxel (Taxol®) 
 
 
a.  Dosage 


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Paclitaxel is an antimicrotubule agent that promotes microtubule assembly and stabilizes 
tubulin polymers by preventing their depolarization, resulting in the formation of extremely 
stable and nonfunctional microtubules, and consequently inhibition of many cell functions. 
The dose of paclitaxel is 175 mg/m2 IV every 2 weeks. 
 
Paclitaxel is commercially available. 
b.  Preparation 
Paclitaxel will be prepared as per MSKCC chemotherapy guidelines (MSKCC and 
affiliates). 
 
c.   Administration 
 
Treatment may be administered in an outpatient setting by administration of 175 mg/m2 IV 
every 2 weeks. If paclitaxel is being administered concomitantly with trastuzumab, 
chemotherapy administration may be given before or after either antibody.  A strict 
sequence of administration of paclitaxel relative to trastuzumab is not mandated.  Patients 
should be observed for fever and chills or other infusion associated symptoms. 
 
d.  Storage 
 
Unopened vials of paclitaxel are stable until the date as indicated on the package.  Vials of 
paclitaxel should be stored at 20-25º C (68-77º F) in the original package. Neither 
freezing nor refrigeration adversely affects the stability of the product.  Upon refrigeration, 
components of paclitaxel may precipitate but will re-dissolve upon reaching room 
temperature with little or no agitation. 
 
e.  Safety 
 
Side-effects include myelosuppression, hypersensitivity (hypotension, flushing, chest pain, 
abdominal or extremity pain, skin reactions, pruritus, dyspnea, bronchospasm, and 
tachycardia), sinus bradycardia, complete heart block, sinus tachycardia, premature 
ventricular beats, ventricular tachycardia, bigeminy, syncope, myocardial infarction, 
hypotension, hypertension, peripheral neuropathy, taste changes, arthralgia, myalgia, 
seizures, mood alterations, neuro-encephalopathy, motor neuropathy, autonomic 
neuropathy, alopecia, radiation recall dermatitis, nausea, vomiting, diarrhea, stomatitis, 
mucositis, pharyngitis, typhlitis, ischemic colitis, pancreatitis, elevated liver function, 
hepatic failure, fatigue, headache, light-headedness, elevated creatinine, elevated 
triglyceride, and blurred vision. 
 
 
 
Trastuzumab (Herceptin
®) 
 
a.  Dosage 
 
The recommended initial loading dose is 4 mg/kg (for weekly dosing schedules) or 8 
mg/kg (for every 3 weeks) Herceptin administered as a 90-minute infusion. The 
recommended maintenance Herceptin dose is 2 mg/kg weekly or 6 mg/kg every 3 weeks 
and can be administered as a 30-minute infusion if the initial loading dose was well 


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tolerated.  Herceptin may be administered in an outpatient setting.  DO NOT ADMINISTER 
AS AN IV PUSH OR BOLUS (see ADMINISTRATION). 
 
b.  Preparation 
 
Use appropriate aseptic technique.  Each vial of Herceptin should be reconstituted with 20 
mL of BWFI, USP, 1.1% benzyl alcohol preserved, as supplied, to yield a multidose 
solution containing 21 mg/mL Herceptin. 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. 
 
Determine the dose of Herceptin needed.  Calculate the correct dose using 21 mg/mL 
Herceptin solution. Withdraw this amount from the vial and add it to an infusion bag 
containing 250 mL of 0.9% sodium chloride, 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. 
 
c.   Administration 
 
Treatment may be administered in an outpatient setting by administration of a 4 mg/kg 
Herceptin loading dose for weekly dosing schedules (OR 8 mg/kg Herceptin loading dose 
for q3wk dosing schedules) by intravenous (IV) infusion over 90 minutes. DO NOT 
ADMINISTER AS AN IV PUSH OR BOLUS.  If Herceptin is being administered 
concomitantly with chemotherapy, Herceptin administration may be given before or after 
chemotherapy administration.  Patients should be observed for fever and chills or other 
infusion associated symptoms (see ADVERSE REACTIONS). If prior infusions are well 
tolerated subsequent doses of 2 mg/kg Herceptin weekly (OR 6 mg/kg Herceptin q3wk) 
may be administered over 30 minutes. 
 
Herceptin should not be mixed or diluted with other drugs.  Herceptin infusions should not 
be administered or mixed with Dextrose solutions. 
 
d.  Storage 
 
Vials of Herceptin are stable at 2C–8C (36F–46F) prior to reconstitution.  Do not use 
beyond the expiration date stamped on the vial.  A vial of Herceptin reconstituted with 
BWFI, as supplied, is stable for 28 days after reconstitution when stored refrigerated at 
2C–8C (36F–46F), and the solution is preserved for multiple use. Discard any 
remaining multi-dose reconstituted solution after 28 days.  If unpreserved SWFI (not 
supplied) is used, the reconstituted Herceptin solution should be used immediately and 


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any unused portion must be discarded. DO NOT FREEZE HERCEPTIN THAT HAS 
BEEN RECONSTITUTED. 
 
The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags 
containing 0.9% sodium chloride for injection, USP, may be stored at 2C–8C (36F– 
46F) for up to 24 hours prior to use.  Diluted Herceptin has been shown to be stable for 
up to 24 hours at room temperature 15C–25C; however, since diluted Herceptin contains 
no effective preservative the reconstituted and diluted solution should be stored 
refrigerated (2C–8C). 
 
e.  Safety 
 
Infusion-Associated Symptoms. During the first infusion with Herceptin, a symptom 
complex consisting of chills and/or fever is observed in approximately 40% of patients. 
Other signs and/or symptoms may include nausea, vomiting, pain, rigors, headache, 
cough, dizziness, rash, and asthenia. These symptoms are usually mild to moderate in 
severity, and occur infrequently with subsequent Herceptin infusions. These symptoms 
can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an 
antihistamine such as diphenhydramine. 
 
Serious Infusion-Associated Events. Serious adverse reactions to Herceptin infusion 
including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation and respiratory distress have been reported infrequently.   In rare cases (4 per 
10,000), these events were associated with a clinical course culminating in a fatal 
outcome. Serious reactions have been treated with supportive therapy such as oxygen, 
beta-agonists, corticosteroids and withdrawal of Herceptin as indicated. 
 
Hematologic Toxicity.  In the clinical trials, an increased incidence of anemia was observed 
in patients receiving Herceptin plus chemotherapy compared with patients receiving 
chemotherapy alone.  The majority of these anemia events were mild or moderate in 
intensity and reversible; none resulted in discontinuation of Herceptin therapy. In the 
clinical trials, the per-patient incidences of moderate to severe neutropenia and of febrile 
neutropenia were higher in patients receiving Herceptin in combination with 
myelosuppressive chemotherapy as compared to those who received chemotherapy 
alone.  In the post marketing setting, deaths due to sepsis in patients with severe 
neutropenia have been reported in patients receiving Herceptin and myelosuppressive 
chemotherapy, although in controlled clinical trials (pre- and post-marketing), the 
incidence of septic deaths was not significantly increased. The pathophysiologic basis for 
exacerbation of neutropenia has not been determined; the effect of Herceptin on the 
pharmacokinetics of chemotherapeutic agents has not been fully evaluated. The observed 
incidence of leukemia among Herceptin-treated patients appears to be consistent with the 
expected incidence of leukemia among patients treated with chemotherapy for metastatic 
breast cancer. Therefore, the contribution of Herceptin to the etiology of acute leukemia 
or myelodysplastic syndrome in these cases is unclear. 
 
Lapatinib Ditosylate (Tykerb®) 
 
a.  Dosage 


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Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 
tyrosine kinases. Lapatinib is supplied as 250 mg oval, biconvex, orange film-coated tablets 
with one side plain and the opposite side de-bossed 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. 
 
The dosage for this study is 1000 mg orally daily. 
Lapatinib is commercially available. 
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). 
 
b.  Administration 
 
Lapatinib 1000 mg is taken orally on an empty stomach (either 1 hour before or 1 hour after 
meals). 
 
c.   Storage 
 
The intact bottles should be stored at controlled room temperature (15°C-30°C).  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). 
 
d.  Safety (See Treatment/Intervention Section 9.0 below for details regarding management 
of toxicity) 
 
Cardiotoxicity. Decreases in left ventricular ejection fraction (LVEF) have been reported 
(usually within the first 3 months of treatment); baseline and periodic LVEF evaluations are 
recommended. Interrupt therapy or decrease dose with decreased LVEF ≥ grade 2 or 
LVEF < LLN. Use with caution in conditions which may impair left ventricular function and 
in patients with a history of or predisposed (prior treatment with anthracyclines, chest wall 
irradiation) to left ventricular dysfunction. Interruption of therapy is recommended with 
decreased LVEF ≥ grade 2. 
 
Diarrhea. Diarrhea is common, may be severe. Management with antidiarrheal agents is 
recommended and severe diarrhea may require hydration, electrolytes, dose reduction or 
interruption of therapy. 
 
Hepatotoxicity. [U.S. Boxed Warning]: Hepatotoxicity (ALT or AST >3 times ULN and total 
bilirubin >2 times ULN) has been reported with lapatinib and may be severe and/or fatal. 
Onset may occur within days to several months after treatment initiation. Monitoring liver 


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function is recommended (at baseline and during treatment); with permanent 
discontinuation recommended with severe changes in liver function during treatment. 
Caution is advised in patients with hepatic impairment. 
 
Pulmonary toxicity. Interstitial lung disease (ILD) and pneumonitis have been reported with 
lapatinib monotherapy and combination chemotherapy.  Monitoring for pulmonary 
symptoms which may indicate ILD or pneumonitis is recommended.  Discontinuation of 
therapy is recommended for grade 3 (or higher) pulmonary symptoms indicative of ILD or 
pneumonitis. 
 
QTc prolongation. QTc prolongation has been observed. Caution is advised in patients with 
a history of QTc prolongation or with medications known to prolong the QT interval. 
Baseline and periodic 12-lead ECG are recommended. 
 
Concurrent drug therapy issues: 
 
High potential for interactions. Avoid use with strong CYP3A4 inhibitors or inducers. 
 
QTc-prolonging agents. Concurrent use with other drugs which may prolong QTc interval 
may increase the risk of potentially-fatal arrhythmias. 
 
Pegfilgrastim (Neulasta) 
 
Pegfilgrastim (Neulasta is a covalent conjugate of recombinant methionyl human G-CSF 
(Filgrastim) and monomethoxypolyethylene glycol.  Both pegfilgrastim and filgrastim are colony- 
stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors 
thereby stimulating proliferation, differentiation, commitment, and end cell functional activation. 
Studies on cellular proliferation, receptor binding, and neutrophil function demonstrate that 
Filgrastim and pegfilgrastim have the same mechanism of action.  Pegfilgrastim has reduced 
renal clearance and prolonged persistence in vivo as compared to Filgrastim. 
 
Pegfilgrastim is indicated to decrease the incidence of infection, as manifested by febrile 
neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer 
drugs associated with a clinically significant incidence of febrile neutropenia. 
 
The standard dose of pegfilgrastim is 6 mg SQ given on the day after (day # 2) chemotherapy 
cycle. This may be dropped at the last infusion of paclitaxel. 
 
Clinical Experience 
 
Pegfilgrastim was evaluated in two randomized, double-blind, active-control studies, using 
doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles in 
the treatment of patients with high-risk stage II or stage III/IV breast cancer (68-69). Study 1 
investigated the utility of a fixed dose of pegfilgrastim. Study 2 used a weight-adjusted dose.  In 
the absence of growth factor support, similar chemotherapy regimens have been reported to 
result in a 100% incidence of severe neutropenia (ANC < 0.5 x 109/L) with a mean duration of 5 to 
7 days, and a 30 to 40% incidence of febrile neutropenia (70). 
 
In study 1, 157 subjects were randomized to receive a single SC dose of 6 mg of pegfilgrastim on 
day 2 of each chemotherapy cycle or filgrastim 5 ug/kg/day SC beginning on day 2 of each cycle. 


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In study 2, 310 subjects were randomized to receive a single SC injection of pegfilgrastim at 100 
ug/kg on day 2 or filgrastim 5 ug/kg/day SC beginning on day 2 of each cycle of chemotherapy. 
Both studies met the primary objective of demonstrating that the mean days of severe 
neutropenia (ANC < 0.5 x 109/L) of pegfilgrastim-treated patients did not exceed that of filgrastim- 
treated patients by more than 1 day in cycle 1 of chemotherapy.  The rates of febrile neutropenia 
were 13% and 9% for pegfilgrastim vs. 20% and 18% for Filgrastim in studies 1 and 2, 
respectively.  Other secondary endpoints included days of severe neutropenia in cycles 2 to 4, the 
depth of ANC nadir in cycles 1 to 4, and the time to ANC recovery after nadir.  In both studies, the 
results for the secondary endpoints were similar between the two treatment groups (68, 69). 
 
The safety and efficacy of once-per cycle pegfilgrastim was also found to be comparable to daily 
Filgrastim in studies in patients with non-small cell lung cancer being treated with carboplatin and 
paclitaxel and patients with NHL or Hodgkin’s lymphoma being treated with ESHAP or CHOP 
chemotherapy (71-73). Pegfilgrastim has also been found to be safe when given in dose-dense 
AC → T q 2 weekly regimen (74). 
 
Filgrastim (Neupogen®) 
 
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant 
DNA technology. G-CSF is a 175 amino aid protein produced by E. Coli bacteria into which has 
been inserted human G-CSF gene. G-CSF regulates the production of neutrophils within the 
bone marrow and affects neutrophil progenitor proliferation, differentiation, antibody dependent 
killing, and the increased expression of some functions associated with cell surface antigens. 
 
G-CSF is a sterile, clear, colorless, preservative-free liquid for parenteral administration 
(subcutaneous).  Each vial of G-CSF contains 300 mcg/ml of filgrastim.  Intact vials must be 
stored under refrigeration at 2-8°C.  Prolonged exposure of G-CSF to temperatures outside this 
range can inactivate the drug. 
 
The standard dose of filgrastim is 5 mcg/kg given SQ daily over the course of several days 
depending on the chemotherapy regimen. 
 
Side-effects include chills, fever, nausea, anorexia, myalgia, bone pain, local injection site pain or 
inflammation, elevated liver function, thinning of hair, enlargement of spleen, and rarely fluid 
retention. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
• 
Patients must have histologically confirmed adenocarcinoma with HER2/neu 
immunohistochemistry 3+ or FISH-amplified breast cancer with a ratio of > 2.0 
 
• 
Tumor size of < 3 cm and node-negative disease. Nodes with single cells or tumor 
clusters < 0.2 mm by H&E or IHC are considered node-negative.  Patients with 
micrometastasis (nodes with tumor clusters between 0.02 and 0.2cm) are allowed. 
Further axillary dissection will be determined by the patient’s surgeon as per 
standard of care. 
 
• 
Patients must be 18 years of age. 


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• 
Patients must have an ECOG performance status of 0 or 1. 
 
• 
Treatment should be started within 90 days of the final surgical procedure for 
breast cancer. 
 
• 
Patients may have bilateral synchronous breast tumors. 
 
• 
Patients may have received hormonal therapy for the purpose of chemoprevention 
but must be willing to discontinue prior to enrollment and while participating in this 
trial. 
 
• 
If patients have peripheral neuropathy, it must be < grade 1. 
 
• 
Patients must be willing to discontinue sex hormonal therapy e.g., birth control 
pills, ovarian hormonal replacement therapy, etc., prior to enrollment. Women of 
childbearing potential must be willing to consent to using effective contraception 
while on treatment and for a reasonable period thereafter. 
 
• 
Hematologic parameters: absolute neutrophil count (ANC) 1500/L and platelet 
count 100,000/L. 
 
• 
Non-hematologic parameters: total bilirubin must be < 1.5 X institutional upper limit 
of normal (ULN), transaminases (SGOT or SGPT) < 3.0 x ULN. 
 
• 
Negative HCG pregnancy test for premenopausal women of reproductive capacity 
and for women less than 12 months after the menopause. 
 
• 
LVEF by ECHO (with strain if possible) with LVEF of > 50%.  If an ECHO cannot 
be done, a MUGA may be performed. 
 
• 
Patients must give written, informed consent indicating their understanding of and 
willingness to participate in the study. 
 
6.2 
Subject Exclusion Criteria 
 
• 
Patients with stage IV breast cancer or undergoing chemotherapy, radiation 
therapy, immunotherapy, or biotherapy for current breast cancer. 
 
• 
Pregnant or breastfeeding patients. 
 
• 
Patients with a concurrently active second malignancy, other than adequately 
treated non-melanoma skin cancers or in situ cervical cancer. 
 
• 
Patients with unstable angina, congestive heart failure, or with a history of a 
myocardial infarction within 12 months.  Patients with high-risk uncontrolled 
arrhythmias (ventricular tachycardia, high-grade AV block, supraventricular 
arrhythmias which are not adequately rate-controlled). Patients are excluded if they 
have grade 3 QT prolongation (Appendix F) (>500 ms) or require drugs that may 
prolong the QT. 
 
• 
Subjects who have current active hepatic (including hepatitis B or C) or biliary 
disease (with exception of patients with Gilbert's syndrome, asymptomatic 
gallstones). 


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• 
Subjects who are concomitantly using certain CYP3A4 Inducers and Inhibitors 
listed in APPENDIX F 
 
• 
Patients with active, unresolved infections. 
 
• 
Patients with a sensitivity to E. coli derived proteins. 
 
 
7.0 
RECRUITMENT PLAN 
 
This study is open to patients with HER2 amplified carcinoma of the breast histologically 
confirmed at MSKCC or MSKCC satellites. These patients will be identified and recruited from the 
breast cancer patients seen at the Breast Cancer Center at MSKCC or MSKCC satellites. 
 
Patients who are potentially eligible will be evaluated at the Breast Cancer Center at MSKCC or 
MSKCC satellites. This initial encounter will include a discussion of the proposed treatment and 
the rationale for its use. Eligible patients will be required to review and sign an informed consent. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
The following must be completed within 2 weeks prior to starting protocol therapy: 
 
• 
Complete medical history 
 
 
• 
Physical examination findings to include blood pressure, weight, height, and calculation of 
body surface area (BSA) 
 
• 
Assessment of ECOG performance status (Appendix A) 
 
 
• 
Pregnancy test for females of child-bearing potential 
 
 
• 
Contraceptive counseling for females of childbearing potential and also for men 
 
The following must be obtained within 1 month prior to starting protocol therapy : 
 
• 
Complete blood count including hemoglobin, WBC with differential, and platelet count 
  
• 
Serum chemistries to include potassium and magnesium 
 
 
• 
Liver function test to include bilirubin, SGPT (ALT), SGOT (AST) 
 
 
• 
Signed informed consent 
 
The following must be obtained within 3 months prior to starting protocol therapy 
 
(Study Table): 


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• 
Assessment of LVEF by echocardiogram (if not feasible will accept MUGA scan). When 
possible, a baseline ECHO with strain imaging is preferred. 
 
• 
EKG 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Paclitaxel (175 mg/m2) IV every 14 days x 4 and trastuzumab (4 mg/kg loading dose, then 2 
mg/kg weekly) IV and lapatinib (1000 mg oral daily); followed by trastuzumab (6 mg/kg IV every 3 
weeks) x 15 doses and lapatinib (1000 mg oral daily) to complete about a year of treatment. 
Trastuzumab at a q 3 week dosage may be given at final paclitaxel infusion. A total of 15 
infusions of trastuzumab will be given q 3 weeks during the HL phase. 
 
During treatment with paclitaxel, pegfilgrastim will be given 24 hours after the completion of 
chemotherapy and may be stopped at the last paclitaxel infusion. Filgrastim may be used in lieu 
of pegfilgrastim at physician’s discretion. 
 
Note: Physicians may omit pegfilgrastim (or filgrastim) after cycle # 4 of paclitaxel. 
 
Total duration of trastuzumab and lapatinib therapy is one year. 
 
 
 
Paclitaxel 
 
Paclitaxel (175 mg/m2) IV every 2 weeks x 4 will be administered. 
 
Premedications for paclitaxel:  Patients should receive the standard IV dexamethasone 
10-20 mg (or a steroid equivalent), diphenhydramine 50 mg (or another H1-blocker), and 
an H2-blocker about 30 minutes before paclitaxel infusion. If patients do not experience a 
hypersensitivity reaction after the first 2 doses of paclitaxel, premedications can be altered 
at physician’s discretion. 
 
 
 
 
Dose Modifications: 
 
This study will use the NCI Common Toxicity Criteria (CTC) AE version 4.0 for toxicity. 
 
After each paclitaxel treatment, dose adjustments of the taxane should be based on 
hematologic and nonhematologic toxicities.  Patients experiencing neutropenic fever 
(ANC <1,000/µL and body temperature 38.5°C) will have a 25% dose reduction. Only 
one dose reduction is allowed. (ie: 175 mg/m2 →130 mg/m2). Physicians may use 
antibiotics as secondary prophylaxis as deemed appropriate. 
 
• 
If on the day that paclitaxel is due, platelet counts are <100,000/µL and/or ANC 
<1000/µL and/or non-hematologic toxicities (excluding alopecia and neuropathy) have 
not recovered to Grade 1, treatment should be delayed by up to 1 week and CBC and 
toxicity grading repeated weekly.  If platelet count and ANC and non-hematologic 
toxicity have not recovered to Grade 1, a further delay of up to1 week is required.  If 
LFTs are checked, paclitaxel can be given at full dose without delay if SGOT/SGPT 
are at < Grade 2, and bilirubin is at < Grade 1. If the SGOT/SGPT are at > Grade 3 or 


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bilirubin is at > Grade 2, LFTS should be checked weekly and paclitaxel can be held 
until the SGOT/SGPT have recovered to < Grade 2 and bilirubin < at Grade 1.  Up to 
3 weeks (21 days) are allowed for the appropriate recovery. If the SGOT/SGPT have 
not recovered to < Grade 2 and bilirubin at < Grade 1 within 3 weeks, the patient will 
be taken off study treatment. Of note, even if the toxicity is felt to be due to lapatinib, 
paclitaxel treatment will not resume unless all of the appropriate hematologic and 
nonhematologic parameters are met.. 
 
• 
Hypersensitivity reactions:  Please see Appendix B for treatment. Treatment should 
be discontinued for Grade 4 hypersensitivity reactions.  There are no dose reductions 
for hypersensitivity reactions.  Consider discontinuation of taxane therapy if patient 
experiences 2 episodes of Grade 3 hypersensitivity reaction. 
 
Trastuzumab 
 
Trastuzumab loading dose (4 mg/kg) IV will be administered on same day as paclitaxel 
cycle # 1 and is continued weekly at the dose of 2 mg/kg IV for the duration of paclitaxel 
treatment. Trastuzumab may also be administered at a dose of 6mg/kg during the last 
dose of paclitaxel in the THL phase. At the completion of paclitaxel, patients will receive 
trastuzumab on a q 3 week schedule at 6 mg/kg IV. Each trastuzumab q 3 week cycle at 6 
mg/kg is equivalent to 3 trastuzumab weekly treatments at 2 mg/kg.  The duration of 
trastuzumab from beginning to end is about a year. 
 
Note:  Patients should not miss more than one q 3 week dose of trastuzumab 
consecutively (except when those missed doses are associated with a HOLD and 
REPEAT for asymptomatic LVEF declines as per table below).  Patients do not have to 
make up missed doses. 
 
Premedications for trastuzumab 
For the first (loading) dose of trastuzumab, premedication with acetaminophen 650 mg po 
will be given. 
 
Dose Modifications 
Dose modification of trastuzumab is not permitted. 
For Adjuvant Breast Cancer Protocols:  Asymptomatic Decrease LVEF Percentage Points 
from Baseline 


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RELATIONSHIP 
OF LVEF TO 
THE LOWER 
LIMIT OF 
NORMAL (LLN) 
ABSOLUTE 
DECREASE OF 
< 10 
PERCENTAGE 
POINTS 
ABSOLUTE 
DECREASE OF 10 
TO 15 
PERCENTAGE 
POINTS 
ABSOLUTE DECREASE OF 
 16 PERCENTAGE POINTS 
 
Within radiology 
facility’s normal 
limits 
Continue H + L 
Continue H + L 
Hold H + L and repeat ECHO 
within 3-4 weeks 
 
1 
to 
5 
percentage 
points below the 
LLN 
Continue H + L 
Hold   H   +   L   and 
repeat ECHO within 
3-4 weeks 
Hold H + L and repeat ECHO 
within 3-4 weeks 
 
 6 percentage 
points below the 
LLN 
Continue H + L 
and 
repeat 
ECHO within 3-4 
weeks 
Hold   H   +   L   and 
repeat ECHO within 
3-4 weeks 
Hold H + L and repeat ECHO 
within 3-4 weeks 
 
H=Herceptin 
 
L=Lapatinib 
 
 Rules f or inter pr eting  and applying  “r epeat”  ECHO scan results: 
 
• 
H + L must be permanently discontinued when two consecutive “hold” categories occur. 
• 
H + L must be permanently discontinued when three intermittent “hold” categories occur. 
(At the investigator’s discretion, H + L may also be permanently discontinued prior to the 
occurrence of three intermittent “hold” categories.) 
• 
If LVEF is maintained at a “continue and repeat ECHO” or improves from a “hold” to a 
“continue and repeat ECHO” category, additional ECHOs prior to the next scheduled 
ECHO will be at the investigator’s discretion. 
 
 
Patients who experience significant “asymptomatic” LVEF decline while on trastuzumab + 
lapatinib which results in permanent discontinuation of H + L will be followed long-term. 
These patients will be seen in the cardiology clinic.  Follow-up ECHOs or MUGAs will be 
performed every 3-6 months until 6 months since the last H + L exposure.  If any of these 
patients experiences CHF or cardiac death later during follow-up, the event will be 
considered a true cardiac event and will be counted towards the stopping rule as defined 
in section 13.0. 
 
Note:  If an ECHO cannot be done, a MUGA may be performed. 
 
Note:  If patients are restarted on trastuzumab and > 2 weeks have lapsed since the last 
intended “q 3 week” dose of trastuzumab, then patients should have a re-loading dose of 
trastuzumab at (8 mg/kg followed by q 3 week dose of 6 mg/kg). 


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Note: Patients will receive 15 doses of trastuzumab every 3 weeks during the HL phase. If 
trastuzumab dose is held for cardiac toxicity, this dose does not need to be made up once 
the patient is re-started on anti-HER2 therapy. In other words, the duration of therapy 
should be about a year from beginning to end. 
 
Lapatinib 
 
 
Lapatinib Administration 
 
Patients should be advised to take lapatinib on an empty stomach (either 1 hour before or 1 hour 
after meals). The starting dose is 1000 mg orally daily. 
 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Starting dose and dose modifications for unacceptable toxicity are listed in Table 2. 
For toxicity that is thought to be related to lapatinib, the daily dose of lapatinib will be decreased 
according to the schedule displayed in the Table 3. 
 
Dose adjustments are to be made according to the greatest degree of toxicity.  Toxicities will be 
graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
 
Table 2. Lapatinib Starting Dose and Dose Reduction Schedule 
 
Starting dose 
1000 mg/day 
One dose reduction 
750 mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3. Dose Reduction Criteria and Guidelines for Management of lapatinib Associated 
Toxicity 
 
Toxicity 
Grade 
Guideline for 
management 
Lapatinib dosage modification* 


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Diarrhea 
(Please see 
APPENDIX 
I) 
1 
Loperamide (4 mg at 
first onset, followed by 
2 mg every 2–4 hrs unti
diarrhea free for 12 hrs 
None 
2 
Loperamide (4 mg at 
first onset, followed by 
2 mg every 2–4 hrs unti
diarrhea free for 12 hrs)
None; If unacceptable to patient or medically 
concerning then hold 
until recovery to < grade 1, up to 21 days*. 
Restart at same dose**. 
> 3 (despite 
optimal use
of 
loperamide)
Hold until recovery to < grade 1, up to 21 days*. 
And then reduce 1 dose level. 
Rash 
1 
No intervention 
None 
2 
Any of the following: 
minocycline+, topical 
tetracycline or 
clindamycin, topical 
silver sulfadiazine, 
diphenhydramine, oral 
prednisone (short 
course) 
None; If unacceptable to patient or medically 
concerning then hold 
until recovery to < grade 1, up to 21 days*. 
Restart at same dose**. 
> 3 
Hold until recovery to < grade 1, up to 21 days*. 
And then reduce 1 dose level. 
Other 
Toxicity 
(excluding 
left 
ventricular 
dysfunction 
and 
pneumonitis
see below) 
1 
No Intervention 
None 
2 
Treatment as 
appropriate 
None; If unacceptable to patient or medically 
concerning then hold 
until recovery to < grade 1, up to 21 days*. 
Restart at same dose **. 
2 prolonged
or clinically
significant 
and grade >
3 
Treatment as 
appropriate 
Hold until recovery to < grade 1, up to 21 days an 
then reduce 
1 dose level* 
* 
if no recovery after 3 weeks of holding drug, patients should go off study 
** 
if dose has been previously held for grade 2 toxicity and grade 2 symptoms 
recur, OR if the patient finds the symptoms unacceptable, hold dose until recovery 
to < grade 1 and then reduce dose one level 
+ 
recommended dose: 200mg po bid (loading dose), followed by 100mg po 
bid for 7-10 days 
 
Note: Only one dose reduction of lapatinib is allowed. 
If grade 3 toxicity recurs (ie: diarrhea, rash,) with lapatinib at 750 mg daily, then 
lapatinib should be held and no further dose reduction is allowed.  Patient is then 
taken off study. 
 
Experience thus far suggests that when lapatinib is used as monotherapy most diarrhea 


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presents as uncomplicated NCI CTCAE Grade 1 or 2 (G1 54%, G2 20%, G3 15%, 
G4<1%). 
 
In rare cases, diarrhea can be debilitating, and potentially life threatening if accompanied 
by dehydration, renal insufficiency, and/or electrolyte imbalances. 
 
Standardized and universal guidelines have been developed by an American Society of 
Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea [Benson, 
2004]. Presented in the sections below are the recommended guidelines for the 
management of diarrhea in subjects receiving lapatinib-based therapy; these guidelines 
were derived from the recommendations published by the ASCO panel [Benson, 2004]. 
 
Early identification and intervention is critical for the optimal management of diarrhea. A 
subject’s baseline bowel patterns should be established so that changes in patterns can 
be identified while subject is on treatment. 
 
It is strongly recommended to give subjects receiving lapatinib-based therapy a 
prescription of loperamide with instructions to start loperamide at the onset of diarrhea as 
per the recommendations outlined below. 
 
Subjects should be instructed to first notify their physician/healthcare provider at onset of 
diarrhea of any severity. 
 
An assessment of frequency, consistency and duration as well as knowledge of other 
symptoms such as fever, cramping, pain, nausea, vomiting, dizziness and thirst should be 
taken at baseline. Consequently subjects at high risk of diarrhea can be identified. 
Subjects should be educated on signs and symptoms of diarrhea with instructions to 
report any changes in bowel patterns to the physician. 
 
It is recommended that subjects keep a diary and record the number of diarrhea episodes 
and its characteristics. They should also include information on any dietary changes or 
other observations that may be useful in the evaluation of their diarrhea history. 
 
If subjects present with diarrhea of any Grade, check they are taking lapatinib correctly, 
i.e. single daily dose, rather than splitting it through the day. . Obtain information on food 
(solid and liquid) and over the counter (OTC) medication, including herbal supplements, 
taken during the lapatinib treatment period. 
 
Definitions 
National Cancer Institute (NCI) guidelines define diarrhea compared to baseline 
(APPENDIX H). 
 
 
 
 
 
 
 
 
Lapatinib hepatotoxicity 
 
Lapatinib can cause abnormal liver function tests (LFTs), but the incidence is rare. A 
crude incidence of 0.4% has been reported for liver dysfunction (predominantly liver 
enzyme abnormalities) in over 8700 patients who have received lapatinib in clinical trials 
as of December 2007.  Recently, there is a report of a small number of liver toxicity-related 
deaths, possibly due to lapatinib.  These patients were being treated for metastatic breast 


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and other cancers, including some cases with liver cancer, so it was difficult to determine 
what role lapatinib may have played. 
 
Due to the rare liver toxicity-related deaths in the metastatic population, the following 
suggestions are recommended: 
 
1)  LFTs (SGOT, SGPT, bilirubin) will be checked serially while patients are actively 
taking lapatinib.  LFTs are checked every 2 weeks during concurrent chemotherapy 
phase (THL) and then every 3-6 weeks after chemotherapy completion (HL). 
 
2) Lapatinib dose modifications are recommended for the following LFT abnormalities: 
 
a)  If SGOT, SGPT, or bilirubin is at > Grade 3, the patient should “stop” lapatinib 
altogether and not resume it. 
 
b)  If SGOT, SGPT, or bilirubin is at Grade 2, the patient may hold the lapatinib 
until the SGOT, SGPT, or bilirubin is at < Grade 1. The patient may have up to 
21 days to hold the lapatinib and LFTs may be checked within 3 weeks (or 
sooner at the physician’s discretion). The patient may then resume the lapatinib 
at one dose reduction (from 1000 mg to 750 mg). 
 
i.  If the lapatinib dose is already at 750 mg when SGOT, SGPT, or 
bilirubin is at > Grade 2, the patient may hold the lapatinib until the 
SGOT, SGPT, or bilirubin is at < Grade 1. The patient may have up to 
21 days to hold the lapatinib and LFTs may be checked within 3 weeks 
(or sooner at the physician’s discretion). The patient may then resume 
the lapatinib at the same dose of 750 mg. If a Grade 2 event occurs 
again, then patient must “stop” lapatinib altogether and “not” resume it. 
 
c)  If SGOT, SGPT, or bilirubin is at < Grade 1, the patient may continue lapatinib 
at the same dose. 
 
 
 
Note:  During the concurrent chemotherapy, trastuzumab, and lapatinib phase 
(THL) when LFTs are checked every 2 weeks, paclitaxel can be given at full dose 
without delay if the SGOT/SGPT are at < Grade 2, and bilirubin is at < grade 1. If 
the SGOT/SGPT are at > Grade 3 or bilirubin is at > Grade 2, LFTS should be 
checked weekly and paclitaxel can be held until the SGOT/SGPT have recovered 
to < Grade 2 and bilirubin < Grade 1.  The patient can have up to 3 weeks (21 
days) for this recovery. If not, then the patient will come off study treatment. 
 
 
 
 
 
 
 
 
Lapatinib Dosing based on LFTs 
 
SGOT/SGPT/bilirubin 
Grade 1 
Grade 2 
Grade > 3 
Lapatinib 
Continue 
Hold up to 21 days and 
resume at one dose 
reduction (from 1000 mg to 
750 mg)* until the 
SGOT/SGPT/bilirubin have 
Stop and not 
resume 


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recovered to <grade 1 
 
*If the lapatinib dose is already at 750 mg when SGOT, SGPT, or bilirubin is at > Grade 2, 
the patient may hold the lapatinib until the SGOT, SGPT, or bilirubin is at < Grade 1. The 
patient may have up to 21 days to hold the lapatinib and LFTs may be checked within 3 
weeks (or sooner at the physician’s discretion). The patient may then resume the lapatinib 
at the same dose of 750 mg. If a Grade 2 event occurs again, then patient must “stop” 
lapatinib altogether and “not” resume it. 
  
 
Paclitaxel Dosing based on LFTs 
 
SGOT/SGPT < Grade 2 
and bili < Grade 1 
SGOT/SGPT > Grade 3 
And bili > Grade 2 
Paclitaxel 
Full dose 
*Hold until SGOT/SGPT < Grade 2 
and bili < Grade 1 
 
*LFTS should be checked weekly and patients can have up to 3 weeks (21 days) for 
SGOT/SGPT to recover to < Grade 2 and bili to < Grade 1.Supportive care guidelines for 
lapatinib toxicities are in Appendix C. 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
• 
Every 2 weeks during THL phase and every 3-6 weeks during the HL phase: 
 
▪ 
History and physical examination with vital signs, ECOG performance 
status. 
 
▪ 
Recording of the adverse events 
 
▪ 
Labs 
 
• 
CBC and differential count will be done prior to (within - 3 days) 
each paclitaxel infusion (paclitaxel can be given +/- 3 days). Labs 
can be done within -3 days of each treatment. 
 
• 
LFTs will be performed every 2 weeks (within - 3 days) during the 
THL phase and every 3-6 weeks (+/- 3 days) during the HL phase. 
 
• 
Magnesium and potassium levels will be performed every 2 weeks 
(within - 3 days) during the THL phase and every 3-6 weeks (+/- 3 
days) during the HL phase. 
 
• 
Patients may have their treatment schedule modified as follows: 
 
▪ 
Patients may have a delay of treatment for up to 3 weeks (for any reason). 
 
▪ 
If there is a delay of > 2 weeks since the last infusion of trastuzumab, then 
a re-loading of trastuzumab is advised. 
 
• 
A lapatinib pill diary will be given to the patient and a pill count will be conducted every 4-6 
weeks (Appendix D). 


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• 
Patients should be educated about medications that are prohibited (ie: CYP3A4 inducers 
or inhibitors) while on lapatinib (Appendix E). 
 
• 
Assessment of left ventricular ejection fraction by echocardiogram (with strain when 
possible) will be performed at baseline and at months 2, 6, 9, 12 and 18 (+/- 4 weeks). 
 
• 
Assessment of EKG will be required at baseline and months 2, 6, 9, 12 and 18 (+/- 4 
weeks). 
 
If QTc prolongation is noted as Grade 3 or greater (> 500 ms) at any time on EKG 
monitoring, lapatinib should be held and a repeat EKG should be done within 4 weeks.  If 
the repeat EKG shows that the QTc is < or equal to 500 ms, then lapatinib can be given 
with one dose reduction (from 1000 mg to 750 mg daily).  If the repeat EKG still shows 
that the QTc as Grade 3 or greater (>500 ms), then lapatinib is still held and patient should 
be removed from study. If the patient is already taking lapatinib at a lower dose of 750 mg 
daily (for any reason) and the QTc is prolonged at Grade 3 or greater (> 500 ms), lapatinib 
should then be held and the patient from study.  The patient will then be treated as 
deemed appropriately by the treating physician. Serial potassium and magnesium levels 
should be followed (and corrected if low) while the patient is on lapatinib (Appendix F). 
 
• 
Evidence of disease evaluation by CT of the chest, abdomen, and pelvis, PET scan, 
and/or bone scan will be conducted if clinically indicated by the patient’s symptomatology, 
by abnormal laboratory values, or at the physician’s discretion. 
 
• 
Correlative blood work consisting of a cardiac troponin I, BNP, and neuregulin-1ß will be 
measured every 2 weeks during THL phase (pre- and post- infusion of paclitaxel, 
trastuzumab) and during months 6, 9, and 18. 
 
• 
Blood for SNP analysis will be drawn once during study, preferably either prior to or the 
day of cycle #1 of paclitaxel. 
 
Biomarker Evaluations: 
 
Troponin 
 
From each patient at every 2 weeks during THL phase (pre- and post- infusion of paclitaxel, 
trastuzumab) and during months 6, 9, and 18  (7 time-points in total) five mL of peripheral 
blood will be collected pre- and post-infusion in a green top (heparin) tube for the 
measurement of TnI. For the troponin assay, plasma will be separated from peripheral blood 
and samples will be frozen for analysis and will not be known to the investigator until the 
patient has completed the study. The TnI samples will be evaluated by Dr. Martin Fleisher’s 
laboratory at MSKCC.   At all MSKCC sites, blood samples should be clearly labeled before 
transfer to Main campus. This labeling should include the study identifier (IRB-assigned 
protocol number), MSKCC-assigned patient identifier (once available), test ("troponin") and 
the time point of sample measurement. 
 
TnI concentrations will be determined by a fluorometric enzyme immunoassay analyzer 
(Tosoh Bioscience, Inc., San Francisco, CA) with a low end sensitivity of 0.06 ng/ml. TnI 
levels will be classified as <0.06 ng/mL (“undetectable”), 0.06-0.31 ng/mL (“minimal 
elevations”), or >0.31 ng/mL (“above normal range”). In addition to categorizing TnI values in 


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this way, the absolute change (represented by the difference between the baseline value and 
the maximum value observed during follow-up) will be calculated for each patient. 
 
Brain Natriuretic Peptide 
 
 
From each patient at every 2 weeks during THL phase (pre- and post- infusion of paclitaxel, 
trastuzumab) and during months 6, 9, and 18 (7 time-points in total) , five mL of peripheral 
blood will be collected pre- and post-infusion into a lavender top (EDTA) tube for 
measurement of BNP.  The BNP assay will be performed within 24 hours of blood collection. 
The BNP samples will be evaluated by Dr. Martin Fleisher’s laboratory at MSKCC.  BNP 
specimens can be refrigerated following collection. Samples from MSKCC Regional Network 
sites will be delivered to the MSKCC Main Campus at least once daily per usual Regional 
practice for preparation and frozen storage. At all MSKCC sites, blood samples should be 
clearly labeled before transfer to Main campus. This labeling should include the study 
identifier (IRB-assigned protocol number), MSKCC-assigned patient identifier (once available), 
test (“BNP”) and the time point of sample measurement. 
 
BNP is assayed in the Clinical Chemistry STAT lab. The BNP assay is performed on a Biosite 
Triage analyzer (Biosite, San Diego, California) using fluorescence immunoassay on EDTA 
anticoagulated whole blood.  Average within day imprecision is 8.5% at 71 pg/ml and 11% at 
630 pg/ml.  BNP results less than or equal to 100 pg/ml are representative of normal values 
in patients without CHF. BNP will be classified as ≤100 pg/mL (“within normal range”) or >100 
pg/mL (“above normal range”). In addition to categorizing BNP values in this way, the absolute 
change (represented by the difference between the baseline value and the maximum value 
observed during follow-up) will be calculated for each patient. 
 
Neuregulin 1ß 
 
From each patient at every 2 weeks during THL phase (pre- and post- infusion of paclitaxel, 
trastuzumab) and during months 6, 9, and 18 (7 time-points in total) , five mL of peripheral 
blood will be collected pre- and post-infusion in a lavender top (EDTA) tube for the 
measurement NRG-1ß. For the NRG-1ß assay, plasma will be separated from peripheral 
blood and samples will be frozen for analysis and will not be known to the investigator until the 
patient has completed the study.  A reproducible assay for assessing serum NRG-1ß levels 
using an indirect sandwich ELISA technique has been developed and validated in the Sawyer 
Lab at Vanderbilt University.  The monoclonal capture antibody used in this assay is against a 
biologically active and cardiac-specific peptide sequence, which has been studied extensively 
by Sawyer et al. This peptide has been shown to play an important role in the activation of the 
ErbB receptor and downstream signaling pathways in ventricular myocytes. The coefficient of 
variation (CV) of this assay is 5.6-13%. 
 
The first generation form of this assay was used in a pilot study performed by Dr. Sawyer’s 
group which sought to define the effects of exercise on circulating NRG-1ß levels in humans 
94. This study demonstrated that there was no significant difference in serum NRG-1ß levels 
pre- and post- exercise in healthy human subjects, but these levels were associated with 
cardiopulmonary exercise capacity. 
 
A second generation ELISA assay with lower detection limits has since been developed with 
NRG-1ß being detected in >98% samples tested to date. This assay was used to quantitate 
NRG-1ß from serum samples in 899 subjects with chronic heart failure. 82 NRG-1ß levels were 


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detected in all non-heart failure samples and all but 12 heart failure patients.  Extensive 
validation of the second generation form of this assay has been performed. The effects of 
multiple freeze/thaw cycles and the differences between plasma and serum NRG-1ß levels 
have also been assessed.  NRG-1ß is detectable in both serum and plasma with a strong 
correlation (R2=0.91), with plasma levels being 50% higher than serum.  Repeated measures 
of NRG-1ß levels after exposure to multiple freeze/thaw cycles are highly correlated 
(R2=0.92), but decrease 25.7% per freeze/thaw cycle.  Because of these findings, we will use 
frozen, previously unthawed plasma for our study. 
 
A third generation form of this assay has also been developed and validated at the University 
of Pennsylvania Translational Core Lab led by Theodore Mifflin, PhD and Stephen Master, 
MD, PhD under Dr. Ky’s direction and Dr. Sawyer’s collaboration. This assay has lower 
detection limits and an improved coefficient of variation 
Neuregulin-1 Assay:  Plasma will be collected, banked, and stored at -80oC at various time- 
points immediately prior to and after specific cycles serially during the course of chemotherapy 
as outlined above. We will measure NRG-1 from previously unthawed plasma samples 
using a reproducible, established 2nd generation ELISA for assessing NRG-1 (CV 5.6-13%) 
(82). This monoclonal capture antibody targets a biologically-active peptide that is relevant to 
the cardiac system and able to induce ErbB receptor activity.  Importantly, as new candidate 
biomarkers arise, we will also test these using robust assays.  
 
As of A(6), we will no longer be measuring NRG-1from previously unthawed plasma 
samples using ELISA, given the scarce incidences of cardiac dysfunction based on the LVEF 
data. 
 
Note:  As the clinical significance of an elevated TnI, BNP, or NRG-1ß in an asymptomatic 
patient is unknown, the TnI and NRG-1ß samples drawn at various time intervals as described 
previously for each patient will be analyzed but the results will be blinded to the treating 
physician until the end of the study, “not in real time”.  Patients and their treating physicians 
will not have the results in real time and thus, treatment decisions will not be affected. The 
BNP assay will be performed within 24 hours of sample collection, but the results will not be 
released to the treating oncologist until the end of the study, as the significance of an elevated 
BNP in an asymptomatic patient is not known. The results will instead be stored for 
interpretation at the end of the study. 
 
Note: The TnI and BNP samples will be collected at the BAIC and will be picked up by the 
courier and delivered to Dr. Fleisher’s lab, as per standard MSKCC’s standard practice. The 
NRG-1ß samples will be frozen and stored at the BAIC. and will be sent to Dr. Bonnie Ky at 
the end of the study for the exploratory analysis. 
  
As of A(6), NRG-1samples will no longer be sent to Dr. Bonnie Ky’s laboratory for 
exploratory analysis. They will be discarded. 
 
 
Pharmacogenomics Determinants of Toxicity to Therapy 
 
Hepatic oxidative drug metabolism is carried out by the cytochrome (CYP) P450 system. 
Sequencing of the genome has revealed 58 different human CYP genes.  Polymorphisms in CYP 
genes may contribute to either diminished or absent metabolism, or excessive metabolism of a 
compound. Within the CYP system, enzyme families CYP 1, CYP2, and CYP3 are responsible for 


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the metabolism of paclitaxel and lapatinib.  Specifically, CYP2C8, CYP3A5, CYP3A4, and 
CYP2C19 have been shown to be involved in metabolism of both drugs.  Inherited variations in 
drug transport proteins are also of interest when considering pharmacogenetics. Members of the 
adenosine triphosphate (ATP)-binding cassette (ABC) family of membrane transporters modulate 
drug action at the cellular level.  Genes relevant to lapatinib and paclitaxel metabolism include 
ABCB1, ABCG2, CYP2C8*2, CYP2C19*2, CYP3A5*3, CYP3A4*1B and can be identified using 
SNP assay analysis. 
 
These samples will be collected at the BAIC and frozen until they are analyzed at the end of the 
study for each patient.  Samples will be analyzed by Sequenom MassArray in the Sequenom 
Core (Diagnostic Molecular Pathology). Assay design, sample plating and preparation will be 
performed in the Clinical Genetics Service laboratory under the direction of Vijai Joseph, Ph.D. 
Quality control will be assessed by inclusion of random duplicates and blanks, per standard 
protocol. In the unlikely event that a SNP cannot be included in the assay design, we will either 
perform a TaqMan assay for that particular SNP or use a more tractable SNP in LD (r2 = 1) with 
the SNP of interest. Genotype calls will be made by V. Joseph and M. Robson by inspection of 
the Sequenom output. For ABCB1, the results of genotyping of rs1045642, rs1128503, and 
rs2032582 will be used to construct haplotypes, and it will be the haplotypes that will be used in 
the analysis rather than the individual genotypes 
 
Echocardiograms (and Strain Imaging Analysis for research purposes): 
 
Echocardiograms will be performed at months 2, 6, 9, 12 and 18 of treatment as defined in the 
study.  Strain imaging will be analyzed off-line using 2D image loops from the routine 
echocardiographic examination. The ECHO machine for the strain imaging analysis should be 
the Vivid 7 or E9 machine (GE healthcare, Milwaukee, WI). In addition to being stored in the main 
ECHO PACS system, these studies will also be stored in an external GE workstation which 
contains the software needed to perform the strain imaging analysis. To calculate strain and strain 
rate, the LV myocardium is traced in a click-to-point approach.  Subsequently, the software 
automatically defines an epicardial and midmyocardial line and processes all frames of the loop. 
The myocardium in each of the 3 standard apical views is divided into 6 segments.  The software 
will automatically calculate strain and strain rate for each of the 18 segments plus a global value 
for the entire myocardium. These measurements will be made by a designated investigator (Dr. 
Jennifer Liu) blinded to patient identification, demographics and clinical characteristics at the end 
of the study. When possible any ECHOs done outside of MSKCC are requested to be done on 
the GE Vivid 7 or E9 machine (GE healthcare, Milwaukee, WI),  and the disc to be sent to Dr. 
Jennifer Liu for the strain imaging analysis. 


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STUDY TABLE: SCHEDULE OF EVENTS ACTIVITY 
 
 
 
Pre- 
Treatment 
Prior to 
each 
chemo- 
therapy 
treatment 
Every 2 weeks 
during THL and 
every 3-6 weeks 
during HL 
Months 2, 
6, 9, 12, 
18 
After 
Treatment 
Completion 
9 
Medical History 
X (w/i 2 
weeks) 
X 
X 
Physical 
examination1 
X (w/i 2 
weeks) 
X 
X 
ECOG PS 
X (w/i 2 
weeks) 
X 
CBC2 
X (w/i 4 
weeks) 
X 
X 
Chemistry 3 
X (w/i 4 
weeks) 
X 
Pregnancy test 4 
X (w/i 2 
weeks) 
Contraceptive 
counseling 4 
X (w/i 2 
weeks) 
ECHO5 and EKG 
X (w/i 3 
months) 
X 
Cardiac 
correlative 
blood-work6 
X 
Blood-work for 
genetic analysis7 
X 
Signed informed 
consent 
X (w/i 4 
weeks) 
Adverse 
event/toxicity 
assessment 
X 
X 
Pill diary 
X8 (every 4 weeks 
during THL, every 3- 
6 weeks during HL) 
1.   Prior to the first cycle of treatment, a height and weight must be obtained. 
 
2.   CBC includes hemoglobin, hematocrit, white cell count, platelets (within -3 days during THL 
and +/- 3 days during HL). 
 
3.   Chemistry profile includes potassium, magnesium, SGOT (AST), SGPT (ALT), total bilirubin 
(within -3 days during THL and +/- 3 days during HL) 
 
4.   Females of child-bearing potential. 
 
5.   LVEF determined via an ECHO with strain imaging.  When an ECHO by the GE Vivid 7 or E9 
system (GE Healthcare, Milwaukee, WI) is not available for strain imaging analysis, then an 
LVEF by a standard ECHO machine per facility may be done. If an ECHO cannot be done, a 
MUGA scan may be done. This can be done within +/- 4 weeks. 


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6.   Correlative cardiac blood-work will consist of TnI, BNP, and NRG-1ß. These will be done pre- 
and post-infusion on day 1 of every THL cycle (4 times, every 2 weeks) and at months 6, 9 and 
18 (7 time-points in total). 
 
7.   Blood for genetic analysis will be done prior to receipt of cycle # 1 paclitaxel (but can be done 
at any time during study if not done at baseline). 
 
8.   A lapatinib pill diary will be collected every 4 weeks during THL phase and every 3-6 weeks 
during HL phase of the study. 
 
9.   Evidence of disease (EOD) evaluation should be considered (CT of chest, abdomen, and pelvis 
and bone scan) if clinically indicated by the patient’s symptomatology or by abnormal laboratory 
values, at the physician’s discretion. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Assessment of Adverse Events: 
 
Investigators will assess the occurrence of AEs at all patient evaluation time points during 
the study. All AEs whether volunteered by the patient, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be recorded in the patient’s medical record and on the appropriate AE CRDB 
page. Each recorded AE will be described by its duration (i.e., start and end dates), 
severity and suspected relationship to the investigational product. Since this trial’s primary 
outcome is to measure safety and feasibility of the intervention by assessing toxicity, 
suspected relationships or attributions of non-hematological adverse events will only be 
collected if assessed as grades ≥ 2 except for the following events: rash and diarrhea. 
Additionally, laboratory toxicities will be collected for assessment if the results are 
considered grades ≥ 2. AE grading (severity) scale found in the NCI CTCAE, Version 4.0 
will be used for AE reporting. 
 
 
 
Trastuzumab (Herceptin®) 
 
Infusion-Associated Symptoms. During the first infusion with Herceptin, a symptom 
complex consisting of chills and/or fever is observed in approximately 40% of patients. 
Other signs and/or symptoms may include nausea, vomiting, pain, rigors, headache, 
cough, dizziness, rash, and asthenia. These symptoms are usually mild to moderate in 
severity, and occur infrequently with subsequent Herceptin infusions. These symptoms 
can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an 
antihistamine such as diphenhydramine. 
 
Serious Infusion-Associated Events. Serious adverse reactions to Herceptin infusion 
including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation and respiratory distress have been reported infrequently.   In rare cases (4 per 
10,000), these events were associated with a clinical course culminating in a fatal 
outcome. Serious reactions have been treated with supportive therapy such as oxygen, 
beta-agonists, corticosteroids and withdrawal of Herceptin as indicated. 
 
Hematologic Toxicity.  In the clinical trials, an increased incidence of anemia was observed 
in patients receiving Herceptin plus chemotherapy compared with patients receiving 
chemotherapy alone.  The majority of these anemia events were mild or moderate in 
intensity and reversible; none resulted in discontinuation of Herceptin therapy. In the 
clinical trials, the per-patient incidences of moderate to severe neutropenia and of 


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febrile neutropenia were higher in patients receiving Herceptin in combination with 
myelosuppressive chemotherapy as compared to those who received chemotherapy 
alone.  In the post marketing setting, deaths due to sepsis in patients with severe 
neutropenia have been reported in patients receiving Herceptin and myelosuppressive 
chemotherapy, although in controlled clinical trials (pre- and post-marketing), the 
incidence of septic deaths was not significantly increased. The pathophysiologic basis for 
exacerbation of neutropenia has not been determined; the effect of Herceptin on the 
pharmacokinetics of chemotherapeutic agents has not been fully evaluated. The observed 
incidence of leukemia among Herceptin-treated patients appears to be consistent with the 
expected incidence of leukemia among patients treated with chemotherapy for metastatic 
breast cancer. Therefore, the contribution of Herceptin to the etiology of acute leukemia 
or myelodysplastic syndrome in these cases is unclear. 
 
 
 
 
Paclitaxel (Taxol®) 
 
Side-effects include alopecia, myelosuppression, fatigue, neuropathy, arthralgia, myalgia, 
onycholysis, taste changes, amenorrhea, teratogenesis, hypersensitivity (hypotension, 
flushing, chest pain, abdominal or extremity pain, skin reactions, pruritus, dyspnea, 
bronchospasm, and tachycardia), fever, sinus bradycardia, complete heart block, sinus 
tachycardia, premature ventricular beats, ventricular tachycardia, bigeminy, syncope, 
myocardial infarction, hypotension, hypertension, dizziness, visual changes, headaches, 
radiation recall, nausea and vomiting, mouth sores, abdominal pain, diarrhea, typhlitis, 
ischemic colitis, abnormal liver function, pancreatitis, abnormal triglyceride, and seizures. 
 
Lapatinib 
 
The most common toxic effects of lapatinib are: 
Diarrhea, nausea, vomiting, rash, anorexia, and fatigue. 
Information on Hepatotoxicity 
 
Lapatinib can cause abnormal liver functions (LFTs), predominantly transaminase 
elevations, but the incidence is rare.  A crude incidence of 0.4% of hepatotoxicity has been 
reported for liver dysfunction in over 8700 patients who have received lapatinib in clinical 
trials as of December 2007.  Recently, there is a report of a small number of liver toxicity- 
related deaths, possibly due to lapatinib. These patients were being treated for metastatic 
breast and other cancers, including some cases with liver cancer, so it was difficult to 
determine what role lapatinib may have played. 
 
Information on pregnancy 
 
As of 28 February 2006 there have been three pregnancy reports within the lapatinib 
clinical program.  Study EGF10004 subject 402 was found to be pregnant at an unknown 
time after the first dose of lapatinib. The subject gave birth to a normal female baby at 36 
weeks gestation by caesarean section.  Study EGF20002 subject 2655 was found to be 
pregnant at an unknown time after receiving lapatinib and zoledronic acid. Treatment with 
lapatinib was discontinued. The patient experienced a spontaneous/missed abortion at 9 
weeks gestational age which was reported as related to lapatinib by the investigator. 
Another subject in study EGF100642 subject 101 became pregnant in the first month 
following her last dose of lapatinib.  She later underwent an elective abortion due to 
progression of her underlying cancer. 


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Cardiac and pulmonary toxicity 
 
Potential risks for the lapatinib program include cardiac toxicity and pulmonary toxicity 
which are known risks associated with other ErbB1 or ErbB2 inhibitors. Cardiac and 
pulmonary events are monitored closely in all lapatinib clinical trials and reviewed regularly 
by GSK.  An Independent Data Monitoring Committee (IDMC) comprising oncologists, a 
cardiologist and a pulmonologist meet quarterly to assess the benefit-risk ratio in ongoing 
trials. Cardiac safety and interstitial pneumonitis are reviewed as part of this responsibility. 
 
 
 
 
 
 
Decreased Left Ventricular Ejection Fraction (LVEF) 
 
Left Ventricular Ejection Fraction (LVEF) has been evaluated using MUGA scans or 
echocardiogram during lapatinib phase I, II and III trials.  As of 28 February 2006 a total of 
60 subjects on the lapatinib program have experienced 62 events of decreased LVEF, 
giving an approximate incidence for this event of 1.5% for the program as a whole. Of 
these 62 events, 57 events (55 subjects) met the protocol specific serious definition 
included in lapatinib phase II and III protocols: 
 
NCI CTC Grade 3 or 4 left ventricular systolic dysfunction (NCI CTC version 4.0) or LVEF 
decrease ≥20% relative to baseline value  and below the institutions lower limit of normal. 
Age range for subjects experiencing decreased LVEF was 31 to 81 years, with a median 
of 59 years.  Seventy three 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.  Sixty percent of the decreased LVEF events occurred within nine weeks of 
treatment onset. In 37 subjects, (62%) the event resolved or improved. 
 
Forty two of the 55 subjects whose LVEF decrease met the protocol specific serious 
definition are known to have received lapatinib, giving an incidence of 1.3%.  For the 
remaining 13 subjects: 5 remain blinded, 4 occurred on placebo, and 4 subjects received 
comparator (capecitabine or medroxy-progesterone) only. 
 
Of the 42 subjects on lapatinib, 33 LVEF decreases were assessed as related to 
investigational product by the investigator. Twenty three subjects (55%) were participating 
in monotherapy studies.   Of the 42 lapatinib subjects, 29 experienced asymptomatic 
LVEF decreases which were complicated by pre-existing conditions and/or 
previous/concurrent medications.  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. 
 
A further nine lapatinib subjects experienced LVEF decreases which resolved or improved 
on discontinuation of lapatinib.  Eight subjects received lapatinib monotherapy, one 
subject received lapatinib in combination with capecitabine. Three of the eight 
monotherapy cases were symptomatic. The symptoms observed were dyspnea and 
cardiac failure, which resolved on discontinuation of lapatinib. The remaining five 
monotherapy cases and one combination therapy report were asymptomatic.  All nine of 
these cases were complicated by pre-existing conditions and/or previous/concurrent 
medications which may have contributed to the observed LVEF decrease and make 
assessment of the event complex. 


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The remaining four subjects had no contributing factors, three subjects were receiving 
lapatinib monotherapy, and one subject received combination therapy with cisplatin. Two 
of the subjects died due to disease progression whilst an asymptomatic LVEF decrease 
was ongoing.  In one case lapatinib was discontinued, the second subject had remained 
on lapatinib. The third subject experienced a symptomatic (palpitations) LVEF decrease. 
Lapatinib was interrupted and the event was ongoing at the time of reporting. The subject 
who received combination therapy experienced an asymptomatic decrease in LVEF three 
weeks after completing treatment with lapatinib. The event resolved. 
 
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 paclitaxel or 
capecitabine, both of 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 has been included in the DCSI for 
lapatinib. 
 
QT prolongation 
 
QT prolongation measured by an EKG was observed in uncontrolled, open-label dose 
escalation study of lapatinib in patients with advanced cancer (81).  In this study 81 
patients received lapatinib at doses ranging from 175 to 1800 mg daily.  Serial EKGs were 
collected on days 1 and 14 to evaluate the effect of lapatinib on QT intervals.  Thirteen of 
81 patients were found to have either QTcF (corrected by the Friedericia method) of > 480 
msec or an increase in QTcF by > 60 msec by an automated machine-read evaluation of 
the EKG. Thus, there may be a relationship between lapatinib concentration and QTc 
interval.  Lapatinib should be administered with caution in those at risk for QTc 
prolongation. These patients include those with hypokalemia, with hypomagnesemia, with 
congenital long QT syndrome, taking anti-arrhythmic drugs or medications that lead to QT 
prolongation (Appendix E), and who had a high cumulative anthracycline exposure.  Thus, 
hypokalemia and hypomagnesemia should be corrected prior to administering lapatinib. 
Baseline and on-treatment EKG monitoring with QT measurement and monitoring of 
potassium and magnesium should be done on patients who are receiving lapatinib. 
 
Interstitial Pneumonitis 
 
Current phase II and III lapatinib protocols include specific requirements for reporting of 
signs or symptoms of pneumonitis:  subjects who have pulmonary symptoms which are 
NCI CTC version 3.0 Grade 3 or greater will be removed from study and the events 
documented as an SAE. As of 28 February 2006, 9 pulmonary events have been 
reported:  5 subjects experienced interstitial lung disease, 4 subjects experienced 
pneumonitis. Given current enrolment of 4084 subjects in the lapatinib program, this gives 
an approximate incidence of 0.2% for ‘pneumonitis type’ events.  Seven of these events 
were reported as related to investigational product.  Six subjects were participating in 
combination studies and one of these subjects did not receive lapatinib. The remaining 
three reports were from lapatinib monotherapy studies. 
 
Age range for subjects experiencing signs or symptoms of pneumonitis was 48 to 73 
years, with a median of 66 years. The majority of the reports (6/9) were for female 
subjects which may be attributed to the fact that there are a large number of breast cancer 
subjects in the lapatinib program.  Five subjects (55%) who experienced pulmonary events 
recovered. Three of these 5 subjects required treatment, commonly methylprednisolone 
or prednisolone.  For the remaining four subjects: two events were fatal, one event was 


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ongoing at the time of the subject’s death due to disease progression, and one event was 
ongoing at the time of reporting.  Both subjects who died were participating in 
monotherapy studies. The first subject died due to interstitial lung disease which the 
investigator attributed to disease progression. The second subject developed interstitial 
lung disease and died approximately seven months after the last dose of lapatinib.  The 
subject had recently completed radiotherapy and the investigator felt that lapatinib may 
have affected the subject’s tolerance to radiotherapy. 
 
In addition to the reports received from the lapatinib program, a report of interstitial 
pulmonary infiltrates was received for a subject participating in study VEG10006 (lapatinib 
and pazopanib). The final diagnosis for this event was bilateral pneumonia, which was 
reported as unrelated to the investigational products.  Reports of signs/symptoms of 
pneumonitis are closely monitored and current data do not support the addition of this 
term to DCSI for lapatinib. 
 
Pegfilgrastim (Neulasta®) 
 
The most common adverse event attributed to pegfilgrastim in clinical trials was medullary 
bone pain, reported in 26% of subjects, which was comparable to the incidence in 
Filgrastim-treated patients. This bone pain was generally reported to be of mild-to- 
moderate severity.  Approximately 12% of all subjects utilized non-narcotic analgesics and 
less than 6% utilized narcotic analgesics in association with bone pain.  No patients 
withdrew from the study due to bone pain. Reversible elevations in LDH, alkaline 
phosphatase and uric acid have been observed in clinical trials.  Pegfilgrastim has been 
associated with leukocytosis (defined as WBC > 100 x 109/L) in < 1% of 465 subjects with 
non-myeloid malignancies, when observed it was not associated with any adverse event. 
 
The maximum amount of pegfilgrastim that can be safely administered in single or multiple 
doses has not been determined.  Single doses of 300 mcg/kg have been administered SC 
to 8 normal volunteers and 3 patients with non-small cell lung cancer without serious 
adverse effects. These subjects experienced a mean maximum ANC of 55 x 109/L, with a 
corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC 
observed was 96 x 109/L with a corresponding absolute maximum WBC observed of 120 x 
109/L. The duration of leukocytosis ranged from 6 to 13 days.  Leukapheresis should be 
considered in the management of symptomatic individuals. 
 
Pegfilgrastim is contraindicated in patients with known hypersensitivity to E coli-derived 
proteins, pegfilgrastim, Filgrastim, or any other component of the product. 
 
Rare cases of splenic rupture have been reported with pegfilgrastim in the post-marketing 
setting.  Similar events have been reported following the administration of the parent 
compound of pegfilgrastim, Filgrastim, for PBPC mobilization in both healthy donors and 
patients with cancer.  Some of these cases with Filgrastim were fatal.  Pegfilgrastim has 
not been evaluated in this setting, therefore, pegfilgrastim should not be used for PBPC 
mobilization.  Patients receiving pegfilgrastim who report left upper abdominal or shoulder 
tip pain should be evaluated for an enlarged spleen or splenic rupture. 
 
Adult respiratory distress syndrome (ARDS) has been reported in neutropenic patients with 
sepsis receiving filgrastim, the parent compound of pegfilgrastim, and is postulated to be 
secondary to an influx of neutrophils to sites of inflammation in the lungs.  Neutropenic 
patients receiving pegfilgrastim who develop fever, lung infiltrates, or respiratory distress 
should be evaluated for the possibility of ARDS.  In the event that ARDS occurs, 
pegfilgrastim should be discontinued and/or withheld until resolution of ARDS and patients 
should receive appropriate medical management for this condition. 


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Rare cases of allergic-type reactions have been experienced by patients receiving 
pegfilgrastim in the post-marketing setting. This is similar to allergic-type reactions, 
including anaphylaxis, skin rash, and urticaria, occurring on initial or subsequent 
treatments that have been reported with the parent compound of pegfilgrastim, filgrastim. 
In some cases, symptoms have recurred with re-challenge with Filgrastim, suggesting a 
causal relationship. If a serious allergic reaction or anaphylactic reaction occurs, 
appropriate therapy should be administered and further use of pegfilgrastim should be 
discontinued. 
 
Severe sickle cell crisis has been reported in patients with sickle cell disease (specifically 
homozygous sickle cell anemia, sickle/hemoglobin C disease, and sickle+ thalassemia) 
who received filgrastim, the parent compound of pegfilgrastim, for PBPC mobilization or 
following chemotherapy. One of these cases was fatal. 
 
Filgrastim (Neupogen®) 
 
Side-effects include chills, fever, nausea, anorexia, myalgia, bone pain, local injection site 
pain or inflammation, elevated liver function, thinning of hair, enlargement of spleen, and 
rarely fluid retention and pericardial effusion. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
At the time of each re-evaluation, patients will be classified in the following manner: 
 
• 
No evidence of disease. 
 
• 
Breast cancer recurrence:  Local/regional breast cancer recurrence is defined as the 
development of tumor (except LCIS) in the ipsilateral breast (after lumpectomy); in the 
soft tissue/chest wall and/or skin of the ipsilateral chest wall; or tumor in the ipsilateral 
internal mammary, supraclavicular, infraclavicular, or axillary nodes or soft tissue of 
ipsilateral axilla.  Suspected tumor recurrence in the ipsilateral breast, chest wall 
structures, supraclavicular, or lower (level I ± II) axillary nodal areas must be confirmed 
by biopsy or cytology.  Histologic or cytologic confirmation of tumor is recommended for 
internal mammary or infraclavicular/high axillary nodal recurrence.  A distant recurrence 
is defined as development of tumor in areas other than the local/regional area that is 
documented by a positive cytology aspirate, biopsy, or imaging studies. 
 
• 
New primary:  A new primary is defined as the development of contralateral breast 
cancer or a second cancer other than squamous or basal cell carcinoma of the skin, 
carcinoma in situ of the cervix or LCIS of the breast that is histologically confirmed. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
• 
Cardiac Death 
 
• 
Symptomatic CHF 
 
• 
Grade 3 or greater QTc prolongation on EKG on 2 consecutive EKGS within 4 weeks 
apart 
 
• 
2 “consecutive” or 3 “intermittent” H + L hold categories for “asymptomatic” LVEF decline 


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• 
More than one dose reduction of paclitaxel due to toxicities 
 
• 
More than one dose reduction of lapatinib 
 
• 
More than 3 consecutive weeks of holding lapatinib due to toxicities (except when holding 
lapatinib due to an asymptomatic LVEF decline) 
 
• 
Disease recurrence 
 
• 
Unacceptable toxicity 
 
• 
Intercurrent, non-cancer related illness that prevents continuation of protocol therapy or 
follow-up 
 
• 
Major protocol violation that would render the patient inevaluable for efficacy (ie: the 
initiation of non-protocol antineoplastic therapy or the discovery of information that, if 
known, would have rendered the patient ineligible for the study) 
 
• 
Repeated non-compliance by the patient with protocol requirements 
 
• 
Changes in the patient’s condition or study drug related toxicity such that, in the opinion of 
the investigator, continued participation in the protocol would compromise patient well- 
being 
 
• 
Withdrawal of patient’s consent 
 
• 
Any signs or symptoms of pneumonitis that are >Grade 3 (NCI CTCAE) (defined as 
radiographic changes and requiring oxygen).  Refer to NCI CTCAE grading of 
pneumonitis/pulmonary infiltrates. 
 
 
14.0 
BIOSTATISTICS 
 
This is a feasibility trial of a dose-dense adjuvant chemotherapy regimen that consists of 
paclitaxel (175 mg/m2) q 14 days x 4 with pegfilgrastim + trastuzumab (4 mg/kg bolus → 2 mg/kg) 
+ daily lapatinib followed by q 21 day trastuzumab (6 mg/kg) + daily lapatinib. The primary 
objective of this trial is to determine the feasibility of this regimen in patients with node-negative 
HER-2/neu overexpressed /amplified breast cancer with a tumor size of < 3 cm. The regimen is 
considered feasible for patients who are able to complete the paclitaxel, trastuzumab, and 
lapatinib (THL) portion of the regimen without a dose delay or reduction or grade 3 or greater QTc 
prolongation.   If the trial stops early for serious cardiac toxicity or excessive grade 3 
gastrointestinal toxicity, the regimen will be deemed not feasible. The allowable incidence of 
cardiac events (CHF, cardiac death) is set to be < 4% and the acceptable incidence of grade 3 
gastrointestinal toxicity is set at 20%.  A cardiac event (CE) is defined as 1) cardiac death or 2) 
symptomatic congestive heart failure (CHF) defined as dyspnea with normal activity or at rest and 
“absolute” decline in LVEF by > 10% to < 50 %. A cardiac event will result in discontinuation of 
trastuzumab and lapatinib. 
 
We will accrue 55 patients for this study. Based on the accrual rate from prior studies, accrual is 
expected to take 12 months.  Any patient who receives treatment on study, regardless of the 
ability to complete treatment, is evaluable. Any patient who is removed from the study for any 
reason prior to the 12 month mark will be classified as not being able to complete the regimen. 


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Greater than 85% of the patients on standard adjuvant trials complete the intended study 
regimens without a dose-delay or reduction.  As the incidence of QT prolongation was reported in 
13/81 (16%) in a group of patients followed with serial EKG monitoring, we anticipate that the 
incidence of QT prolongation on this study to be < 20%.  Thus, for this study, we would like to be 
able to discriminate between feasibility rates of 65% (unpromising) and 80% (promising). If a 
patient has more than one dose delay or dose reduction for any reason, these events are 
collectively counted as one entity in the same patient. With 55 patients, this design discriminates 
between true completion rates of ≤ 65% and ≥ 80% at a Type I error of 5% and a Type II error of 
20%.  A feasibility rate of ≤ 65% will indicate that this regimen is not feasible and not worthy for 
further investigation. The paclitaxel, trastuzumab, and lapatinib (THL) portion of the regimen will 
be considered feasible and warrant further clinical study if 42 or more patients are able to 
complete this portion of the regimen without a dose delay or reduction. 
 
We have incorporated two early stopping rules. First, the study design includes early termination 
in the event of excessive grade 3 diarrhea. The allowable grade 3 diarrhea rate is set at 20% and 
the unacceptable rate is set at 40%. The boundaries are based on a maximum accrual of 55 
patients. The below table provides the stopping boundary based on repeated significance testing: 
 
First 10 patients 
stop if 5 grade 3 GI toxicities are observed 
 
20 patients 
stop if 8 grade 3 GI toxicities are observed 
 
30 patients 
stop if 10 grade 3 GI toxicities are observed 
 
40 patients 
stop if 13 grade 3 GI toxicities are observed 
 
50 patients 
stop if 15 grade 3 GI toxicities are observed 
 
55 patients 
stop if 17 grade 3 GI toxicities are observed 
 
 
 
If the true toxicity rate is 20%, the probability the study will be stopped is 12%, while if the true 
toxicity rate is 40%, the probability the study will be stopped is 97%. The study will not be halted 
after each set of 10 patients is accrued. 
 
For the second stopping rule, the study design includes an early stopping rule to account for the 
possibility of cardiac events. The allowable incidence of cardiac events (CHF, cardiac death) is 
set to < 4%, to be consistent with the reported adjuvant trastuzumab trials (19-21).  Since the 
clinical significance of asymptomatic LVEF decline is unknown, patients will be followed long- 
term. The study will be stopped if there are 3 cardiac events that occur at any time as one of the 
following two scenarios: 1) if there is 1 cardiac death and 2 symptomatic CHF events 2) if there 
are 3 symptomatic CHF events.  The probability of stopping the trial is 38% if the true cardiac 
event rate is 4% and 83% if the true cardiac event rate is 8%.In addition, if there are any cardiac 
deaths at any time, the trial will be terminated. 
 
Patients from the terminated trial will receive care according to the discretion of their treating 
physicians. 
 
Upon completion of the study, the rate of patients who complete the paclitaxel, trastuzumab, and 
lapatinib portion of the regimen without a dose delay or reduction will be estimated via the 
observed completion rate and an exact confidence interval will be constructed. 


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Selected non-hematologic and hematologic toxicities will be described by frequency and grade, 
by cycle and over all cycles, with the maximum grade over all cycles used as the summary 
measure per patient. 
 
There are several secondary analyses planned.  Serial blood measurements of cardiac markers 
(cTnI, and BNP) will be examined. We will also assess the LVEF at baseline at months 2, 6, 9, 12 
and 18 with an ECHO. When an ECHO cannot be done, a multi-gated acquisition scan (MUGA) 
may be done. EKG will also be done at months 2, 6, 9, 12 and 18.To assess cardiac safety of 
this regimen, analysis of the cardiac biomarkers and changes seen on echocardiogram/EKG will 
be correlated. In a descriptive, graphical analysis, changes in cardiac biomarkers will be 
examined in patients who develop cardiac toxicity and compared to changes seen in patients who 
did not develop a cardiac toxicity. We will also explore the use of single-nucleotide polymorphism 
(SNP) genotyping in evaluation of pharmacogenetic determinates of gastrointestinal toxicity. 
 
All toxicities following chemotherapy will be graded using the National Cancer Institute – Common 
Toxicity Criteria version 4.0. We will use logistic regression models to estimate the odds ratio and 
95% confidence intervals for the association of each SNP with the incidence of grade 3 or higher 
diarrhea. The major endpoint in this clinical pharmacogenomics study is to determine the 
association between variant genotypes and toxicity. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/). The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant 
documents must be uploaded via the PPR Electronic Registration System. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
 
The Clinical Research Database (CRDB) will be used for data collection. The data will be 
reported to the institution (IRB) and the sponsor (Roche) as appropriate. 
 
It is estimated that 5-7 patients will be accrued per month and it will take 12 months to 
accrue. 


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Participating sites that are consulting and/or conducting specimen or data analysis should 
submit this protocol to their IRB according to local guidelines. Copies of any site IRB 
correspondence should be forwarded to MSKCC. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals, protocol 
compliance, eligibility verification, informed consent procedure, data accuracy, and 
completeness of registration data.  Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period and 
potential problems will be brought to the attention of the study team for discussion and 
action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of  2 times a year,  more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address 
the new policies set forth by the NCI in the document entitled “Policy of the National 
Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Qu 
ality%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20P 
lan.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality.  There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the activities 
of our clinical trials programs. The committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board 
(DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 


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17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side 
effects. Every effort will be made to keep study records private. Neither the patient's name 
nor anything else that could identify the patient will be used in any reports or publications that 
result from this study. Trained staff at Memorial Hospital will be able to review the medical 
records if necessary. The patient may terminate her participation in the study at any time 
during the trial. 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 


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written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
 
17.2.1 Reporting SAEs: 
 
All SAE reports must also be forwarded as soon as possible to: 
 
Study Coordination Center/Principal Investigator: Chau Dang, M.D. 
Contact Information phone: 646-888-4554 fax: 646-888-4555 
 
 
All SAEs that are serious and reasonably or probably related to the use of lapatinib (this 
applies to both expected and unexpected events) should be recorded on an MSK CRDB 
SAE report and faxed as soon as possible to: 
 
Stephen Rubin, M.D., 
Office: (610) 917-5235 
Mobile: (484) 620-9545
or 
Rob Friedman, B.Sc. 
Office: (610) 917-7456 
Mobile: (484) 802-4002
or 
Allitia DiBernardo 
Office fax: (610) 675-2602 
Mobile: (484) 620-9545 
 
 
 
 
 
Toll Free Number: (800) 877-7074, ext. 5731 or 6862 
 
After Hours or Weekends: (800) 366-8900, ask for physician on call 
 
 
 
GlaxoSmithKline UP4420 
 
1250 S. Collegeville Road, 
P.O. Box 5089 
Collegeville, PA  19426-0989 
 
 
Adverse Event Reporting Definitions: 
 
A serious treatment emergent adverse event (STEAE) is any sign, symptom or medical condition that 
emerges during lapatinib treatment or during a post-treatment follow-up period that (1) was not 
present at the start of lapatinib treatment and it is not a chronic condition that is part of the patient’s 
medical history, OR (2) was present at the start of lapatinib treatment or as part of the patient’s 
medical history but worsened in severity and/or frequency during therapy, AND that meets any of the 
following regulatory serious criteria: 
 
• 
Results in death 


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• 
Is life-threatening 
• 
Requires or prolongs inpatient hospitalization 
• 
Is disabling 
• 
Is a congenital anomaly/birth defect 
• 
Is medically significant or requires medical or surgical intervention to prevent one of the 
outcomes listed above. 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCES 
 
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2.        Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and the 
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Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for 
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Slamon DJ, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin 
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Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized 
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Perez EA, Romond EH, Suman VJ, et al. Updated results of the combined analysis of 
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combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic 
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relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem 
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45. 
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of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 2001;11:597– 607. 
 
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the CYP2C8 gene result in reduced in vitro paclitaxel metabolism. Biol Pharm Bull 2001;24:1427– 
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47. 
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ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res 2005;11:8097– 
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48. 
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polymorphic cytochrome P450 2C19. Pharmacogenomics J 2005;5:365–373. 
 
51. 
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metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, 
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hydroxycyclophosphamide. Pharmacogenet Genomics 2008;18:515–523. 
 
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Rodriguez-Antona C, Sayi JG, Gustafsson LL et al. Phenotype-genotype variability in the 
human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 
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53. 
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hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 
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the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383–391. 
 
58. 
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E, van der Straaten T, Baak-Pablo RF, Wessels JA, Guchelaar HJ, Gelderblom H. 
Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol. 
2009;27(26):4406. 
 
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Braunwald E. Biomarkers in heart failure. The New England journal of medicine 
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Cardinale D, Sandri MT, Martinoni A, et al. Myocardial injury revealed by plasma troponin I in 
breast cancer treated with high-dose chemotherapy. Ann Oncol 2002;13:710-5. 
 
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Morris PG, Chen C, Steingart R, et al.  Troponin I and C-reactive protein are commonly 
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trastuzumab and lapatinib. Clin Cancer Res 15:3490-3499, 2011. 
 
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Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced cardiotoxicity: clinical and 
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Perik PJ, De Vries EG, Boomsma F, et al. Use of natriuretic peptides for detecting cardiac 
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73.      Aggarwal S, Pettersen MD, Bhambhani K, Gurczynski J, Thomas R, L'Ecuyer T. B-type 
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scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast 
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Jones LW, Haykowsky M, Peddle CJ, et al. Cardiovascular risk profile of patients with 
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76. 
Kutteh LA, Hobday T, Jaffe A, et al. A correlative study of cardiac biomarkers and left 
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trastuzumab as adjuvant therapy for HER2-positive breast cancer. J Clin Oncol (Meeting Abstracts) 
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Lemmens K, Doggen K, De Keulenaer GW. Role of neuregulin-1/ErbB signaling in 
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Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM. Modulation of 
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79. 
Liu FF, Stone JR, Schuldt AJ, et al. Heterozygous knockout of neuregulin-1 gene in mice 
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80. 
Chien KR. Herceptin and the heart--a molecular modifier of cardiac failure. The New England 
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Ky B, Kimmel SE, Safa RN, et al. Neuregulin-1 beta is associated with disease severity and 
adverse outcomes in chronic heart failure. Circulation 2009;120:310-7. 


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APPENDIX A: ECOG PERFORMANCE STATUS SCALE 
 
 
Grade 
Description 
0 
Fully active, able to carry out all normal activity without restriction 
(Karnofsky 100) 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out light work (Karnofsky 90-80) 
2 
Ambulatory and capable of all self-care but unable to carry out any work. 


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Up and about more than 50% of waking hours (Karnofsky 70-60) 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours (Karnofsky 50-40) 
4 
Completely disabled.  Cannot carry out any self-care. Totally confined to 
bed or chair (Karnofsky 30-20) 
5 
Death 


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APPENDIX B: MANAGEMENT OF ACUTE HYPERSENSITIVITY 
 
Severity of Symptoms 
Treatment Guidelines 
Mild symptoms: localized cutaneous 
reactions such as mild pruritus, 
flushing, rash 
· 
consider decreasing the rate of infusion until 
recovery from symptoms, stay at bedside and 
monitor patient 
· 
then, complete taxane infusion at the initial 
planned rate 
Moderate symptoms: any symptom that 
is not listed above (mild symptoms) or 
below (severe symptoms) such as 
generalized pruritus, flushing, rash, 
dyspnea, hypotension with systolic BP > 
80 mm Hg 
· 
interrupt taxane infusion 
· 
give diphenhydramine 50 mg IV with or 
without dexamethasone 10 mg IV; monitor 
patient until resolution of symptoms 
· 
resume taxane infusion after recovery of 
symptoms; depending on the physician’s 
assessment of the patient, taxane infusion 
should be resumed at a slower rate, then 
increased incrementally to the initial planned 
rate, (eg. infuse at an 8 hour rate for 5 
minutes, then at a 4-h rate for 5 minutes, and 
then finally, resume at the 3-h infusion rate) 
· 
depending on the intensity of the reaction 
observed, additional oral or IV premedication 
with an antihistamine should also be given for 
the next cycle of treatment, and the rate of 
infusion should be decreased initially and 
then increased back to the initial planned rate, 
(eg. infuse at an 8 hour rate for 5 minutes, 
then at a 4-h rate for 5 minutes, and finally, 
administer at the 3-h infusion rate) 
Severe symptoms: any reaction such as 
bronchospasm, generalized urticaria, 
systolic BP  80mm Hg, angioedema 
· 
immediately discontinue taxane infusion 
· 
give diphenhydramine 50 mg IV with or 
without dexamethasone 10 mg IV and/or 
epinephrine as needed; monitor patient until 
resolution of symptoms 
· 
the same treatment guidelines outlined under 
moderate symptoms (i.e. the third and fourth 
bullets) should be followed. 
Anaphylaxis  (NCI grade 4 reaction) 
· 
NO FURTHER STUDY DRUG THERAPY 
 
 
 
 
 
APPENDIX C: Supportive Care Guidelines for Lapatinib 


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Rash: Skin rash (usually grade 1-2) has been observed during the first several days of treatment 
with EGFR inhibitors and has been observed to diminish in severity after 4 weeks of treatment in 
many patients.  In some patients, this rash appeared to be treatable with standard acne therapies, 
including topical and oral antibiotics used to treat acne.  Anecdotal reports of improvement have 
occurred with several agents. In patients with severe rash, treatment may need to be discontinued 
or the dose reduced.  Anecdotal reports of improvement have occurred with any of the following: 
minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, diphenhydramine, 
oral prednisone (short course). 
 
Diarrhea: Diarrhea has been seen with lapatinib and with other EGFR inhibitors. In general EGFR 
inhibitor-induced diarrhea has been transient, usually not of sufficient severity to hinder 
administration of the agents, and responsive to loperamide. The recommended dose of loperamide 
is 4 mg at first onset, followed by 2 mg q 2–4 hr until diarrhea free for 12 hr. 
 
Lapatinib Diarrhea Management Guidelines: 
 
Uncomplicated grade 1-2 diarrhea: 
Stop all lactose containing products; 
Drink 8-10 large glasses of clear liquids a day; 
Eat frequent small meals; 
Grade 2 diarrhea hold cytotoxic chemotherapy; 
Grade 2 diarrhea consider dose reduction of lapatinib (discuss with medical monitor); 
Administer standard dose of loperamide: 
Initial dose 4mg followed by 2mg every 4 hours or after every unformed stool. 
We suggest continuation of loperamide until diarrhea free for 12 hours. 
 
For grade 3 or 4 diarrhea or grade 1 or 2 with complicating features (severe 
cramping, severe nausea/vomiting, decreased performance status, fever, sepsis, 
grade 3 or 4 neutropenia, frank bleeding, dehydration): 
Use intravenous fluids as appropriate, consider hospital admission; 
Use prophylactic antibiotics as needed (example fluoroquinolones), especially if 
diarrhea is persistent beyond 24 hours or there is fever or grade 3-4 neutropenia; 
Hold both cytotoxic chemotherapy and lapatinib and discuss with medical monitor. 
 
These broad general management principles are recommended to proactively try and 
avoid more serious complications by active management of the diarrhea syndrome. 
Guidelines such as these should never replace sound clinical judgment. Our 
experience thus far suggests that when lapatinib is used as monotherapy we mostly 
are dealing with uncomplicated grade 1 or 2 diarrheas. These general management 
principles do not discuss comprehensive management of more serious or protracted 
diarrhea syndromes. 
 
Nausea: Routine premedication for nausea is not necessary, but symptomatic patients should be 
treated with standard antinausea/antiemetic therapy as necessary. 
 
If the patient vomits after taking the tablets, the dose is replaced only if the tablets can actually be 
seen and counted. 
 
 
 
 
APPENDIX D 


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Lapatinib Diary Take 1000 mg (4 tablets) either 1 hour (or more) before meals or 1 hour (or more) after meals. 
Lapatinib should not be taken with grapefruit or grapefruit juice. Please remember to return your pill bottle (with any 
remaining pills) and log sheet when you are due to start a new bottle. 
 
Lapatinib 
Date: 
AM Time: 
PM Time: 
Day # 1: 
Day # 2: 
Day # 3: 
Day # 4: 
Day # 5: 
Day # 6: 
Day # 7: 
Day # 8: 
Day # 9: 
Day # 10: 
Day # 11: 
Day # 12: 
Day # 13: 
Day # 14: 
Day # 15: 
Day # 16: 
Day # 17: 
Day # 18: 
Day # 19: 
Day # 20: 
Day # 21: 
Day # 22: 
Day # 23: 
Day # 24: 
Day # 25: 
Day # 26: 
Day # 27: 
Day # 28: 
  
Date Returned:   
 #Pills returned:   
 
 
Patients’ signature:  
RN Signature:    
 


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APPENDIX E: Prohibited Concomitant Medications with Lapatinib 
 
 
Drug Class 
Agent 
Wash-out1 
CYP3A4 Inducers 
Antibiotics 
All rifamycin class agents (ie: 
rifampicin, rifabutin, 
rifapentine) 
14 days 
Anticonvulsants 
phenytoin, carbamazepine, 
barbiturates (ie: 
phenobarbital) 
14 days 
Antiretrovirals 
efavirenz, nevirapine 
14 days 
Glucocorticoids 
cortisone (>50 mg), 
hydrocortisone (>40 mg), 
prednisone (>10 mg), 
methylprednisolone (>8 mg), 
dexamethasone (>1.5 mg)2 
14 days 
Other 
St. John’s Wort, modafinil 
14 days 
CYP3A4 Inhibitors 
Antibiotics 
clarithromycin, erythromycin, 
troleandomycin 
7 days 
Antifungals 
itraconazole, ketoconazole, 
fluconazole (>150 mg daily), 
voriconazole 
7 days 
Antiretrovirals, Protease 
Inhibitors 
declaviridine, nelfinavir, 
amprenavir, ritonavir, 
indinavir, saquinavir, lopinovir 
7 days 
Calcium channel blockers 
verapamil, diltiazem 
7 days 
Antidepressants 
nefazodone, fluvoxamine 
7 days 
GI agents 
cimetidine, aprepitant 
7 days 
Other 
grapefruit, grapefruit juice, 
7 days 
amiodarone 
6 months 
Miscellaneous 
Antacids 
Mylanta, maalox, tums, 
rennies 
1 hour before and after dosing 
Herbal supplements3 
Ginkgo biloba, kava, grape 
seed, valerian, ginseng, 
echinacea, evening primrose 
oil 
14 days 
 
1.  At the time of screening, if a patient 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 lapatinib 
and throughout the study period in order for the patient to be eligible to participate in the 
study. 
2.  Glucocorticoid daily doses (oral) of < 1.5 mg dexamethasone (or equivalent) are allowed. 
Oral or IV steroids given prior to paclitaxel administration as part of this study are allowed. 
3.  This list is not all-inclusive; thus, for herbal supplements not listed, please contact GSK 
Medical Monitor or Clinical Scientist. 


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APPENDIX F: National Cancer Institute Prolonged QTc Clinical Terminology Criteria for 
Adverse Events 
 
QTc Prolongation Grade 
Definition 
I 
QTc > 450-470 ms 
II 
QTc > 470-500 ms or > 60 ms above baseline 
III 
QTc > 500 ms 
IV 
QTc > 500 ms; life-threatening signs or 
symptoms (ie: arrhythmia, CHF, hypotension, 
shock, syncope), torsades de pointes 
V 
Death 
 
Abbreviations: 
QTc = corrected QT 
ms = millisecond 
CHF = congestive heart failure 


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APPENDIX  G: National Cancer Institute Terminology Criteria for Grading Diarrhea Adverse 
Events 
  
 
 
Adverse 
Event Grade 
Olarmea 
1 
Increase of <4 stoolslday over baseline  rruld tncrease tn ostomy output compared to 
baseltne 
2 
Increase of 4-6 stools/day over baseftne.moderate tnaease tn ostomy output 
compared to baseline 
3 
Increase of ?!7 stools/day over baseltne.incontilence.hospitafJZabon tndtcaled. severe 
increase in ostomy output compared to baseline,limiting self care activities of daily 
IMng (AOL) 
4 
Lifelhreatening consequences,urgent mterventionincicated 
5 
Death 
1.  Nabonal Cancer lnsbhr.e Common Termmaogy Critena 'nr Adverse Events (CTCAE) Versm 4 0 
 
 
l ocompticared diarrhea 
15 cons1ded nuld-to-moderate and defined  as CTCAE 
Grade 1 or 2 wtth  no comphcahng signs or symptoms. 
 
Complicated diarrhea 
tS  st-vere and defined  as an , CTCAE  Grade 3 or 4 diarrhea. 
or Grade 1 or 2 wllh one or more of the follo\\'lllg stgns or symptoms: 
 
• 
Moderate  ro severe abdorrunnl crampwg 
• 
Naust-a vonutmg .?Grnde2 
• 
Dt"creased performance status 
• 
Fever 
• 
epSlS 
• 
Neutropt-rua 
• 
Frank bleeding  (d blood in stool) 
• 
Deh •drahon 


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APPENDIX H: Management Guidelines for Subjects Receiving Lapatinib Alone or as 
Combination Therapy 
 
 


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Algorithm for the management of diarrhea in subjects treated with lapatinib-based therapy 
 
RECOMMENDATION 
• 
Loperamide prescription with instructions on administration for all subjects receiving 
lapatinib 
• 
Patient diary to record baseline bowel patterns and changes; dietary changes 
EVALUATION 
• 
Obtain history of onset and duration of diarrhea 
• 
Describe number of stools and stool composition (Refer to baseline) 
• 
Assess subject for fever, dizziness, abdominal pain/cramping or weakness 
 
 
UNCOMPLICATED 
Grade 1 or Grade 2 with no 
complicating signs or symptoms 
 
 
MANAGEMENT 
ADDED RISK 
FACTORS 
COMPLICATED 
Grade 3 or 4 diarrhea or Grade 1 or 2 with ≥1 of these signs 
or symptom: 
• 
Cramping (Moderate/severe) 
• 
Nausea/Vomiting (≥ Grade 2) 
• 
Decreased performance status 
• 
Subjects should be instructed to administer loperamide and 
notify physicians 
• 
Discontinue lactose products 
• 
Drink 8-10 large glasses of clear liquids per day 
• 
Eat frequent small meals 
• 
Eat foods low in fiber 
• 
Continue with lapatinib-based treatment 
 
 
 
Reassess 24 hours later 
 
 
Diarrhea Unresolved 
• 
Continue loperamide 
• 
Continue dietary 
modifications 
• 
Evaluate for possible 
infection (Grade 2) 
• 
Fever 
• 
Sepsis 
• 
Neutropenia 
• 
Frank bleeding 
• 
Dehydration 
  
 
MANAGEMENT 
• 
Subjects should call physician immediately 
• 
Grade 3: hold lapatinib and chemotherapy (if applicable) 
• 
Grade 4: discontinue lapatinib 
• 
Evaluate for possible infection 
• 
Consider hospitalization 
SUGGESTED TREATMENT 
• 
Administer loperamide 
• 
Hydration (i.v. fluids as needed) 
• 
Consider need for antibiotics and consider second line 
 
 
 
 
Diarrhea Resolving 
• 
Continue instructions for 
dietary modifications 
• 
Gradually add solid food to 
diet 
• 
Discontinue standard anti- 
diarrheal after 12-hour 
diarrhea-free interval 
• 
If applicable resume 
treatment with lapatinib and 
chemotherapy 
Reassess 24 hours 
 
 
 
 
Diarrhea unresolved 
• 
Continue loperamide (Grade 1) 
• 
Start second line anti-diarrheal 
agents (Grade 2) 
• 
Start second line anti-diarrheal 
agents for Grade 1 diarrhea 
that does not improve after 1 
week of loperamide treatment 
 
 
Diarrhea Free for 24 hours 
• 
Discontinue diarrhea intervention 
 
For Grade 3 
• 
Reintroduce lapatinib as a reduced 
dose (if dose was >750mg) and 
chemotherapy (if applicable) 
o 
Consider dose reduction 
for chemotherapy