Conditions: Breast Cancer
Keywords: Neoadjuvant Breast Cancer HER2 positive Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: no

Brief summary:
This is a randomized, open label Phase II neoadjuvant study comparing the efficacy and safety of trastuzumab emtansine (T-DM1) plus lapatinib (L)followed by abraxane (A) versus trastuzumab plus pertuzumab followed by paclitaxel in patients with HER2-overexpressing breast cancer.

Detailed description:
This is a randomized, open label Phase II neoadjuvant study comparing the efficacy and safety of trastuzumab emtansine (T-DM1) plus lapatinib (L) followed by abraxane (A) versus trastuzumab plus pertuzumab followed by paclitaxel in patients with HER2-overexpressing breast cancer. Patients will be randomized (1:1) to one of the two treatment arms: arm 1, trastuzumab emtansine plus lapatinib for 6 weeks, followed by trastuzumab emtansine plus lapatinib plus abraxane for 12 weeks; arm 2, trastuzumab plus pertuzumab for six weeks, followed by trastuzumab plus pertuzumab plus paclitaxel for 12 weeks. Patients will undergo surgery after neoadjuvant therapy. All patients will have a core needle biopsy at baseline, after week 6, and at the time of disease progression. Surgical specimens will be obtained after week 18.

Arms:
arm 1: T-DM1 intravenously (IV) every three weeks plus L orally once daily for 6 weeks followed by abraxane IV weekly for 12 weeks. arm 2: Trastuzumab IV weekly plus pertuzumab IV every 3 weeks for 6 weeks, followed by paclitaxel IV weekly for 12 weeks.

Interventions: intervention 1: T-DM1 intervention 2: Trastuzumab intervention 3: Lapatinib intervention 4: Abraxane intervention 5: Paclitaxel intervention 6: Pertuzumab
Intervention descriptions: intervention 1: antibody-drug conjugate of trastuzumab and emtansine intervention 2: anti-Her2 monoclonal antibody intervention 3: Dual tyrosine kinase inhibitor (HER2 and EGFR) intervention 4: albumin-bound paclitaxel. chemotherapy - microtubule inhibitor. intervention 5: chemotherapy - microtubule inhibitor intervention 6: anti-HER2 monoclonal antibody

Protocol document:
Prot_SAP_000.pdf: 
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RANDOMIZED OPEN LABEL PHASE II TRIAL OF NEOADJUVANT TRASTUZUMAB 
EMTANSINE (TE) IN COMBINATION WITH  LAPATINIB (L) FOLLOW BY ABRAXANE (A) 
COMPARED WITH TRASTUZUMAB PLUS LAPATINIB FOLLOW BY PACLITAXEL  IN 
HER 2 NEU OVER-EXPRESSED BREAST CANCER PATIENTS 
 
 
 
 
 
 
 
 
 
 
Authors 
Jenny Chang, M.D. 
Jaime A. Mejia, M.D. 
Document type 
Trastuzumab Emtansine  (TDM-1)-Lapatinib-Abraxane Use Protocol  
IRB  number 
N/A 
Version number 
V1 
Development  phase 
II  
Document status 
Final 
Release date 
(01/23/2014) 


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Table of contents 
Table of contents ..................................................................................................................................... 2 
List of figures ........................................................................................................................................... 3 
List of tables ............................................................................................................................................ 3 
List of abbreviations................................................................................................................................. 3 
Glossary of terms .................................................................................................................................... 5 
1. 
Background ............................................................................................................................................. 6 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .................................. 6 
2. 
Significance and Rationale ...................................................................................................................... 7 
2.1 
Innovation .................................................................................................................................. 9 
2.2 
Approach Preliminary Studies .................................................................................................. 10 
3. 
Hypothesis: ............................................................................................................................................ 13 
4. 
Objectives and endpoints ...................................................................................................................... 13 
5. 
Study design .......................................................................................................................................... 14 
5.1 
Description of study design ...................................................................................................... 14 
6. 
Treatment Arms ..................................................................................................................................... 14 
7. 
Population ............................................................................................................................................. 15 
8. 
Inclusion and Exclusion criteria ............................................................................................................. 15 
8.1 Inclusion criteria ............................................................................................................................ 16 
8.2 Exclusion criteria ........................................................................................................................... 17 
9. 
Treatment .............................................................................................................................................. 17 
9.1 Trastuzumab Emtansine (TDM-1) General Infortmation ................................................................ 18 
9.2 Trastuzumab (Herceptin) General Infortmation ............................................................................. 20 
9.3 Lapatinib General Infortmation ...................................................................................................... 23 
9.4 Abraxane General Infortmation ..................................................................................................... 36 
9.5 Paclitaxel General Infortmation ..................................................................................................... 45 
10. Prohibited concomitant therapy ............................................................................................................. 50 
11. Visit schedule and assessments ........................................................................................................... 50 
11.1 
Study flow and visit schedule ................................................................................................... 50 
12. Assessment types ................................................................................................................................. 55 
12.1 
Criteria For Response .............................................................................................................. 56 
12.2 
RECIST Criteria ....................................................................................................................... 56 
12.3 
Withdrawal of subjects from study ........................................................................................... 56 
12.4 
Pregnancy and assessments of fertility .................................................................................... 57 
13. Safety monitoring and reporting ............................................................................................................ 57 
13.1 
Adverse events ........................................................................................................................ 58 
13.1.1 
Definitions and reporting ....................................................................................... 58 
13.1.2 
Laboratory test abnormalities ................................................................................ 58 


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14. Serious Adverse Events ........................................................................................................................ 59 
14.1 
Definitions ............................................................................................................. 59 
14.1.1 
Reporting ............................................................................................................... 59 
14.1.2 
Pregnancy ............................................................................................................. 60 
15. Statistical methods ................................................................................................................................ 61 
15.1 
Sample Size. ............................................................................................................................ 61 
16. Protocol amendments, or changes in study conduct ............................................................................. 61 
17. References: ........................................................................................................................................... 62 
18. Appendices ............................................................................................................................................ 64 
LIST OF FIGURES 
Figure 1 
Inhibitory effects of various HER2 drug combinations ........................................... 10 
Figure 2 
Changes in apoptosis as measured by cleaved caspase 3 ................................... 11 
Figure 3 
Gene mutation profile ............................................................................................ 12 
Figure 4 
Somatic chromosomal copy number alterations .................................................... 12 
Figure 5 
Study design ......................................................................................................... 14 
LIST OF TABLES 
 
Table 1 
Trastuzumab Emtansine dose modifications ............................................................... 17 
Table 2 
Trastuzumab Emtansine side effects ........................................................................... 19 
Table 3 
Trastuzumab Pharmacokinetics  ................................................................................. 20 
Table 4 
Trastuzumab Side effects ............................................................................................ 21 
Table 5  
Trastuzumab Interactions Agents ................................................................................ 23 
Table 6 
Trastuzumab dosage Guidelines ................................................................................. 23 
Table 7 
Lapatinib Pharmacokinetics ......................................................................................... 24 
Table 8 
Lapatinib Side Effects .................................................................................................. 25 
Table 9 
Lapatinib Side Effects .................................................................................................. 26 
Table 10 
Lapatinib Dose holding & interruptions ........................................................................ 32 
Table 11 
Lapatinib Interactions ................................................................................................... 33 
Table 12 
Lapatinib prohibited medications ................................................................................. 34 
Table 13 
Lapatinib Reporting SAEs ............................................................................................ 35 
Table 14 
Abraxane AEs  ............................................................................................................. 41 
Table 15 
Abraxane Dose Modifications ...................................................................................... 42 
Table 16 
Abraxane Hematologic Toxicities................................................................................. 42 
Table 17 
Paclitaxel Pharmacokinetics ........................................................................................ 46 
Table 18 
Paclitaxel Side Effects ................................................................................................. 47 
Table 19 
Paclitaxel Side Interactions .......................................................................................... 49 
Table 20 
Paclitaxel in hepatic failure .......................................................................................... 49 
Table 21 
SOE Arm 1................................................................................................................... 51 
Table 22 
SOE Arm 2................................................................................................................... 53 
List of abbreviations 


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Glossary of terms 
 


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1. 
Background 
1.1 Overview of disease pathogenesis, epidemiology and current treatment 
Several drugs have been developed and are in clinical use to block the HER pathway, most aimed at the receptor 
level.  [T-DM1] Trastuzumab Emtansine Antibody-drug conjugates (ADCs) are monoclonal antibodies to which 
highly potent cytotoxic agents have been conjugated. They represent a novel approach to conferring selectivity to 
systemically administered anti-tumor therapeutics. ADCs are designed to focus the delivery of highly potent 
cytotoxic agents to tumor cells by targeting surface antigens that are tumor-specific and/or overexpressed. This 
approach potentially creates a more favorable therapeutic window for such agents than can be achieved by their 
administration as free drugs. 
Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate which contains the humanized anti-
HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via 
the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-
DM1 complex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.  
Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumor cells, 
thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab 
emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in 
release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).  
Trastuzumab emtansine has the mechanisms of action of both trastuzumab and DM1  
- Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain (ECD), as well 
as to Fcγ receptors and complement C1q. In addition, trastuzumab emtansine, like trastuzumab, inhibits shedding 
of the HER2 ECD, inhibits signaling through the phosphatidylinositol 3-kinase (PI3-K) pathway, and mediates 
antibody-dependent cell-mediated cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.  
- DM1, the cytotoxic drug component of trastuzumab emtansine, binds to tubulin. By inhibiting tubulin 
polymerization, trastuzumab emtansine causes cells to arrest in the G2/M phase of the cell cycle, ultimately leading 
to apoptotic cell death. Results from in vitro cytotoxicity assays show that DM1 is 20-200 times more potent than 
taxanes and vinca alkaloids.  
- The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, as demonstrated by 
detection of very low levels of free DM1 in plasma.  
Trastuzumab emtansine has demonstrated a consistent toxicity and tolerability profile across all studies conducted 
to date in breast cancer patients. Thrombocytopenia, increases in serum AST and ALT, infusion/hypersensitivity 
reaction, and pneumonitis have been identified as risks with trastuzumab emtansine use. Refer to the trastuzumab 
emtansine Investigator Brochure for additional details about the clinical experience with trastuzumab emtansine. 1 
 
Lapatinib is an orally active dual HER1/HER2 kinase inhibitor that blocks signal transduction pathways.  It markedly 
reduces tyrosine phosphorylation of HER1 and HER2, as well as activation of ERK1,2 MAPK and PI3K/AKT, 
affecting downstream effectors of both proliferation and survival.  It recently has shown remarkable activity in 
patients with HER2-overexpressing breast cancers after escape from a monoclonal antibody targeted therapy, 
nearly doubling progression-free survival compared to chemotherapy alone in these patients.  This mix of HER 
inhibitors is important because when used in combination they could theoretically more completely block the 
network input layer to make treatment more effective. 
Given the highly specific and potent tyrosine kinase inhibition of lapatinib, it is postulated that breast cancer cells 
resistant to trastuzumab due to enhanced signaling through alternative pathways (i.e., HER2/HER3 
heterodimerization) or decreased antibody binding to HER2 receptors would still retain sensitivity to lapatinib.  In 
breast cancer, HER2/HER3 dimerization promotes the strongest mitogenic signaling, primarily through the 
PI3K/AKT pathway, which is critical in maintaining cell proliferation and survival.2,3  Constitutive activation of the 
PI3K/AKT pathway through upregulation of HER3 and direct binding to PI3K in both ligand-dependent and ligand-
independent mechanisms have been implicated in resistance to targeted therapies.4,5  In HER2 overexpressing 


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cells and tumors that are ligand-independent, enhanced downstream signaling is inhibited by trastuzumab whereas 
ligand-dependent signaling can be blocked by the addition of pertuzumab to disrupt HER2 homo- and 
heterodimers.6,7  Tyrosine kinase inhibitors such as lapatinib have shown potent activity against HER2-
overexpressing breast cancer cells/tumor xenografts by inhibiting phosphorylation and activation of HER2/HER2, 
EGFR/HER2, and HER2/HER3 homo- and hetero-dimers and downstream signaling effectors (RAF, ERK, AKT) 
regardless of trastuzumab resistance or ligand association.8-11   In addition, we have strong correlative, statistically 
significant, data that activation of the PI3K pathway was associated with resistance to trastuzumab, consistent with 
published data.12,13 With lapatinib, the opposite was observed where activation of this pathway lead to increased 
sensitivity, with 87% (13/15) of patients achieving pCR while only 13% (2/15) had residual disease (p=0.04).  Thus, 
activation of the PI3K pathway was associated with response to this lapatinib-containing regimen. 
 
Abraxane Paclitaxel, nanoparticle albumin-bound (nab), its active ingredient paclitaxel, is an antimicrotubule agent 
that promotes the assembly and stabilization of microtubules, thus inhibiting normal dynamic reorganization of the 
microtubule network. Paclitaxel induces abnormal bundles of microtubules throughout the cell cycle and multiple 
asters of microtubules during mitosis. It is thought that albumin-bound paclitaxel (nab-paclitaxel) facilitates the 
transport of paclitaxel across the endothelial cell via an albumin-receptor mediated pathway. Nab-paclitaxel is cell 
cycle phase-nonspecific. 14 
Nab-paclitaxel is a unique albumin formulation of a non-crystalline, amorphous form of paclitaxel in an insoluble 
nanoparticle state. While nab-paclitaxel has been shown to be one of the most active agents in metastatic breast 
cancer, it has not been approved as part of combination therapy in the neoadjuvant setting. A prior neo-adjuvant 
study showed that newly diagnosed HER2 Neu over-expressed stage I to III breast cancer received lapatinib 1000 
mg po/d and nab-paclitaxel 260 mg/m2 IV every three weeks for a total of four cycles. Postoperative therapy was 
at the discretion of the investigator. The primary endpoint of the study was the clinical response rate (CRR) as 
determined by clinical examination and imaging studies. Response data in 29 patients showed a CRR of 82%, 
with 4 (13.8%) patients demonstrating a complete response and 20 (69%) showing a partial response. Five (17.2%) 
patients had stable disease. Five (18.5%) patients achieved pathologic complete response (pCR). The most 
common toxicities were rash, neuropathy, fatigue, and myalgias. Most toxicities were grade 1 & 2 although one 
patient developed grade 3 rash and five patients developed grade 3 diarrhea. There were no cases of cardiac 
toxicity. 15 Toxicities such as diarrhea and rash were medically managed, and patients did not receive prophylactic 
medications for rash or diarrhea.    Nab-Paclitaxel had shown favorable efficacy and toxicity profiles compared to 
other taxanes in the treatment of metastatic breast cancer. A pilot study using nab-paclitaxel-containing adjuvant 
regimen in patients with node-positive or high-risk node-negative early-stage breast cancer was well tolerated, and 
full doses of all agents were administered in >90% of cycles.  All the patients received four cycles, at 21-day 
intervals, of nab-paclitaxel (100 mg/m(2) IV days 1, 8, and 15) and cyclophosphamide (600 mg/m(2) IV day 1). 
HER2-positive patients also received trastuzumab 8 mg/kg IV on cycle 1 day 1, followed by 6 mg/kg every 21 days 
for a total of 52 weeks. The purpose of this trial was to evaluate feasibility and toxicity of this nab-paclitaxel-
containing adjuvant regimen. 62 patients were treated between 2/08 and 11/08. The majority of the patients (87%) 
were HER2-negative. This adjuvant regimen Grade 3/4 neutropenia occurred in 53% of the patients; however, 
only one episode of febrile neutropenia occurred in a total of 249 cycles administered. Other grade 3/4 adverse 
events occurred in less than 5% of patients. After short follow-up, all the patients remain alive and disease-free. 
The combination of nab-paclitaxel and cyclophosphamide, with or without trastuzumab, was feasible and well 
tolerated in patients with early stage breast cancer. 16 
 
2. 
              Significance and Rationale 
The significance of this proposal is to establish the superior efficacy and predictive molecular-genetic biomarkers 
of the combination of the antibody-drug conjugate trastuzumab-emtansine with lapatinib followed by the addition 
of chemotherapy (Abraxane) in patients with HER2 overexpressing breast cancers in the neoadjuvant setting. The 


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estrogen receptor (ER) and HER signaling pathways are the dominant drivers of cell proliferation and survival in 
the majority of human breast cancers.  Not surprisingly, targeting these pathways provides the most effective 
therapies in appropriately selected patients19,20 .  However, de novo and acquired resistance remain major 
obstacles to successful treatment. By increasing the understanding of the molecular mechanisms of combined 
HER2-targeted therapies, we aim to be better able to select patients who would respond to these treatments and 
understand some of the escape mechanisms of HER2-targeted treatments.  
 
The HER family of transmembrane type I receptor tyrosine kinases play an important role in cell processes 
like cell proliferation and survival.  Upon ligand binding to the active domain of HER1, HER3, or HER4, these 
receptors preferentially recruit HER2 into a heterodimeric complex in which the HER2 kinase can modulate 
receptor internalization and prolong signal transduction.  Conformational changes occur upon dimerization, leading 
to autophosphorylation and initiation of divergent signal transduction cascades21.  These signaling pathways from 
these receptor heterodimers are not absolutely linear and some of their functions may overlap, laboratory data 
generally indicate that HER1/HER2 heterodimers activate cell proliferation by the ERK1,2 MAPK pathway22, while 
HER2/HER3 heterodimers predominantly activate the PI3K/AKT cell survival pathway23.   
 
Several drugs have been developed and are in clinical use to block the HER pathway, most aimed at the 
receptor level.  The anti-HER2 antibody trastuzumab is approved for treatment of breast cancer. Pivotal multicenter 
efficacy trials showed improved survival in patients who received trastuzumab24. Lapatinib is an orally active dual 
HER1/HER2 kinase inhibitor that blocks signal transduction pathways.  It reduces tyrosine phosphorylation of 
HER1 and HER2, as well as activation of ERK1,2 MAPK and PI3K/AKT, affecting downstream effectors of both 
proliferation and survival25. It recently has shown activity in patients with HER2-overexpressing breast cancers 
after escape from trastuzumab26-28. Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to 
extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors in particular 
HER2-HER3 complex29. 
In addition to these receptor targeted therapies, a new class of antibody-drug conjugates has recently 
shown superior clinical activity. Trastuzumab-emtansine (TE) is an antibody–drug conjugate that incorporates the 
HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent 
mertansine (DM1) (derivative of maytansine); the antibody and the cytotoxic agent are conjugated by means of a 
unique stable linker. TE allows intracellular drug delivery specifically to HER2-overexpressing cells, thereby 
improving the therapeutic index and minimizing exposure of normal tissue. Earlier this year, TE was approved for 
the treatment of HER2 overexpressing breast cancer patients30. TE has shown superiority over 
lapatinib/capecitabine combinations, and has recently been approved for the treatment of metastatic HER2 
overexpressing breast cancer patients30.   
Despite some success of these agents that target the HER family as single agents, there are a number 
of escape mechanisms from HER-targeted therapies. Clinically, a more complete blockade of the HER receptor 
layer has been shown to be therapeutically meaningful in prolonging survival in patients. With incomplete blockade 
of the receptor input layer, proliferative and survival signals can be generated from several different dimer pairs.  
The idea that the redundancy in the input layer of the network might provide an escape mechanism around a 
single-agent block has been explored. Using combinations of inhibitors (e.g. trastuzumab+pertuzumab or 
lapatinib+trastuzumab), higher responses with higher pathologic complete responses (pCR) have been observed. 
In a recently completed randomized phase 2 study, patients given dual blockade with pertuzumab and trastuzumab 
plus taxane, compared to trastuzumab and taxane (NeoSphere study), had a significantly improved pathological 
complete response rate (46% vs. 29%; p=0·0141)31. Similar improved efficacy was observed with dual blockade 
with trastuzumab and lapatinib (NeoAltto study). In this randomized phase 3 study, the pCR rate was significantly 
higher in the group given lapatinib and trastuzumab plus taxane vs. trastuzumab plus taxane (51% vs.30%; 
p=0·0001)32. To date, these studies have shown the highest pathologic complete responses in HER2 
overexpressing patients with the combinations of trastuzumab and either pertuzumab or lapatinib, together with 
paclitaxel chemotherapy. Here, we aim to build on these observations, and propose the use of trastuzumab-
emtansine, that incorporates the antibody antitumor effect with trastuzumab with a cytotoxic agent, together with 


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lapatinib to overcome incomplete blockade of the HER receptor in the neoadjuvant setting so as to improve the 
pathologic complete responses and thus survival of women with HER2 overexpressing cancers.  
 
Amplification of the PI3K pathway, as a result of low levels of the phosphatase PTEN or PIK3CA 
mutations, has been also been associated with resistance to trastuzumab in clinical patient samples33,34.  PTEN 
loss has been described in approximately 50% of breast tumors.  Nagata et al. reported that trastuzumab resulted 
in activation of PTEN by inhibiting Src tyrosine kinase, thus preventing Src binding to HER233,34.  Mechanisms for 
lapatinib resistance are less well established.  Recent in vitro data suggests that, unlike trastuzumab, loss of PTEN 
function was not associated with lapatinib resistance35.  We determined in biopsies obtained from women enrolled 
in two prior neoadjuvant studies that  PIK3CA mutations or loss of PTEN predicted resistance to trastuzumab, but 
sensitivity to a lapatinib-containing regimen36. In a third recently completed study, we determined that PIK3CA 
mutations or loss of PTEN might also predict for resistance to the combination of lapatinib and trastuzumab 
(Preliminary Studies).   
 
In this last decade, the availability of next-generation high-throughput technologies, many pioneered at 
Baylor College of Medicine (BCM), has opened up the potential to sequence entire tumor genomes to interrogate 
protein-encoding genes, non-coding RNA genes, and the mitochondrial genome. These technologies allows for 
comprehensive interrogation of the genetic landscape of residual tumors after therapy, to understand the 
mechanisms and pathways of resistance and escape. The Human Genome Sequencing Center (HGSC) at BCM 
is one of the three large-scale sequencing centers funded by the National Institutes of Health. The HGSC was a 
key member in the Cancer Genome Atlas Pilot Network (TCGA) which entered a pilot phase in 2006 to identify 
important genetic changes involved in lung, brain, and ovarian cancers. TCGA constitutes a comprehensive effort 
to accelerate the understanding of the molecular basis of cancer through the application of genome analysis 
technologies, especially large-scale genome sequencing. We propose here to interrogate clearly annotated tissues 
obtained in a clinical trial, that have known response to HER2-targeted therapy, to determine mutational profiles, 
along with PI3K pathway alterations, that might predict for differential response to HER2-targeted therapies. To 
our knowledge, such studies have not as yet been performed. Summary of significance The HER pathway is the 
driving force behind 30% of human breast cancers, and understanding how targeted therapies block different 
cellular pathways, and mechanisms of escape, is crucial in the development of strategies to overcome resistance. 
Understanding the mechanisms of escape from HER pathway inhibitors may reveal general mechanisms of 
escape from other therapies as well. The neoadjuvant platform is especially attractive for evaluation of promising 
novel combinations, as this approach will allow for early assessment of response and access to primary tumors 
for serial tissue sampling to examine in vivo mechanisms of action and predictive markers. In addition, we are 
proposing to comprehensively sequence these HER2-overexpressing cancers, in order to identify potential somatic 
changes that may better select patients who will benefit from therapy, and to determine new targets that may 
overcome resistance and improve outcome with known current HER2-targeted therapies. 
2.1 
Innovation 
Therapies directed at HER2 establish a successful treatment paradigm, but de novo and acquired resistance exist. 
With this neoadjuvant model, we have previously demonstrated that single agent HER2-targeted therapies are 
efficacious but response is incomplete. Consistent with large randomized clinical trials, we have also demonstrated 
that dual HER2- targeted combinations with trastuzumab/lapatinib are synergistic. Recently, the antibody-drug 
conjugate trastuzumab-emtansine, which targets the HER2 receptor conjugated to the potent antimicrotubule 
agent emtansine allowing for intracellular release of the cytotoxic drug, has recently been approved.  Here, we 
propose a rational combination of dual HER2- targeted treatments with trastuzumab-emtansine (TE) and lapatinib 
(L), together with nab-paclitaxel to demonstrate improved efficacy in patients.  By determining somatic mutations 
in HER2-overexpressing tumors, we will comprehensively characterize these alterations and identify those patients 
most likely to respond, as well as discovering new targets that may overcome resistance to HER2-directed therapy.  
We propose a randomized neoadjuvant clinical trial in HER2-overexpressing breast cancer patients who 
will receive TE+L+A vs. T+L together with paclitaxel before definitive surgery.  We will determine the efficacy of 


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TE+L+A gather data germane to the mechanisms of action, and discover predictive markers for sensitivity and 
resistance.  
 
2.2 
Approach Preliminary Studies 
Preclinical MCF-7/HER2 mouse xenograft studies Trastuzumab (T), pertuzumab (P), lapatinib (L), and gefitinib 
(G) represent a group of therapeutic agents that target the HER family by different molecular mechanisms.  These 
drugs, when used as single agents in the MCF7/HER2-18 xenograft model, restored or enhanced sensitivity to 
tamoxifen. However, tumor growth inhibition lasted only 2-3 months before resistance to treatments occurred and 
tumor growth resumed. We next investigated the efficacy of various drug combinations. The addition of the HER1 
inhibitor G to the two-antibody (T+P) regimen to block signals from HER1 dimers resulted in complete 
disappearance of nearly all tumors with evidence of complete tumor eradication in >50% of the mice.  The 
combination of lapatinib + trastuzumab (L+T) was highly effective (Fig. 1). The combination HER-targeting therapy 
more effectively induced apoptosis and inhibited proliferation and more effectively reduced levels of p-AKT and 
MAPK.   
Three completed phase II neoadjuvant HER2-targeted 
clinical studies Over the past 10 years, our group has 
carried out neoadjuvant trials of HER pathway blockers.  
The first study (40 patients) used trastuzumab for a 3-
week period with serial tissue sampling, and major 
endpoints have been published37. The second completed 
trial (49 patients) investigated the dual kinase inhibitor 
lapatinib but for a longer duration, 6 weeks, before 
chemotherapy was added. Again, dramatic responses 
were observed in most patients, with clinical response 
(>50% tumor regression) in 73% (33/45) by 6 weeks of 
lapatinib.  In the third study, the combination of lapatinib 
plus trastuzumab (L+T) was studied as neoadjuvant 
therapy. Sixty-six patients were enrolled, and 64 were 
eligible and evaluable for response. Median tumor size 
was 6 cm (range, 1.5 to 30 cm). Adverse events were 
mainly grades 1 to 2 (GI, 63%; skin, 46%). Grade 3 
metabolic, GI, and liver (18%; 12 patients) and grade 4 
liver toxicities (one patient) were also observed. Overall, 
pCR rate was 27% (ER positive, 21%; ER negative, 36%) 
with 
targeted 
dual 
blockade 
alone 
without 
chemotherapy38  
Biologic correlative studies from clinical studies 
Δ Apoptosis 
Δ Ki67 
Figure 1. Inhibitory effects of various HER2 drug combinations on 
MCF7/HER2-18 xenograft growth and endocrine sensitivity. The 
combinations of P+T+G in the presence of tamoxifen (A) and L+T 
with tamoxifen or estrogen deprivation (ED) lead to complete 
tumor regression in almost all mice in the presence of ED (B). 
1      25     50     75    100    125    150   175   200
0
200
400
600
800
1000
1200
Days
Tumor Volume (mm3)
Tam
ED
ED+L
ED+T
Tam+L+T
ED+L+T
B
0
200
400
600
800
1
21
42
63
84
105
126
147
168
189
209
Days
Tumor Volume (mm3)
Tam+P+T
Tam+P+T+G
Tam+P
1      25    50     75   100 
125   150   175    200
A


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Neoadjuvant 
trastuzumab: 
We 
completed the first single-agent 
neoadjuvant trastuzumab study from 
2000 to 2003 (R21CA 87649-01 from 
the National Cancer Institute, NCI).  
Core biopsies of the primary cancers 
were taken before administration of 
single-agent 
trastuzumab 
as 
neoadjuvant treatment.  Apoptosis 
(cleaved caspase 3, CC3) was 
significantly induced with a median 
increase 
from 
2.6% 
to 
4.0% 
(p=0.004) within one week after 
starting trastuzumab therapy, as 
shown in Fig. 2A.  Trastuzumab did 
not decrease cell cycle proliferation, 
suggesting 
that 
trastuzumab 
primarily exerts its effects through the 
PI3K/AKT 
survival 
pathway. 
Neoadjuvant 
lapatinib: 
Next, 
a 
neoadjuvant study with lapatinib 
(R01CA112305, NCI) was conducted 
from 2004-2009.  Unlike with trastuzumab, the apoptosis index did not change significantly.  On the other hand, 
lapatinib decreased Ki67 significantly by week 2, and this decrease in proliferation continued through weeks 4 and 
6 (p<0.0001) (Fig. 2B). Consistent with this decrease, p-MAPK showed a significant decrease by week 2 through 
week 4 (p=0.02).  These data suggest that lapatinib exerts its effects by decreasing proliferation through the MAPK 
pathway. 
Activation of the PI3K pathway as a pretreatment predictive marker of response:  Considering next the biomarkers 
in the pretreatment specimens that might be predictive indicators, we examined primarily activation of the 
PI3K/AKT pathway.  Activation of the PI3K pathway was statistically significantly associated with resistance to 
trastuzumab33,34. Only 18.2% (4/22, 95% exact CI = 5.2% - 40.3%) patients with PI3K activation achieved pCR 
compared to 66.72% (6/9, 95% exact CI = 29.9% - 92.5%, p=0.015).  With lapatinib, the opposite effect was 
observed - activation of this pathway led to increased sensitivity, with 86.7% (13/15) of patients achieving pCR 
when compared to 45.5% (5/11, p=0.038)36. The interaction between low PTEN/PI3KCA mutations and 
trastuzumab or lapatinib response was highly statistically significant, p=0.001636. For dual blockade with T+L, of 
64 evaluable patients, tissue was available on 59 for PTEN assay, and sufficient DNA was available on 33 for the 
mutation panel. PTEN was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p=0.04).   Activating 
PIK3CA mutations were identified in 12 out of 33 tumors (36%). None of the patients whose tumors harbored a 
PIK3CA mutation achieved pCR (p=0.06).  When PIK3CA mutations were considered along with PTEN status, 
0/17 cases (0%) with a mutation and/or PTEN low expression had a pCR compared to 5/14 cases (36%) with no 
mutation or high PTEN (p=0.01), suggesting that the PI3K pathway activation results in resistance to the 
combination of T+L. These findings needs validation in larger cohorts, as planned in the control arm of this 
proposed study.  
Large-scale mutation profiling in human cancers For the past 5 years, the technologies of high throughput DNA 
sequencing have been increasingly brought to bear on the problem of cancer. Results from these global and high 
throughput “genomic” approaches promise a new understanding of cancer biology in terms of a) classification of 
disease, b) identification of novel genes overlooked in previous studies due to insufficient breadth (sampling of too 
few genes) or depth (too few patients, and therefore insufficient statistical power), and c) a view of inter-
 
Trastuzumab: 
No change in Ki67
Lapatinib:
Decrease in Ki67
Ki67(%)
0
10
20
30
40
50
60
70
80
90
100
Initial
Week 2
Week 4
Week 6
P<0.0001
0
10
20
30
40
50
60
70
80
90
100
Initial
Week 1
Week 3
P=NS
 
Figure 2A.  Change in apoptosis as measured by cleaved caspase 3.  With 
trastuzumab, CC3 (apoptosis) was increased in week 1, p=0.03.  With 
lapatinib, no change in CC3 was observed.  
Figure 2B. Change in proliferation as measured by Ki67. With trastuzumab, 
Ki67 was unchanged.  With lapatinib, Ki67 was significantly decreased by 
week 2, which continued in weeks 4 and 6 (p<0.0001). 
 
Apoptotic Index
0
5
10
15
Initial
Week 1
Week 3
Apoptotic Index
0
5
10
15
Initial
Week 2
Week 4
Week 6
Trastuzumab:
Increase in CC3 
Lapatinib:
No change in CC3
P=0.03
P=NS
 
Δ Apoptosis 
Δ Ki67 


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dependence of the critical pathways, important for biological 
interpretation, as well as new treatment strategies. Recently, the 
HGSC began a collaborative project with two other sequencing 
centers to sequence 623 genes in 188 lung adenocarcinoma 
patients39.  The approaches developed in lung adenocarcinoma 
project were applied to glioblastoma multiforme (GBM) tumors, with 
1,300 genes and 153 patients as part of The Cancer Genome Atlas 
project40. These studies are among the largest undertaken and have 
dramatically revealed the power of genome-wide mutational analysis 
in cancer. The gene mutation profile of GBM (Fig. 3) revealed for the 
first time that ERRB2, NF1 and PIK3R1 play a significant role in GBM. 
Moreover, the first two are drug targets in other cancers.  Genes 
mutated in a significant portion of tumors re considered to be "drivers" 
of the tumor phenotype; presumably they confer growth advantage 
and/or evasion of the body's natural defenses against cancer. These 
significantly mutated genes in GBM (Fig. 3) were found to affect three 
primary pathways: “Apoptosis”, “Cell Cycle Control”, and “Mitogenic Stimulus”. Over 90% of all mutations found in 
GBM were in genes in these three pathways. Results similar to these were found in the mutation profile of lung 
adenocarcinoma but with different genes involved. Thus, in addition to TP53, EGFR, and NF1 found in GBM, the 
KRAS, STK11 and LRPB1 were also significantly mutated in lung adenocarcinomas. In contrast, ERBB2 and RB1 
that 
were 
mutated significantly in GBM were not significantly mutated in lung adenocarcinoma. Thus, not unexpectedly, 
different cancers vary in which genes and which pathways drive the tumor phenotype. With the advent of next 
generation sequencers that afford even more comprehensive surveys, we now use targeted oligonucleotide arrays 
to capture exons across the entire genome (whole exome capture, WEC). Whole genome shotgun sequencing 
enables detection of copy number alterations (CNA) frequent in cancer.  We have accurately mapped somatic 
structural variants in GBM, ovarian and pancreatic cancers by comparing sequencing coverage from tumor and 
matched normal genomes. Reads from tumor sample are partitioned into variably sized bins, averaging 10Kb.  
Figure 4 shows two major changes identified in a GBM patient using these methods: an amplification of 
chromosome 7 at the EGFR locus and a deletion at chromosomal 19 at the tumor suppressor gene CDKN2A 
locus. These changes were mirrored in CNA data obtained by SNP array as part of the TCGA copy number 
alteration platform (data not shown). 
 
Figure 3. Gene mutation profile from large-
scale study of Glioblastoma Multiforme (GBM). 
The genes shown in this figure were 
significantly mutated (p < 0.0001) above the 
expect background rate.  In this data set, some 
patients had been treated with Temozolomide 
which causes a hypermutation phenotype in 
patients treated long enough; patients were 
tallied separately by treatment status. 
Figure 4.  Somatic chromosomal copy number alterations are readily detected by DNA sequencing. 
Chromosomal gain, red bars and loss, green.  The most dominant gain is at Chr7 EGFR locus and loss at 
Chr9 CDKN2A (in green).  In addition, large segments of chr1, chr7 and chr19 show strong gain while 


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3. 
 Hypothesis:  
We hypothesize that combining antibody-drug conjugate trastuzumab-emtansine and lapatinib together with 
Abraxane will improve clinical efficacy by affecting both PI3K and ERK1,2 MAPK pathways. We are proposing in 
this randomized phase 2 study to perform comprehensive sequencing to better define novel mutations that could 
predict for response and to interrogate residual tumors after exposure to TE/L and abraxane to define mechanisms 
of resistance to HER2-targeted therapy.  
Research Strategy  General considerations The neoadjuvant setting is especially attractive for several reasons; 
these include early assessment of response to therapy, access to the tumor specimens for correlative studies, and 
fewer patient numbers compared to those required in the adjuvant setting.  The aims of this study are first to 
demonstrate the superior clinical efficacy of combined trastuzumab-emtansine/ lapatinib/Abraxane vs. 
lapatinib/trastuzumab, in combination with paclitaxel in the neoadjuvant setting; second, to comprehensively 
interrogate the genomic landscape by next generation whole exome sequencing to define novel predictive markers 
of sensitivity and resistance; and third, to validate predictors by protein markers on tissue microarrays.   
 
4. 
Objectives and endpoints 
Primary Objective: 
 
To evaluate the pathological complete response rate (pCR) in the breast after treatment with Trastuzumab 
Emtansine plus Lapatinib follow by Abraxane in women with HER2 Neu over-expressed breast cancer 
patients. 
Secondary Objective(s): 
 
To determine the clinical response rate in patients with palpable disease. 
 
To determine the imaging response to neoadjuvant therapy. 
 
To compare overall objective response rate in both treatment groups. 
 
To assess toxicity, safety and efficacy of Trastuzumab Emtansine when combine with Lapatinib follow by 
Abraxane 
Exploratory Objective(s): 
 
To determine predictive markers for sensitivity and resistance 
 
To determine baseline transcriptional profiling 
 
To evaluate the somatic mutational analysis 
 
To validate predictors of response and resistance with protein biomarkers 
 
Endpoints 
The primary endpoint will be the evaluation of the Pathological Complete Response (pCR) in the breast when 
TDM-1 plus Lapatinib plus Abraxane is combined. 
 
Secondary endpoints will include the evaluation of a) clinical and radiological response b) toxicity related with the 
study arm treatment (toxicities will be defined as any treatment- related death or any ≥ Grade 3 non-
hematological toxicity excluding alopecia and constitutional symptoms as assessed by NCI-CTC AE ver. 4.0.).  
c) biological tissue effect of the proposed combination  on HER2 expression levels, Gene expression analysis, sub 
typing Characterization, Transcriptional profiling,  PTEN, PI3K and possibly other candidate markers related to the 
drug’s mechanism of action, and d) pathologic CR in axillary nodes. 
 


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5. 
Study design 
5.1 Description of study design 
RANDOMIZED OPEN LABEL PHASE II TRIAL OF NEOADJUVANT TRASTUZUMAB EMTANSINE (TE) IN COMBINATION 
WITH  LAPATINIB (L) FOLLOW BY ABRAXANE (A) COMPARED WITH TRASTUZUMAB PLUS LAPATINIB FOLLOW BY 
PACLITAXEL  IN HER 2 NEU OVER-EXPRESSED BREAST CANCER PATIENTS
S
U
R
G
E
R
Y
E
S
T
R
A
T
I
F
I
C
A
T
I
O
N
LAPATINIB 750 mg/daily p.o
TRASTUZUMAB EMTANSINE 3.6 mg/kg  IV Q3W
Mammogram 
Ultrasound
MRI
Baseline
Core biopsy
Mammogram  
Ultrasound
MRI
R
A
N
D
O
M
I
Z
A
T
I
O
N
MRI and Core biopsy
At the end of
the biological window
TRASTUZUMAB EMTANSINE DOSE LEVELS 
Dose level (0): 3.6 mg/m2 iv ninety minutes infusion* 
Dose level (-1): 3.0 mg/m2 iv ninety minutes infusion *
Dose level (-2): 2.5 mg/m2 iv ninety minutes infusion *
For patients who are unable to tolerate the protocol-specified dosing schedule, dose reductions or interruptions are permitted to manage drug-related toxicities
E
R
+
E
R
-
ABRAXANE 100 mg/m2 iv  QW
X 12 w
LAPATINIB 750 mg/daily p.o
TRASTUZUMAB 4 mg/kg  IV loading dose follow by 
2 mg/kg IV weekly
PACLITAXEL 80 mg/m2 iv  QW
X 12 w
STUDY DESIGN AND TREATMENT
Endocrine Therapy if  indicated
MRI and Core biopsy
At the end of
the biological window
Vs
Baseline
Core biopsy
Six  weeks 
of biological 
window
Six  weeks 
of biological 
window
* First dose only
     
                                                                                                                                                                    Figure 5 
6. 
Treatment Arms 
This is a randomized, open label Phase II neo-adjuvant study comparing the efficacy of neoadjuvant trastuzumab 
Emtansine plus lapatinib follow by Abraxane, versus trastuzumab plus Lapatinib follow by paclitaxel, given as 
neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer. 
Arm 1: Trastuzumab Emtansine 3.6 mg/kg IV every three weeks plus Lapatinib 750 mg/daily p.o for a total of six 
(6) weeks, after this biological window patients will continue the same targeted therapy plus Abraxane 100 mg/m2 
IV weekly for twelve (12) weeks  
 
Arm 2: Trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly plus Lapatinib 750 mg/daily for a total of 6 
weeks, after this biological window, patients will continue on the same weekly targeted therapy plus weekly 
paclitaxel 80 mg/m2 for a further 12 weeks, up to definitive surgery.  
 
GCSF allowed after taxane (Nab or Taxol) chemotherapy.   After surgery Trastuzumab will continue for 52 weeks 
(off study).  
Pegfilgrastim (Neulasta®) is not allowed. 
 


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All patients will have an initial core needle biopsy at time of diagnosis, with additional biopsies at week 6 after the 
biologic window. Surgical specimens will be obtained after week 18.  Biopsies will also be performed in primary 
cancers that do not respond to therapy. 
 
7. 
Population 
The study is being designed for Her2 Neu over-expressed breast cancer patients.  The investigator or designee 
must ensure that the patient meets all the following inclusion and none of the exclusion criteria before being offered 
enrollment in the study. 
 
Study Duration:   
The duration of patient participation in the study treatment will be a total of 6 to 7 months, which is counted from 
the start of treatment.  Study Follow-up for all patients will include medical history update (30 days after the last 
dose of the study drug)   
Safety Criteria:   
All participants will be assessed by a physician for pre-existing medical conditions and baseline physical 
abnormalities prior to the initiation of investigational therapy. Patients presenting with any medical history, physical 
exam, or laboratory abnormality that, in the in the opinion of the treating physician, would put the subject’s safety 
at risk will be excluded. Baseline signs and symptoms are to be recorded and followed throughout the trial.  These 
will be monitored throughout the study and recorded if they increase in severity or frequency during treatment or 
within the follow up period. Participants will be assessed for adverse events by a physician or designated midlevel 
provider prior to each chemotherapy infusion while the patient is on study. Vital signs including blood pressure, 
heart rate and temperature should be performed at each physical exam.  Assessments may be performed more 
frequently if clinically indicated. In addition, hematology and serum chemistry profiles will be drawn prior to the 
initiation of treatment and prior to every infusion to determine whether the study drug combination affects 
hematologic values, electrolytes or liver function tests. Laboratory assessments will be performed more frequently 
if clinically indicated. This clinical and laboratory data will be used to determine whether these women in the study 
with trastuzumab Emtansine  plus laptinib plus Abraxane therapy have any symptoms or side effects associated 
with the study medications. Subjects will be followed for adverse events for a period of 30 days after the completion 
of investigational therapy (Six (6) to seven (7) months). Patients with abnormal laboratory or clinical findings that 
are believed to be treatment related will be followed every four weeks until the condition resolves or stabilizes, or 
until the laboratory values are no longer considered clinically significant.  CTC Version 4.0 will be used to grade 
toxicities.  Laboratory tests may be done more frequently if medically indicated. If CTC Grade 4 hematologic toxicity 
is seen; CBC + differential + platelets should be repeated every 3 - 4 days until recovery. 
At suspected recurrence: CT scans of the chest, abdomen, pelvis, and additional directed evaluation as 
appropriate.  Recurrence should be documented by biopsy and/or evidence of metastatic disease on radiologic 
studies. Abnormal blood studies alone (e.g., elevated liver function tests, CA 15-3, CEA, etc.) are not sufficient 
evidence of relapse. 
8. 
Inclusion and Exclusion criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion 
and exclusion criteria. Results of all baseline evaluations, which assure that all inclusion and exclusion criteria 
have been satisfied, must be reviewed by the Principal Investigator or his/her designee prior to enrollment of that 
patient. In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit 
schedule and required evaluations and all regulatory requirements for informed consent. The written informed 
consent must be obtained from the patient prior to enrollment. The following criteria apply to all patients enrolled 
onto the study unless otherwise specified. 


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8.1 Inclusion criteria: 
Patient must meet all of the following criteria: 
 
Female gender;  
 
Age ≥18 years;  
 
Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1  
 
Histologically confirmed invasive breast cancer:  
 
Primary tumor greater than 1 cm diameter, measured by clinical examination and mammography or 
ultrasound. 
 
Any N,  
 
No evidence of metastasis (M0) (isolated supra-clavicular node involvement allowed);  
 
Over expression and/or amplification of HER2 in the invasive component of the primary tumor and 
confirmed by a certified laboratory prior to randomization. 
 
Known hormone receptor status.  
 
Hematopoietic status:  
 
CBC not less than .75 of institutional lower limit. 
Absolute neutrophil count ≥ 1,5 x 10^9/L,  
Platelet count ≥ 100 x 10^9/L,  
Hemoglobin at least 9 g/dl,  
 
Hepatic status:  
Serum total billirubin ≤ 2 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher 
serum total billirubin (< 1.5 x ULN) is allowed,  
Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3.5 times ULN,  
Alkaline phosphatase ≤ 2.5 times ULN,  
 
Renal status:  
Creatinine ≤ 1.5mg/dL,  
 
Cardiovascular:  
Baseline left ventricular ejection fraction (LVEF) ³ ≥50% measured by echocardiography (ECHO) or 
Multiple Gate Acquisition (MUGA) scan,  
 
Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing potential within 
2-weeks (preferably 7 days) prior to randomization.  
 
Fertile patients must use effective contraception (barrier method - condoms, diaphragm - also in 
conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives 
are not allowed)  
 
Signed informed consent form (ICF)  
 
Patient accepts to make available tumor samples for submission to central laboratory to conduct 
translational studies as part of this protocol. 
 
 
 
 
 
 
 
 
 
 
 


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8.2 Exclusion criteria: 
 
 Previous (less than 5 years) or current history of malignant neoplasms, except for curatively treated: 
Basal and squamous cell carcinoma of the skin; Carcinoma in situ of the cervix.  
 
Patients with a prior malignancy diagnosed more than 5 years prior to randomization may enter the study.  
 
Preexisting peripheral neuropathy ≥ grade 2 
 
Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart 
failure, transmural myocardial infarction, uncontrolled hypertension (≥180/110), unstable diabetes 
mellitus, dyspnea at rest, or chronic therapy with oxygen;  
 
Concurrent disease or condition that would make the subject inappropriate for study participation or any 
serious medical disorder that would interfere with the subject's safety;  
 
Unresolved or unstable, serious adverse events from prior administration of another investigational drug;  
 
Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or 
rendering of ICF;  
 
Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the 
stomach or small bowel. Subjects with ulcerative colitis are also excluded;  
 
Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic 
therapy other than the trial therapies);  
 
Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;  
 
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to 
trastuzumab Emtansine, trastuzumab, lapatinib, paclitaxel, abraxane or their components;  
 
Pregnant or lactating women;  
 
Concomitant use of CYP3A4 inhibitors or inducers  
 
Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled 
infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance 
with the protocol 
 
Patients have an active infection and require IV or oral antibiotics.  
 
Pregnant or breast-feeding women 
 
Patients unwilling or unable to comply with the protocol 
 
9. 
Treatment 
Table 1 Trastuzumab Emtansine dose modifications 
Trastuzumab Emtansine Dose  Level 
 Trastuzumab Emtansine Dose and Schedule 
Starting dose level (0) 
3.6 mg/m2 iv ninety minutes infusion first dose only 
Dose level – 1 
3.0 mg/m2 iv ninety minutes infusion first dose only 
Dose level – 2 
2.5 mg/m2 iv ninety minutes infusion first dose only 
First infusion: Administer infusion over 90 minutes. Patients should be observed during the infusion and for at 
least 90 minutes following the initial dose for fever, chills, or other infusionrelated reactions.  Subsequent infusions: 
Administer over 30 minutes if prior infusions were well tolerated. Patients should be observed during the infusion 
and for at least 30 minutes after infusion. 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event including abnormal 
laboratory value must be followed at least once a week for 4 weeks, and subsequently at 4-week intervals, until 
resolution or stabilization of the event, whichever comes first.  Dose interruptions should be reported on the 
appropriate Dosage Administration CRF.  The maximum time allowed for treatment interruption due to toxicity is 
21 days (3 weeks) from the intended dosing day.  If interruption is > 3 weeks, the patient must be discontinued 
from the study treatment.  However, the patient will continue to be followed for toxicity. 


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9.1 Trastuzumab Emtansine (TDM-1) General Infortmation 41 
DRUG NAME: Trastuzumab emtansine  
SYNONYM(S): T-DM1, Trastuzumab-DM1, Trastuzumab-MCC-DM1 antibody-drug conjugate; ado-
trastuzumab emtansine (USA) 
COMMON TRADE NAME(S): KADCYLA® (USA) 
MECHANISM OF ACTION:  
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the monoclonal antibody 
trastuzumab and the cytotoxic agent emtansine (DM1). The trastuzumab moiety binds to the human epidermal 
growth factor 2 (HER2) receptor on the tumour surface. Once internalized, the emtansine moiety binds to tubulin, 
the protein component of microtubules, and disrupts the assembly and disassembly of the microtubules, leading 
to inhibition of mitosis and proliferation of cancer cells with HER2 overexpression. 
USES: Primary uses:  
Breast cancer 
 SPECIAL PRECAUTIONS:  
Contraindications: patients with known hypersensitivity reaction to trastuzumab or Chinese hamster ovary cell 
proteins 
Caution: in patients with pre-existing cardiac dysfunction or a left ventricular ejection fraction (LVEF) of 50% 
or less 
in patients with pre-existing pulmonary disease: patients who experience dyspnea at rest due to complications 
of advanced malignancy and co-morbidities may be at an increased risk of pulmonary events and/or a fatal infusion 
reaction 
SIDE EFFECTS:  
The table includes adverse events that presented during drug treatment but may not necessarily have a causal 
relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event 
rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they 
were reported in more than 1% of patients in the product monograph or pivotal trials. 
ORGAN SITE 
SIDE EFFECT 
blood and lymphatic system/ febrile neutropenia  
anemia (10%, severe 3%)  
bleeding (30%, severe 1%)  
neutropenia (6%, severe 2 %)  
thrombocytopenia (28%, severe 13%)  
cardiac  
left ventricular dysfunction (2%)  
gastrointestinal  
emetogenic potential: low5  
diarrhea (23%, severe 2%)  
mucosal inflammation (7%, severe <1%)  
nausea (40%, severe <1%)  
vomiting (19 %, severe <1%)  
general disorders and administration site conditions  
extravasation hazard: non-vesicant6  
fatigue (35%, severe 2%)  
immune system  
infusion-related reactions (7%, severe <1%)1; see 
paragraph following Side Effects table  
investigations  
hypokalemia (9%, severe 2%)  
ALT, elevated (17%, severe 3%)  
AST, elevated (22%, severe 4%)  


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musculoskeletal and connective tissue  
arthralgia (19%, severe <1%)  
myalgia (14%, severe <1%)  
musculoskeletal pain (36%, severe 2%)  
respiratory  
pneumonitis (1%)  
dyspnea (12%, severe <1%)  
cough (18%, severe <1%)  
epistaxis (22%, severe <1%)  
skin and subcutaneous tissue  
palmar–plantar erythrodysesthesia (1%)  
                                                                                                                                                                                                                        Table 2  
In a recent communication from Genentech/ROCHE,  nine (9) fatal cases of bleeding including six central nervous 
system (CNS) hemorrhages have been reported among approximately 4,200 patients exposed to trastuzumab 
emtansine as a single agent or in combination with other drugs in clinical trials. Six of the 9 patients were exposed 
to trastuzumab emtansine as a single agent. Three patients received trastuzumab emtansine in combination: one 
case with pertuzumab, one case with blinded pertuzumab, and one case with paclitaxel. Six cases were associated 
with decreased platelet counts ranging from Grade 1 to Grade 4, and in 3 cases platelet counts were not provided. 
In 4 cases the patients were also receiving anticoagulation therapy. These cases occurred independent of 
ethnicity.  Per investigator assessment, one of the nine fatal cases (with Grade 4 thrombocytopenia) was related 
to trastuzumab emtansine and the other eight cases were not related to drug. 
These hemorrhagic events are not considered to impact the overall risk/benefit of trastuzumab emtansine. Patients 
with thrombocytopenia and patients on anti-coagulant treatment should be monitored closely while on trastuzumab 
emtansine treatment. It is recommended that platelet counts are monitored prior to each trastuzumab emtansine 
dose. 
Infusion-related reactions ranging from flushing, chills, pyrexia, dyspnea, hypotension, wheezing, 
bronchospasm, and tachycardia have been reported in clinical trials. In most cases, these symptoms were not 
severe and reactions resolved over several hours to one day after the infusion was terminated. Consider 
discontinuing treatment for severe hypersensitivity reactions, including anaphylaxis, angioedema, or acute 
respiratory distress syndrome.  Interrupt infusion for patients developing dyspnea or clinically significant 
hypotension. Symptoms are managed with diphenhydramine, acetaminophen, epinephrine, corticosteroids, 
oxygen, or intravenous fluids.   
SUPPLY AND STORAGE:  
TDM-1 will be considered part of the study arm and will be provided by the sponsor for those patients randomized 
in this arm. Genentech, Inc. produces trastuzumab Emtansine as 100 mg or 160 mg vials of sterile, preservative-
free lyophilized powder. Sterile water for injection (containing benzyl alcohol) is supplied for reconstitution. 
Refrigerate. 
SOLUTION PREPARATION AND COMPATIBILITY:  
Intermittent infusion 
Initial dose: over 90 minutes (observe at least 90 minutes post-infusion) Subsequent doses: over 30 
minutes (observe 30 minutes post-infusion) 
DOSAGE GUIDELINES:  
Cycle Length: 3 weeks 
Intravenous:  
3.6 mg/kg (range 2.4-3.6 mg/kg) IV for one dose on day 1 (total dose per cycle 3.6 mg/kg [range 2.4-3.6 mg/kg]) 
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, 
response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count 
(ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to 
cytotoxic/radiation therapy or with other toxicities.  
 


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9.2 Trastuzumab (Herceptin) General Infortmation42 
DRUG NAME: Trastuzumab  
SYNONYM(S): anti-c-erB-2; anti-ERB-2; MOAB HER2; rhuMAb HER2 
COMMON TRADE NAME(S): HERCEPTIN®  
CLASSIFICATION: Monoclonal antibody  
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.  
MECHANISM OF ACTION:  
Trastuzumab is a human monoclonal IgG antibody which selectively targets HER2, a human epidermal growth 
factor receptor (EGFR). Trastuzumab inhibits the growth of tumour cells that overexpress HER2 on the surface of 
breast, gastric, ovarian, lung, and prostate cancer cells.  Mechanisms involved include: decreasing VEGF 
production, activating antibody-dependent cell-mediated cytotoxicity, G0/G1 cell cycle cytotoxicity, and inhibiting 
intracellular signaling pathways. 
PHARMACOKINETICS: 
Interpatient variability  
interpatient variability noted in clearance and volume of 
distribution 
Distribution  
steady state, AUC, Cmax, Cmin are lower in metastatic gastric 
cancer than metastatic breast cancer; steady state trough levels 
are similar between weekly and 3-weekly regimens 
cross blood brain 
barrier?  
unlikely, due to large molecule size 
volume 
of 
distribution  
3-4L  
plasma 
protein 
binding  
no information found  
Metabolism  
no information found  
active 
metabolite(s)  
no information found  
inactive 
metabolite(s)  
no information found  
Excretion  
via the reticuloendothelial system 
urine  
no information found  
feces  
no information found  
terminal half life  
12-29 days; shorter half life in metastatic 
gastric cancer due to increased clearance  
clearance  
0.225-0.378 L/day; increased with more 
metastatic sites
  
Elderly  
no differences reported  
                                                                      
 
 
 
 
 
 
 
      Table 3 
USES: Primary uses:  
Other uses:  
*Breast cancer *Gastric cancer 
SPECIAL PRECAUTIONS:  
Contraindications: history of hypersensitivity reaction to trastuzumab or Chinese hamster ovary cell proteins 
Caution: in patients with pre-existing cardiac dysfunction or a left ventricular ejection fraction (LVEF) of 55% or 
less; see paragraph following Side Effects table.  
In patients with pre-existing pulmonary disease or extensive pulmonary tumor involvement; patients who 
experience dyspnea at rest due to comorbidities or advanced malignancy may be at increased risk of a fatal 
infusion reaction. 
Special populations:  
Patients aged 65 years and older may be at greater risk for cardiac dysfunction and hematologic toxicities 


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(leukopenia and thrombocytopenia).  
Patients who received prior adjuvant therapy with anthracyclines for treatment of early breast cancer are at greater 
risk of developing cardiotoxicity. 
Carcinogenicity: no information found  
Mutagenicity: Not mutagenic in Ames test. Trastuzumab is not clastogenic in mammalian in vitro and in vivo 
chromosome tests.  
Fertility: Formal fertility studies have not been conducted in women. No evidence of impaired fertility was reported 
in animal studies. 
Pregnancy: FDA Pregnancy Category D. There is evidence of human fetal risk, but the benefits from use in 
pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for 
a serious disease for which safer drugs cannot be used or are ineffective).  
Impaired fetal renal growth and function, intrauterine growth retardation, and skeletal abnormalities associated 
with oligohydramnios during the second and third trimesters have been reported. Women of childbearing potential 
are advised to use effective contraception during treatment and for at least 6 months post treatment.  
Breastfeeding is not recommended due to the potential secretion into breast milk. In animal studies, trastuzumab 
was detected in the milk of lactating monkeys, although no adverse effects on growth or development were seen.  
SIDE EFFECTS:  
The table includes adverse events that presented during drug treatment but may not necessarily have a causal 
relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event 
rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they 
were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be 
clinically important. 
nervous system  
Dizziness (4%) , headache (10%) , paresthesia (2%) , vertigo 
(2%)  
psychiatric  
Anxiety (2%) , depression (3%) , insomnia (4%)  
ORGAN SITE 
SIDE EFFECT 
blood and lymphatic system/ febrile neutropenia  
Anemia (4%), leukopenia (3%) 
cardiac  
Arrhythmia (3%), congestive heart failure (2%; severe <1%), 
palpitations (3%) , tachycardia (1%)  
gastrointestinal  
emetogenic potential: low, abdominal pain (2%) , constipation (2%) 
, diarrhea (7%) , dyspepsia (2%) , gastritis (1%) , nausea (6-
14%)2,18 , stomatitis (2%) , vomiting (4-28%)  
general disorders and administration site conditions  
Extravasation hazard: none , asthenia (5%) , chills (5%)  
fatigue (8%) , fever (6%) , influenza-like illness (2%) , infusion-
related reaction (21-40%, severe 1%); , non-cardiac chest pain 
(3%) , peripheral edema (5%)  
immune system  
Allergic reaction (3%)  
infections and infestations  
Herpes zoster (1%) , influenza (4%) , nasopharyngitis (8%)  
pharyngitis (1%) , rhinitis (2%) , sinusitis (2%) , upper respiratory 
tract infection (3%) , urinary tract infection (2-5%) 
investigations  
alkaline phosphatase, elevated , ALT, elevated, AST, elevated 
bilirubin, elevated (1%) , ejection fraction, decreased (4-10%) 
weight gain (2%)  
musculoskeletal and connective tissue  
Arthralgia (8%) , back pain (5%) , bone pain (3%) , chest wall pain 
(2%) , muscle spasms (3%) , myalgia (4%) , pain in extremity (4%) 
, shoulder pain (2%) 


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renal and urinary  
Cystitis (1%)  
reproductive system and breast disorders  
Breast pain (1%)  
respiratory, thoracic and mediastinal  
Cough (5%) , dyspnea (3%) , epistaxis (1%) , pharyngolaryngeal 
pain (2%) , rhinitis (2%)  
skin and subcutaneous tissue  
Erythema (1%) , nail disorder (3%) , pruritus (2%) , rash (4%)  
vascular  
Hot flashes (6%) , hypertension (4%) , lymphedema (3%)  
      
 
 
 
 
 
 
 
 
 
 
 
     Table 4 
Cardiotoxicity has been reported with trastuzumab. Signs and symptoms include: dyspnea, increased cough, 
paroxysmal nocturnal dyspnea, peripheral edema, S3 gallop, congestive heart failure (CHF), or a reduced ejection 
fraction of 10% or greater. Cardiac dysfunction from trastuzumab is not dose-related and is reported to be highly 
reversible so patients have relatively good prognosis following CHF or LVEF dysfunction.  LVEF usually returns 
toward baseline during the 1.5 months post-trastuzumab treatment; however, some cases have resulted in 
disabling heart failure, thrombosis and stroke, and/or death. 
Risk factors for trastuzumab-related cardiotoxicity include: older age (>65 years), prior or concurrent use of 
antihypertensive medications, higher cumulative dose of anthracycline prior to trastuzumab, a lower left ventricular 
ejection fraction (LVEF) at baseline, a declining LVEF (<55%), a low LVEF prior to or following paclitaxel treatment, 
a higher body mass index (>25) at screening  
An increase in cardiac events is observed when trastuzumab is administered after anthracycline-containing 
chemotherapy compared to non-anthracycline-containing chemotherapy. The incidence is more marked when 
trastuzumab is administered concurrently, rather than sequentially, with a taxane. There is some uncertainty 
whether smoking, diabetes, hypothyroidism, or hyperlipidemia is associated with trastuzumab-related 
cardiotoxicity.  Prior or concurrent radiation does not increase cardiac events, but may increase the incidence of 
leukopenia.  There is inadequate long term data, however, to correlate cardiac dysfunction from trastuzumab with 
concurrent or prior radiation.  Trastuzumab interrupts the HER2 signalling pathway in the heart which maintains 
normal growth, repair, and survival of cardiac cells. This results in changes to cardiac contractility, but does not 
cause myocardial cell death. Suggested management for trastuzumab-related cardiotoxicity includes withholding 
trastuzumab for approximately 3 weeks if LVEF falls 10-15 ejection points below baseline and/or below 50%. 
Trastuzumab can be resumed once LVEF improves. If the LVEF does not improve within approximately 3 weeks, 
consider discontinuing trastuzumab. Trastuzumab may be considered in patients with a LVEF less than 50% if 
their risk of disease recurrence is very high.  The LVEF should be assessed prior to starting trastuzumab, repeated 
every 3 months during treatment, and then, every 6 months following completion of treatment until 24 months from 
the last dose of trastuzumab. For early breast cancer patients who received anthracycline-based chemotherapy, 
yearly monitoring of LVEF up to 5 years or longer from the last dose of trastuzumab is suggested.  Refer to protocol 
by which patient is being treated.  
Infusion-related reactions range from mild reactions of chills and/or fever (occurring in 40% of patients with first 
infusion) to mild-moderate reactions of nausea, vomiting, pain, rigors, headache, cough, dizziness, dyspnea, rash, 
and asthenia. Severe reactions include hypotension, hypertension, wheezing, bronchospasm, tachycardia, 
reduced oxygen saturation, and respiratory distress. Pre-existing pulmonary disease or co-morbidities may 
increase risk of pulmonary toxicities or a fatal reaction. Clinical course is variable; initial improvement may be 
followed by clinical deterioration and death. Management of infusion-related reactions includes decreasing the rate 
for mild or moderate reactions and interrupting the infusion in patients experiencing dyspnea or hypotension. 
Consider discontinuing treatment for severe reactions such as anaphylaxis, angioedema, pneumonitis, or 
respiratory distress. Patients who react to the initial trastuzumab infusion may receive further treatment after 
complete resolution of symptoms. Infusion duration may be increased at the physician’s discretion. Symptoms are 
managed with diphenhydramine, acetaminophen, meperidine, epinephrine, corticosteroids, oxygen, 
bronchodilators, or IV fluids. Patients experiencing infusion-related symptoms should not drive or use machines 
until symptoms resolve completely. 


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INTERACTIONS: AGENT 
EFFECT 
MECHANISM 
MANAGEMENT 
anthracycline 
chemotherapy 
increase in trastuzumab-
induced cardiac dysfunction  
negative 
inotropic 
effect on the heart  
avoid 
use 
of 
anthracyclines 
concurrently with trastuzumab  
paclitaxel 
1.5 
fold 
increase 
in 
trastuzumab serum levels  
mechanism 
unclear; 
animal studies report a 
2 fold decrease in 
trastuzumab clearance  
monitor 
for 
signs 
of 
cardiac 
dysfunction  
  Table 5 
SUPPLY AND STORAGE:  
Trastuzumab (Herceptin) will be considered standard of care and will be provided by the insurance company for 
those patients randomized for the control arm. Hoffmann-La Roche Limited produces trastuzumab as 440 mg vials 
of sterile, preservative-free lyophilized powder. Bacteriostatic water for injection (containing benzyl alcohol) is 
supplied for reconstitution. Refrigerate. 
SOLUTION PREPARATION AND COMPATIBILITY: Benzyl alcohol should not be administered intrathecally due 
to the risk of anaphylaxis and increased potential for neurotoxicity. 
For intrathecal administration of trastuzumab or in patients with a known hypersensitivity to benzyl alcohol: 
reconstitute vial with sterile water for injection instead of the supplied preservative-containing diluent.use 
immediately; discard unused portion. 
PARENTERAL ADMINISTRATION: over 30-90 minutes
 3-weekly dosing: loading dose over 90 minutes; 1
st 
maintenance dose over 60 minutes; 2
nd and further maintenance doses over 30 minutes if no adverse reactions. 
Weekly dosing: loading dose over 60 minutes; maintenance doses over 30 minutes if no adverse reactions  
Intrathecal has been used (not approved to use in this protocol) 
DOSAGE GUIDELINES:  
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, 
response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count 
(ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to 
cytotoxic/radiation therapy or with other toxicities.  
Adults: 
Cycle Length:  
Intravenous:  
weekly 
Loading dose: 4 mg/kg IV for one dose on day 1 of first cycle  
Maintenance dose: 2 mg/kg IV for one dose on day 1 of each subsequent cycle  
3 weeks 
Loading dose: 8 mg/kg IV for one dose on day 1 of first cycle  
Maintenance dose: 6 mg/kg IV for one dose on day 1 of each subsequent cycle  
3 weeks 
Loading dose: 6 mg/kg IV for one dose on days 1, 8, and 15 of first cycle.  Maintenance 
dose: 6 mg/kg IV for one dose on day 1 only of each subsequent cycle  
Using a reloading dose has been recommended to quickly regain a therapeutic serum level after a treatment delay; however the optimal way to reload 
trastuzumab after interruption of maintenance therapy is unclear. Trastuzumab has a long elimination half-life so serum level declines slowly with short treatment 
delays. In addition, the minimal therapeutic serum level is not clearly defined, since the targeted serum level in dosing design
 is based on in vitro tumor growth 
inhibition
 and is lower than the actual steady state level observed in efficacy trials.
   
Concurrent radiation:  
3 weeks 
Loading dose: 8 mg/kg IV for one dose on day 1 of first cycle  
Maintenance dose: 6 mg/kg IV for one dose on day 1 of subsequent cycles  
Dosage in myelosuppression:  
modify according to protocol by which patient is being treated;  
Dosage in renal failure:  
no adjustment required 
Dosage in hepatic failure:  
no information found  
Dosage in dialysis:  
no significant removal 
     
 
 
 
 
 
 
 
 
 
 
 
   Table 6 
 
 
9.3 Lapatinib General Infortmation43 
DRUG NAME: Lapatinib  


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Chemical Name: N-{3-Chloro-4-[(3-fluorobenzyl) oxy] phenyl}-6-[5-({[2-(methylsulfonyl) ethyl amino} 
methyl)-2 furyl]-4-quinazolinamine, 
SYNONYM(S): lapatinib ditosylate monohydrate, lapatinib tosylate, GW572016  
COMMON TRADE NAME(S): TYKERB®  
CLASSIFICATION: miscellaneous  
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.  
MECHANISM OF ACTION:  
Lapatinib is an orally active small molecule tyrosine kinase inhibitor. It is a potent, reversible, and selective inhibitor 
of both EGFR and HER2 receptors, and induces growth arrest or apoptosis in EGFR-dependent or HER2-
dependent tumour cell lines.  Lapatinib binds to the intracellular cytoplasmic ATP-binding site of the tyrosine kinase 
domain, blocking receptor phosphorylation and activation, thereby blocking downstream signaling pathways. 
PHARMACOKINETICS: 
 Oral Absorption  
incomplete and variable; increased when administered with food  
Distribution  
highly protein bound; peak plasma concentrations in 4h  
cross blood brain barrier?  
yes 
volume of distribution  
no information found  
plasma protein binding  
>99% to albumin and alpha-1 acid glycoprotein  
Metabolism  
extensive; primarily by CYP 3A4 and CYP 3A5, minor metabolism by CYP 2C19 and CYP 2C8 to 
oxidized metabolites  
active metabolite(s)  
activity not characterized  
inactive metabolite(s)  
activity not characterized  
Excretion  
primarily in feces; increased systemic exposure with moderate to severe hepatic impairment  
urine  
<2%  
feces  
3-67% as unchanged drug and oxidized metabolites  
terminal half life  
14 h after single dose, 24 h with repeated dosing 
clearance  
no information found  
 
 
 
 
 
 
 
 
 
 
 
 
     Table 7 
USES: Primary uses: *Breast cancer 
SPECIAL PRECAUTIONS:  
Caution: lapatinib is associated with QT/QTc prolongation. Patients who are at risk for developing torsades de 
pointes (an atypical ventricular tachycardia with changes in QT interval) include those with cardiac disease, history 
of arrhythmias, electrolyte disturbances, nutritional deficits, etc. and should be closely monitored. Baseline and 
periodic electrolyte measurements and electrocardiograms with QT measurement should be considered. 
Concurrent therapy with other QT prolonging drugs may increase the risk of potentially fatal arrhythmias and should 
be avoided if possible; see paragraph in Interactions section. Concurrent medication should be carefully reviewed 
for potential drug interactions, particularly in regard to CYP 3A4, CYP 2C8, P-glycoprotein, BCRP and OATP1B11; 
see paragraphs in Interactions section.  
Hypokalemia, hypomagnesemia, and hypocalcemia should be corrected prior to treatment initiation. Caution is 
advised with concurrent medications that disrupt electrolyte levels, including diuretics, laxatives, and high dose 
corticosteroids.   Lapatinib has been reported to decrease left ventricular ejection fraction (LVEF). LVEF should 
be evaluated prior to initiation of therapy and periodically throughout treatment (eight week intervals have been 
used in clinical trials); see table and paragraph in Side Effects section.  
Interstitial lung disease and pneumonitis have been associated with treatment. Patients should be monitored for 
pulmonary symptoms, and treatment discontinued if reported symptoms are Grade 3 or greater.  
Hepatoxicity has been observed. Liver function should be monitored prior to initiation of therapy, every four to six 
weeks during treatment, and as clinically indicated; see table and paragraph in Side Effects section. 
The presence of food significantly alters the bioavailability of lapatinib, with 3-5 fold increases in AUC reported with 
low and high fat meals relative to fasting. Multiple mechanisms are believed to be involved. Administration on an 
empty stomach is believed to be the most reliable way to achieve consistent systemic exposure and reduce 


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potential toxicity during chronic therapy. 
Carcinogenicity: No evidence of carcinogenicity in mammalian studies at doses up to twice the expected human 
clinical exposure. 
Mutagenicity: Not mutagenic in Ames test or clastogenic in mammalian in vitro and in vivo chromosome tests.  
Fertility: No effects on mammalian gonadal function, mating, or fertility at doses up to 3-8 times the expected 
human clinical exposure.  
Pregnancy: FDA Pregnancy Category D.9 Lapatinib was not teratogenic in mammalian studies, but decreased 
pup survival, decreased fetal body weights, and minor skeletal anomalies in mammals have been reported. There 
is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite 
the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs 
cannot be used or are ineffective).  
Breastfeeding is not recommended due to the potential secretion into breast milk. 
SIDE EFFECTS:  
The table includes adverse events that presented during drug treatment but may not necessarily have a causal 
relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event 
rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they 
were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be 
clinically important. 
Table 8. Adverse Reactions Occurring in ≥10% of Patients  
lapatinib1,250 mg/day + Capecitabine 2,000 mg/m2/day 
Capecitabine 2,500 mg/m2/day  
 
(N = 198) 
(N = 191) 
 
All Grades a  
Grade 3  
Grade 4  
All Grades a  
Grade 3  Grade 4  
Reactions  
%  
%  
%  
%  
%  
%  
Gastrointestinal disorders  
Diarrhea 
65 
13 
1 
40 
10 
0 
Nausea 
44 
2 
0 
43 
2 
0 
Vomiting 
26 
2 
0 
21 
2 
0 
Stomatitis 
14 
0 
0 
11 
<1 
0 
Dyspepsia 
11 
<1 
0 
3 
0 
0 
Skin and subcutaneous tissue disorders  
Palmar-plantar 
erythrodysesthesia 
53 
12 
0 
51 
14 
0 
Rash b 
28 
2 
0 
14 
1 
0 
Dry skin 
10 
0 
0 
6 
0 
0 
General disorders and administrative site conditions  
Mucosal inflammation 
15 
0 
0 
12 
2 
0 
Musculoskeletal and connective tissue disorders  
Pain in extremity 
12 
1 
0 
7 
<1 
0 
Back pain 
11 
1 
0 
6 
<1 
0 
Respiratory, thoracic, and mediastinal disorders  
Dyspnea 
12 
3 
0 
8 
2 
0 
Psychiatric disorders  
Insomnia 
10 
<1 
0 
6 
0 
0 
Laboratory Abnormalities  
Hematologic  


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Hemoglobin 
56 
<1 
0 
53 
1 
0 
Platelets 
18 
<1 
0 
17 
<1 
<1 
Neutrophils 
22 
3 
<1 
31 
2 
1 
Hepatic  
Total Bilirubin 
45 
4 
0 
30 
3 
0 
AST 
49 
2 
<1 
43 
2 
0 
ALT 
37 
2 
0 
33 
1 
0 
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 
b Grade 3 dermatitis acneiform was reported in <1% of patients in Lapatinib plus capecitabine group. 
Table 9. Adverse Reactions Occurring in ≥10% of Patients  
lapatinib 1,500 mg/day + Letrozole 2.5 mg/day  
Letrozole 2.5 mg/day  
(N = 654) 
(N = 624) 
All Grades a 
Grade 3  
Grade 4  
All Grades a  
Grade 3  
Grade 4  
Reactions  
%  
%  
%  
%  
%  
%  
Gastrointestinal disorders  
Diarrhea 
64 
9 
<1 
20 
<1 
0 
Nausea 
31 
<1 
0 
21 
<1 
0 
Vomiting 
17 
1 
<1 
11 
<1 
<1 
Anorexia 
11 
<1 
0 
9 
<1 
0 
Skin and subcutaneous tissue disorders  
Rashb 
44 
1 
0 
13 
0 
0 
Dry skin 
13 
<1 
0 
4 
0 
0 
Alopecia 
13 
<1 
0 
7 
0 
0 
Pruritus 
12 
<1 
0 
9 
<1 
0 
Nail Disorder 
11 
<1 
0 
<1 
0 
0 
General disorders and administrative site conditions  
Fatigue 
20 
2 
0 
17 
<1 
0 
Asthenia 
12 
<1 
0 
11 
<1 
0 
Nervous system disorders  
Headache 
14 
<1 
0 
13 
<1 
0 
Respiratory, thoracic, and mediastinal disorders  
Epistaxis 
11 
<1 
0 
2 
<1 
0 
Hepatic Parameters    
AST 
53 
6 
0 
36 
2 
<1 
ALT 
46 
5 
<1 
35 
1 
0 
Total Bilirubin 
22 
<1 
<1 
11 
1 
<1 
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 
b In addition to the rash reported under "Skin and subcutaneous tissue disorders", 3 additional subjects in each treatment arm had rash under 
"Infections and infestations"; none were Grade 3 or 4. 
Gastrointestinal adverse events 
If GI adverse events are not appropriately managed, they may be associated with the development of dehydration. 
Management of gastrointestinal adverse events is discussed in detail in below. 


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Nausea, vomiting, or both. In subjects who have emesis and are unable to retain lapatinib, every attempt should 
be made to obtain control of nausea and vomiting. A dose may be repeated if tablets can be visually found after 
the vomiting episode. 
Diarrhea is commonly reported, mainly as grade 1 or 2 events.  Moderate to severe diarrhea may be complicated 
by severe cramping, nausea or vomiting, fever or dehydration.  Diarrhea incidence appears to be related to dose, 
but not serum concentration, suggesting a local effect on the gut as opposed to a systemic effect. Proactive 
management with anti-diarrheal agents is important. A loperamide dosing regimen, including an initial dose of 4 
mg, followed by 2 mg every four hours, and continued until twelve hours diarrhea-free, has been suggested. 
Therapy interruption or discontinuation may be required until recovery, and severe cases may also require oral or 
intravenous electrolytes and fluids.  
Diarrhea management 
These broad general management principles are recommended to proactively try and avoid more serious 
complications by active management of diarrhea syndrome. Guidelines such as these should never replace sound 
clinical judgment. Experience thus far suggests that when lapatinib is used as monotherapy, uncomplicated Grade 
1 or 2 diarrhea is most prevalent. These general management principles do not address comprehensive 
management of more serious or protracted diarrhea syndromes. 
Common clinical sense with the onset of uncomplicated Grade 1-2 diarrhea: stop all lactose containing products: 
drink 8-10 large glasses of clear liquids a day; eat frequent small meals; for Grade 2 diarrhea hold cytotoxic 
chemotherapy, and consider hold lapatinib (discuss with medical monitor); 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. 
Initial dose 4 mg followed by 2 mg every 4 hours or after every unformed stool. It is suggested to continue 
loperamide until the subject is free from diarrhea for 12 hours. 
For Grade 3 or 4 diarrhea or Grade 1 or 2 with complicating features ((CTCAE) Version 4.0) 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 administration. Use prophylactic antibiotics 
as needed (example fluoroquinolones) especially if diarrhea is persistent beyond 24 hours or there is a fever or 
Grade 3-4 neutropenia, hold both cytotoxic chemotherapy and lapatinib and discuss with medical monitor. (See 
Algorithm for the management of diarrhea appendix F) 
Treatment of gastrointestinal adverse events 
Diarrhea can be debilitating, and on rare occasions, it is potentially life-threatening. Based on experience with 
lapatinib alone or in combination with taxanes and/or trastuzumab, diarrhea should be managed proactively to 
avoid complications or worsening of the patient’s condition. Guidelines developed by an American Society of 
Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea are abstracted below.  
Pharmacological approaches include the following: 
Loperamide, administered as an initial 4-mg dose, followed by 2-mg doses every 4 hours. This dose and regimen 
are moderately effective. 
Clonidine, non-steroidal anti-inflammatory drugs, and the serotonin antagonist cyproheptadine have been shown 
to be effective in controlling diarrhea associated with inflammation of the bowel. 
The synthetic octapeptide, octreotide, has been shown to be effective in the control of diarrhea induced by 
fluoropyrimidine-based chemotherapy regimens when administered as an escalating dose by continuous infusion 
or subcutaneous injection. Octreotide can be administered at doses ranging from 100 g twice daily to 500 g 
3 times daily, with a maximum-tolerated dose of 2000 g 3 times daily in a 5-day regimen. 
Hepatoxicity, although reported in less than 1%, may be severe and may occur days to several months after 
treatment initiation. ALT or AST greater than three times the upper limit of normal and total bilirubin of 1.5 times 
the upper limit of normal have been described. Deaths have been reported, although causality is uncertain. Monitor 
liver function tests (transaminases, bilirubin, and alkaline phosphatase) before treatment initiation, every four to 
six weeks during treatment, and as clinically indicated. Lapatinib should be discontinued and not restarted if liver 


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function changes are severe or if severe hepatotoxicity develops during treatment, as moderate to severe hepatic 
impairment has been associated with 56-85% increases in systemic exposure. Clinical experience with severe 
pre-existing hepatic impairment is limited and safety and efficacy data are not available. Based on pharmacokinetic 
modeling, it has been suggested that a dose reduction from 1250 mg/day to 750 mg/day is warranted. 
Hepatotoxicity Addition to SAE Definition 
Hepatobiliary events have been seen in subjects taking lapatinib and other tyrosine kinase inhibitors.  As a 
precaution, the following will be reported as an SAE: 
 
ALT >3×ULN and total bilirubin >2.0×ULN (>35% direct; bilirubin fractionation required). 
NOTE:  If bilirubin fractionation testing is unavailable and a subject meets the criterion of total bilirubin >2.0 × ULN, 
then the event should still be reported as an SAE. 
Other hepatic events should be documented as an AE or an SAE as appropriate. 
Safety: Ensure LFT assessment is included in the protocol as follows: 
 
During treatment phase: every 4-6 weeks (to best fit protocol schedule) for first 6 months, then every 8 – 
12 weeks (or more frequently, if clinically indicated) for remainder of  treatment period 
 
During post-treatment phase:  continue to monitor any liver chemistry abnormalities noted during 
treatment or within 30 days after last dose of investigational product until values return to normal or baseline 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and follow up criteria have been designed to assure subject safety and evaluate liver 
event etiology.  All subjects who meet liver chemistry criteria requiring permanent discontinuation of investigational 
product must continue to be followed per the Liver Chemistry Follow-up Criteria below. 
If a subject experiences ALT >3 × ULN and total bilirubin >2.0 × ULN (>35% direct; bilirubin fractionation required), 
or ALT>3 x ULN and INR>1.5 (if INR measured), then the following actions must be taken: 
immediately and permanently discontinue investigational product;  
complete the SAE data collection tool, the liver event CRF, and the liver imaging and/or liver biopsy CRFs, if these 
tests are performed; 
in addition to the liver event follow up assessments, the following are suggested:  specialist or hepatology 
consultation; anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal 
antibodies; and liver imaging and/or liver biopsy to evaluate liver disease; 
promptly report the event to GSK within 24 hours of learning its occurrence  
monitor every week until liver chemistries resolve, stabilize or return to within baseline values; 
Do not re-challenge with investigational product. 
*NOTE:  If bilirubin fractionation testing is unavailable and a subject meets the criterion of total bilirubin >2.0 × 
ULN, then the aforementioned actions must still be performed. If bilirubin fractionation testing is unavailable, record 
the presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury. 
If a subject experiences: 
ALT >8 × ULN or 
ALT >5 × ULN persisting for 2 weeks : retest within 3 days from the first occurrence and then weekly to determine 
if ALT elevation persists or 
ALT >3 × ULN with signs or symptoms of hepatitis or hypersensitivity (the appearance or worsening of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia) then hold investigational 
product for 2 weeks, repeat liver chemistry testing in 2 weeks, and then call the GSK Medical Monitor to discuss 
the possibility of re-challenging with investigational product.   Liver chemistries and aforementioned signs and 
symptoms should be monitored at a minimum of every 2 weeks until resolution, stabilization, or a return to baseline 
values, at which point monitoring should be continued per protocol. 
If a subject experiences ALT >3 × ULN but <5 × ULN and total bilirubin 2 × ULN, without signs or symptoms of 
hepatitis or hypersensitivity, and who can be monitored weekly, then the following actions should be taken: 
continue investigational product; monitor weekly until liver chemistries resolve, stabilize, or return to within 


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baseline, then monitor liver chemistries as per protocol assessment schedule; If ALT >3 and < 5 × ULN persists 
for > 4 weeks, discontinue treatment. 
for subjects who have ALT >3 × ULN and total bilirubin >2.0 × ULN (>35% direct; bilirubin fractionation required*), 
or ALT>3 x ULN and INR>1.5 (if INR measured), promptly report the event as SAE to GSK within 24 hours of 
learning its occurrence (refer to pages 34 & 35)  for guidance on prompt reporting to GSK); 
complete the SAE data collection tool for all other subjects only if the event meets the criteria for an SAE; 
complete the liver event CRF and the liver imaging and/or liver biopsy CRFs, if these tests are performed; 
monitor every week until liver chemistries resolve or return to within baseline values 
Do not re-challenge with study treatment. 
If a subject experiences ALT >3 × ULN but <5 × ULN and total bilirubin 2 × ULN, without signs or symptoms of 
hepatitis or hypersensitivity, and who can be monitored weekly, then the following actions should be taken: 
continue study treatment; 
monitor weekly until liver chemistries resolve or return to within baseline, then monitor liver chemistries as per 
protocol assessment schedule; 
if at any time the subject meets any of the liver chemistry stopping criteria, then proceed as described above; 
Liver Chemistry Follow-up Criteria 
For all subjects who meet any of the liver chemistry criteria described above, make every attempt to carry out the 
liver event follow up assessments described below: 
Viral hepatitis serology including: 
Hepatitis A IgM antibody; 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; 
Cytomegalovirus IgM antibody; 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); 
Hepatitis E IgM antibody (if subject resides or has traveled outside USA or Canada in past 3 months); 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
Complete blood count with differential to assess eosinophilia; 
Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, fatigue, decreased 
appetite, nausea, vomiting, abdominal pain, jaundice, fever, or rash as relevant on an AE report form; 
Record use of concomitant medications, acetaminophen, herbal remedies, other over-the-counter medications, 
other putative hepatotoxins, and/or alcohol use 
The following assessments are required for subjects with ALT3xULN and bilirubin 2xULN (>35% direct) but are 
optional for other liver chemistries: 
A specialist or hepatology consultation is recommended; 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies; 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease; 
Refer to Appendix E,  for a liver safety algorithm detailing stopping and follow up criteria. 
Left ventricular ejection fraction (LVEF) has been reported to decrease with lapatinib.  Events are usually 
reversible and asymptomatic.  Caution is advised in patients with conditions that impair left ventricular function. 
Previous anthracycline or trastuzumab treatment are suggested as possible risk factors for cardiotoxicity, although 
similar rates of occurrence have been reported for pretreated patients in pooled data.  The majority of LVEF 
decreases (69%) occurred within the first 9 weeks of treatment during clinical trials, but long-term data is limited.  
Events resolved or improved in 62% of patients, with 42% of this continuing treatment. Average event duration 
was reported to be 4 weeks. Symptomatic events responded to standard CHF therapy in most.  Baseline LVEF 
should be evaluated in all patients prior to initiation of treatment and periodically throughout treatment. LVEF was 
monitored at eight week intervals during clinical trials. Lapatinib should be discontinued in patients with symptoms 
associated with decreased LVEF (grade 3 or greater), or if LVEF drops 20% or greater relative to baseline or below 
the lower limit of normal.   


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Concentration dependent QT/QTc interval prolongation has been reported with lapatinib. Events of ventricular 
fibrillation, cardiac arrest, and sudden death have been reported. Risk factors for experiencing torsade de pointes 
during treatment with a QT/QTc prolonging drug include female gender, age ≥65 years, family history, history of 
cardiac disease or arrhythmias, electrolyte disturbances, acute neurological events, hepatic dysfunction, diabetes, 
and nutritional deficits. Concurrent therapy with other QT/QTc prolonging drugs should be avoided where possible. 
Hypokalemia, hypomagnesemia, and hypocalcemia should be corrected prior to lapatinib treatment.  
Addition to SAE definition: 
Cardiovascular events have been seen in subjects taking other compounds that inhibit ErbB2 when used in 
combination with or following anthracyclines, and interstitial pneumonitis has been reported in subjects taking 
compounds that inhibit ErbB1. As a precaution, the following will be reported as an SAE: 
• 
Cardiac dysfunction will be reported as an SAE and will be defined as any signs or symptoms of deterioration 
in left ventricular cardiac function that are Grade 3 (NCI CTCAE) or a ≥20% decrease in left ventricular cardiac 
ejection fraction (LVEF)  relative to baseline which is below the institution's lower limit of normal. 
Refer to NCI CTCAE grading of left ventricular cardiac function. 
Criteria for Evaluating Cardiac Events 
Asymptomatic cardiac events: 
Subjects who have a ≥20% decrease in LVEF  relative to baseline, and the ejection fraction is below the institution's 
lower limit of normal, should have a repeat evaluation of ejection fraction 1-2 weeks later while still receiving 
investigational product. 
• 
If the repeat ejection fraction evaluation confirms a ≥20% decrease in LVEF, and the ejection fraction is below 
the institution's lower limit of normal, then investigational product should be temporarily discontinued. 
• 
If repeat ejection fraction evaluation still shows a decrease ≥20% in LVEF relative to baseline, and the value 
is below the institution's lower limit of normal, then the subject should be withdrawn from investigational 
product. 
Symptomatic cardiac events: 
Subjects with an NCI CTCAE grade 3 or 4 LVEF relative decrease must be withdrawn from study medication. 
Rash (including rash, acne, and dermatitis acneiform) is generally mild to moderate in intensity. Skin rash generally 
appears on the trunk, and sometimes the face.  Rash incidence does not appear to relate to dose, serum 
concentration or clinical response to treatment.3 Onset of rash and other dermatologic events tends to develop 
early in treatment, usually occurring between days 2 to 66, with a median duration of 29 days. Most dermatologic 
events with lapatinib monotherapy resolve without dose adjustment or treatment interruption. Treatment should be 
permanently discontinued for intolerable grade 3 or 4 reactions or for grade 3 or 4 reactions which recur after 
treatment interruption and rechallenge.  Patients are advised to moisturize dry skin with a thick alcohol-free 
emollient upon treatment initiation and minimize sun exposure for treatment duration. Appropriate use of sunscreen 
is recommended to prevent exacerbation of dermatologic toxicity. Treatment of dermatologic events is anecdotal 
and is based on type of reaction and severity of toxicity: skin rash may respond to short-term oral steroids; topical 
or systemic antihistamines may be beneficial for pruritic reactions; antiseptic baths, potent local corticosteroids, 
and silver nitrate are recommended to treat paronychia; and topical or systemic antibiotics are indicated for 
superinfection.  
Management of interstitial lung disease 
If a patient develops symptoms suggestive of interstitial pneumonitis, adult respiratory distress syndrome (ARDS), 
or non-cardiogenic pulmonary edema, lapatinib or trastuzumab therapy should be interrupted and a thorough 
evaluation performed. If NCI-CTCAE v3.0 Grade 3 or 4 pneumonitis/fibrosis or pulmonary infiltrate is confirmed 
(and the relationship to lapatinib and/or trastuzumab cannot be excluded), lapatinib and/or trastuzumab must be 
permanently discontinued. All incidences of interstitial lung disease/ interstitial pneumonitis regardless of grade 
must be reported as serious adverse events (SAEs). 


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Other adverse events 
For any other NCI-CTCAE v3.0 Grade 3 or 4 adverse events or any clinically significant, lower-grade adverse 
event, treatment with lapatinib should be interrupted for a maximum of 14 days until the patient recovers completely 
or the adverse event reverts to NCI-CTCAE v3.0 Grade 1 or to baseline grade. 
If recurrence of adverse event after drug holiday / interruptions is observed a dose reduction by 250mg is 
recommended. Dose reduction should only be implemented when all supportive care measures have been 
exhausted without an improvement of patient status.  
Dermatologic (skin) adverse events 
Significant skin adverse events (Grade 3 or more) resulting from lapatinib are rare (1-3%).  For NCI-CTCAE v4.0 
Grade 4 rash manifested as toxic epidermal necrolysis (i.e. Stevens-Johnson’s Syndrome etc) lapatinib must be 
permanently discontinued. 
Severe Skin Events 
Lapatinib-related severe dermatological events are infrequent (1-3%).  Table 1 displays the NCI-CTCAE (version 
4.0)  Grade 3 skin events, which are defined as:Macules/papules covering >30% BSA with or without associated 
symptoms; limiting self care ADL 
Surgical intervention or IV antibiotics indicated; limiting self care ADL 
Intense or widespread; constant; limiting self care ADL or sleep; oral corticosteroid or immunosuppressive therapy 
indicated 
Covering >30% BSA and associated with pruritus; limiting self care ADL 
Erythema covering >30% BSA and erythema with blistering; photosensitivity; oral corticosteroid therapy indicated; 
pain control indicated (e.g., narcotics or NSAIDs 
Despite the rarity of these events among subjects treated with lapatinib, it is recommended that subjects which 
present with these events be assessed for shortness of breath, angioedema, or generalized mucosal/cutaneous 
affectation with blisters or ulcers, suggestive of Type I hypersensitivity and/or NCI-CTCAE Grade 4 rash or 
dermatologic event, manifested as toxic epidermal necrolysis (i.e., Stevens-Johnson’s Syndrome etc).  If Grade 4 
rash or dermatologic event occurs, lapatinib must be permanently discontinued. 
Stopping and holding rules 
If any Grade 4 dermatologic event occurs, lapatinib must be permanently discontinued. 
Stopping rules 
Lapatinib should be permanently discontinued if an NCI-CTCAE Grade 3 dermatological reaction is intolerable to 
the patient despite recommended treatment interventions, or if a Grade 3 reaction recurs after one drug 
interruption/re-challenge cycle.  For any occurrence of Stevens Johnson syndrome (toxic epidermal necrolysis), 
study therapy must be immediately and permanent discontinued. 
Holding rule 
For NCI-CTCAE Grade 3 dermatological reactions, or a Grade 2 dermatological reaction which is not improved 
after 2 weeks with recommended management strategies, a brief (up to 14 days) therapy interruption is 
recommended; the daily dose of lapatinib should then be reinstated.  In some cases, the skin event may improve 
without the need for interrupting therapy with lapatinib.  In the lapatinib clinical program to date, many subjects 
were able to resume lapatinib therapy at the same dose after resolution of skin event; these subjects had less 
extensive and/or severe skin events. 
Re-challenge 
One re-challenge may be considered, if indicated in the opinion of the investigator, for subjects who present with 
NCI-CTCAE Grade 3 skin events which recover briskly to NCI-CTCAE Grade 1 (within 14 days) after holding 
lapatinib. 
Subjects with poorly tolerated skin adverse events may be successfully managed by providing a brief (up to 14 
days) therapy interruption; the daily dose of lapatinib should then be reinstated. However, the rash may improve 
without the need for interrupting therapy with lapatinib. Of note in current studies, many subjects were able to 
resume lapatinib therapy at the same dose after resolution of rash, and they then had less extensive and/or severe 


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rashes. A variety of agents can be used to manage skin rashes. These include mild-to-moderate strength steroid 
creams, topical or systemic antibiotics, topical or systemic antihistamines, and occasionally, retinoid creams. 
There is no standard, known, or established treatment proven effective for drug-related skin rashes or changes 
due to lapatinib. If the rash is severe (1-3%) then most commonly, a papular/pustular rash has been observed, 
which frequently improves even though the same dose of lapatinib therapy is continued uninterrupted. The need 
for oral or topical antibiotics is a clinical decision of the investigator and should be preceded by a culture of affected 
areas and, if indicated, a dermatology consultation. Oral retinoids should not be given because of theoretical 
concerns about negatively affecting the lapatinib mechanism of action. Oral steroids are also strongly discouraged. 
Other options for treatment of significant rashes may be determined upon consultation with dermatologist.  
General Summary of dose holding/interruptions  
(graded according to NCI-CTCAE v3.0) 
Adverse events 
Action 
Non-hematological, Grade 3 or 4 
Apply maximum supportive care recommendations.  Hold lapatinib therapy until 
recovery to Grade  1 (up to 14 days). 
Grade 3 or 4 left ventricular cardiac dysfunction - please refer to Appendix C.  
For NCI-CTCAE v3.0 Grade 3 or 4 interstitial pneumonitis or Grade 4 rash 
manifested as toxic epidermal necrolysis (e.g. Stevens-Johnson Syndrome etc) 
lapatinib must be permanently discontinued 
If recurrence of adverse event after drug hold / interruptions is observed, and 
maximum supportive care measures applied, a dose reduction must be 
considered 
Non-hematological, Grade 3 or 4 and 
adverse events NOT resolved to Grade  2 
within a maximum of 2 weeks from last 
planned administration  
Evaluate risk benefits, Contact the PI for further guidance. 
Cardiac* (asymptomatic drop in LVEF or 
symptomatic congestive heart failure) 
Lapatinib therapy to be discontinued permanently in case of symptomatic NYHA 
class III and IV CHF. Lapatinib therapy to be hold continued or resumed 
according to appendix B,  for patients with NYHA class I or II CHF. 
Hematological adverse events: 
Absolute neutrophil count (ANC) <1.0 x 
109/L 
Platelets <75 x 109/L 
Hemoglobin <9.0 g/dL (after transfusion if 
needed) 
Hold chemotherapy if lapatinib given simultaneously; if the adverse event is 
related to chemotherapy please refer to appropriate label (until recovery to 
Grade 1). 
If ANC recovers to 1.5 x 109/L within 7days, then merely delaying dose is 
acceptable. If no recovery to ANC of 1.5 x 109/L within 7 days then decrease 
chemotherapy as indicated above. 
Dose modifications for thrombocytopenia, at the start of subsequent courses of 
therapy are the same as recommended for neutropenia above. Next cycle 
should not begin until the platelet count has recovered to 100 x 109/L or more. 
 
In case of multiple short interruptions of dose due to either adverse events or 
drug supply or other reasons the sum of days without lapatinib treatment should 
not exceed 21 days in any 90 day treatment period. 
*Severity corresponding to NYHA criteria 
    Table 10 
 
 
 
 
 
 
INTERACTIONS: 


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AGENT  
EFFECT  
MECHANISM  
MANAGEMENT  
grapefruit and grapefruit 
juice 
may increase plasma level of 
lapatinib  
may 
inhibit 
CYP 
3A4 
metabolism of lapatinib in the 
intestinal wall  
avoid grapefruit and grapefruit 
juice  
   
 
 
 
 
 
 
 
 
 
 
 
    Table 11 
Lapatinib is a weak base with low, pH dependent solubility that declines above pH 4.8 Clinical significance is 
unknown. It has been suggested that antacids which modify gastric pH may affect lapatinib absorption and should 
be avoided for 1 hour pre and post lapatinib doses. 
Lapatinib is a substrate for CYP 3A4. Strong inducers and inhibitors (see appendix G) of this enzyme may alter 
lapatinib pharmacokinetics. Concurrent use with strong inducers or inhibitors should be avoided as clinical data 
for dose adjustment is lacking. Based on pharmacokinetic studies, however, it is suggested that if co-administered 
with a strong CYP 3A4 inhibitor, lapatinib dose reduction from 1250 mg/day to 500 mg/day could be considered, 
with a washout period of 1 week if the inhibitor is discontinued, or if co-administered with a strong CYP 3A4 inducer, 
gradual titration of lapatinib to 1250-4500 mg/day (based on tolerability), with gradual dose reduction over 2 weeks 
if the inducer is discontinued.  Lapatinib is an inhibitor of CYP 3A4, therefore, it may decrease the metabolism or 
increase bioavailability of substrates of this enzyme. Concurrent therapy is discouraged. Dose reduction of the 
substrate drug should be considered.  Lapatinib inhibits CYP 2C8 in vitro and may decrease the metabolism of 
substrates of this enzyme. Dose reduction of the substrate drug should be considered.  Lapatinib is a substrate for 
the transport proteins P-glycoprotein and BCRP. Inhibitors or inducers of these proteins may alter the exposure or 
distribution of lapatinib and QT prolongation is expected to be increased in the presence of inhibitors of these 
proteins. Drugs that prolong QT/QTc interval should be avoided due to the risk of potentially fatal arrhythmias.  In 
vitro, lapatinib is an inhibitor of the transport proteins P-glycoprotein, BCRP, and OATP1B1. Clinical relevance of 
this effect has not been established but elevated bilirubin may occur due to inhibition of hepatic uptake or reduced 
excretion into bile. Reduced metabolism of substrates of these proteins is considered likely, resulting in increased 
concentrations of the substrate drugs. 
Prohibited Medications 
Lapatinib is a substrate for CYP3A4.  Inducers and inhibitors of CYP3A4 may alter the metabolism of lapatinib.  
The following list of CYP3A4 inducers and inhibitors are prohibited from screening through discontinuation from 
study. 
Drug Class 
Specific Agents 
Wash-out1 
CYP3A4 Inducers 
rifamycin antibiotics 
rifampicin, rifabutin, rifapentine 
 
 
 
 
2 weeks 
anticonvulsants 
phenytoin, carbamezepine, barbiturates (e.g., phenobarbital) 
antiretrovirals 
efavirenz, nevirapine, tipranivir, etravirine 
 
glucocortical steroids 
(oral only) 
cortisone (>50 mg), hydrocortisone (>40 mg), prednisone or 
prednisolone (>10 mg), methylprednisolone or triamcinolone (>8 
mg), betamethasone or dexamethasone (>1.5 mg)2 
other 
St. John’s Wort, modafinil 
CYP3A4 Inhibitors 
antibiotics 
clarithromycin, erythromycin, troleandomycin, flucloxacillin 
 
 
 
 
1 week 
antifungals 
itraconazole, ketoconazole, fluconazole (>150 mg daily), 
voriconazole 
antiretrovirals 
delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, 
lopinavir, atazanavir 
calcium channel blockers 
verapamil, diltiazem 
antidepressants 
nefazodone, fluvoxamine 
gastrointestinal agents3 
cimetidine 
fruit juices 
grapefruit, star fruit, and papaw 
other 
amiodarone 
6 months 


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Miscellaneous 
antacids 
Mylanta, Maalox, Tums, Rennies 
1 hour before and 
after dosing 
herbal supplements4 
ginkgo biloba, kava, grape seed, valerian, ginseng, echinacea, 
evening primrose oil 
2 weeks 
                                                                                                                                                                             Table 12 
1. 
Time period between last dose of listed drug and first dose of lapatinib, required to avoid drug-drug interaction potential for toxicity (inhibitors) or loss of 
efficacy (inducers) that could make the patient unevaluable.  Clinically appropriate substitution of drugs not on the list is recommended. 
2. 
A standard 3-5 day course of dexamethasone at a dose following the institutions standard of care for the prevention and/or treatment of platinum-induced 
nausea and vomiting is allowed.  Glucocortical steroid oral dose equivalents (in parentheses) to dexamethasone 1.5 mg (or less) given daily are allowed.  
Intravenous dosing should be considered if clinically appropriate. 
3. 
Emetogenic chemotherapy may require 3-4 daily doses of aprepitant.  CYP3A4 inhibition by oral (not IV) Oral aprepitant will be contraindicated in this 
trial.   
4. 
This list is not all-inclusive; therefore, for herbal supplements not listed, please contact a GSK Medical Monitor or Clinical Scientist. 
NOTE: If future changes are made to the list of prohibited medications, formal documentation will be created and stored with the study file.  Any changes will 
be communicated to the investigative sites in the form of a letter. 
Agent Accountability 
The Investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
inventory and disposition of all agents received from GSK. 
REGULATORY AND REPORTING REQUIREMENTS 
It is the responsibility of the investigator to document all adverse events which occur during the investigation.  An 
adverse event is any untoward medical occurrence in a patient or clinical investigation subject, temporally 
associated with the use of the medicinal product, whether or not considered related to the medicinal product.  An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease (new or exacerbated) temporally associated with the use of a medicinal product.  Anticipated day-to-day 
fluctuations of the disease under study that do not represent a clinically significant exacerbation or worsening need 
not be considered an adverse event. 
All adverse events occurring from the first dose of investigational product until five days after the last dose must 
be recorded REGARDLESS OF WHETHER OR NOT THEY ARE CONSIDERED DRUG RELATED.  In addition, 
any SAEs which occur as a result of protocol specific diagnostic procedures or interventions must also be reported. 
It is the responsibility of the IND holder to comply with IND safety reporting as set forth in the Code of Federal 
Regulations, Section 312.32. 
Assessment of Causality 
Every effort should be made by the investigator to explain each adverse event and assess its relationship, if any, 
to study drug treatment.  Causality should be assessed using the following categories: no (not related), or yes 
(reasonable possibility). 
The degree of certainty with which an adverse experience is attributed to drug treatment (or alternative causes, 
e.g. natural history of the underlying diseases, concomitant therapy, etc.) will be determined by how well the 
experience can be understood in terms of the following: 
 
Known pharmacology of the drug 
 
Reaction of similar nature being previously observed with this drug or class of drug 
 
The event having often been reported in literature for similar drugs as drug related (e.g. skin rashes, blood 
dyscrasia) 
 
The event being related by time to drug administration terminating with drug withdrawal (dechallenge) or 
reproduced on rechallenge. 
The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE form.  
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
 
 
Reporting Serious Adverse Events 


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Prompt Reporting of Serious Adverse Events and Other Events to GSK 
SAEs, pregnancies, and liver function abnormalities meeting pre-defined stopping criteria will be reported promptly 
to GSK as described in the following table once the investigator determines that the event meets the protocol 
definition for that event.   
 
 
 
 
 
 
 
     
 
Initial Reports 
Follow-up Information on a Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
“SAE” data collection tool 
24 hours 
Updated “SAE” data 
collection tool  
Pregnancy 
2 Weeks 
Pregnancy Notification 
Form 
2 Weeks 
Pregnancy Follow up 
Form 
Liver chemistry abnormalities: 
ALT >3 × ULN and bilirubin0 
>2 × ULN (35% direct) or 
ALT>3xULN and INR>1.5, if 
INR measured 
24 hours 
Liver Event and Liver 
Imaging and/or Biopsy 
CRFs, if applicable 
24 hours 
Updated Liver Event 
CRF 
    Table 13 
a. 
bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject meets the criterion of total bilirubin 
>2.0 × ULN, then the event should still be promptly reported as defined 
 
Any serious adverse events which occur during the clinical study or within 5 days of receiving the last dose of 
study medication, whether or not related to the study drug, must be reported by the investigator.  In addition, any 
SAEs which occur as a result of protocol specific diagnostic procedures or interventions must also be reported.   
All related and unexpected adverse events, in addition to being reported to the local IRB by the investigator, must 
be reported by facsimile within 24 hours to GlaxoSmithKline as follows: 
Oncology MDC Fax:      (610) 917-6715 
For medical emergencies contact:  
Michael Arbushites: 
Office: (610) 917-4039 
After Hours or Weekends: (800) 366-8900, ask for physician on call 
GlaxoSmithKline  
1250 S. Collegeville Road, UP4420 
Collegeville, PA  19426-0989 
The SAE report should comprise a full written summary, detailing relevant aspects of the adverse events in 
question.  Where applicable, information from relevant hospital case records and autopsy reports should be 
included.  Follow-up information should be forwarded to GSK within 24 hours. 
SAEs brought to the attention of the investigator at any time after cessation of lapatinib and considered by the 
investigator to be related or possibly related to lapatinib must be reported to GSK if and when they occur. 
Additionally, in order to fulfill international reporting obligations, SAEs that are related to study participation (e.g., 
procedures, invasive tests, change from existing therapy) or are related to a concurrent medication will be collected 
and recorded from the time the subject consents to participate in the study until he/she is discharged. 
Pregnancy 
Patients who become pregnant during the study should discontinue the study immediately.  Investigators should 
notify GlaxoSmithKline of the pregnancy within 14 days of notification. 
Patients should be instructed to notify the investigator if it is determined after completion of the study that they 
become pregnant either during the treatment phase of the study or within five days after the treatment period. 
Whenever possible a pregnancy should be followed to term, any premature termination reported, and the status 
of the mother and child should be reported to GlaxoSmithKline after delivery. 
SUPPLY AND STORAGE:  
Oral: GlaxoSmithKline Inc. supplies lapatinib ditosylate as 250 mg film-coated tablets. Store at room temperature.  


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DOSAGE GUIDELINES:  
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, 
response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count 
(ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to 
cytotoxic/radiation therapy or with other toxicities.  
Adults: Oral: 1250 mg PO once daily.  Administer on an empty stomach (one hour before or one hour after meals). 
Do not take with food. The protocol will require 750 mg no dose reduction will be needed except for severe adverse 
events.  
Dosage in myelosuppression: modify according to protocol by which patient is being treated; Dosage in renal 
failure: dosage adjustment likely not required; less than 2% eliminated by kidneys 
Dosage in hepatic failure: moderate and severe impairment have been associated with increased systemic 
exposure; consider dose reduction to 750 mg PO once daily; treatment should be stopped if severe hepatotoxicity 
develops (See appendix E) 
Recommended Dosing Procedure for Slurry Preparation of Lapatinib Kool-Aid Suspension 
Prepare Lemonade or Tropical Punch Kool-Aid as directed on the package.  Place 2 or 4 oz of Kool-Aid in a glass 
container, then add three lapatinib tablets to the container.  Cover the container, let it stand for 5 minutes, and 
then stir the mixture intermittently for 10 minutes or until it is fully dispersed.  Stir the mixture for 5 seconds then 
administer.  Rinse the container with a 2 oz aliquot of water and repeat the administration process.  This completes 
the administration process (total of 4-6 oz of liquid is dispensed). 
How Supplied: lapatinib is supplied as 250 mg oval, biconvex, orange film-coated tablets with one side plain and the 
opposite side debossed with FG HLS.  The tablets contain 410 mg of lapatinib Ditosylate Monohydrate, equivalent to 
250 mg lapatinib free base per tablet.  The tablets are packaged into HDPE bottles with child-resistant closures. 
Excipients present in the tablet include: Microcrystalline cellulose, povidone, sodium starch glycolate, and 
magnesium stearate. The film-coat contains: Hydroxypropyl methylcellulose, titanium dioxide, triacetin/glycerol 
triacetate, and yellow iron oxide. 
Storage: The intact bottles should be stored at controlled room temperature (15°C-30°C). 
Stability: Shelf life surveillance studies of the intact bottle are on-going.  Current data indicates lapatinib is stable 
for at least 2 years at controlled room temperature (15°C - 30°C). 
 
9.4 Abraxane General Infortmation44 
DRUG NAME: ABRAXANE  
SYNONYM(S): Albumin-Bound Paclitaxel 
COMMON TRADE NAME(S): ABRAXANE® 
CLASSIFICATION: antimicrotubule agent  
MECHANISM OF ACTION:  
ABRAXANE ABRAXANE for Injectable Suspension (also known as ABI-007, nab-paclitaxel, paclitaxel protein-
bound particles for injectable suspension) is an albumin-bound form of paclitaxel with a mean particle size of 
approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. 
ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% 
Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 100 mg of paclitaxel 
and approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted suspension contains 5 mg 
paclitaxel. ABRAXANE is free of solvents.   The active agent in ABRAXANE is paclitaxel.  Abraxane is a biologically 
interactive albumin-bound paclitaxel combining a protein with a chemotherapeutic agent in the particle form. This 
composition provides a novel approach of increasing intra-tumoral concentrations of the drug by a receptor-
mediated transport process allowing transcytosis across the endothelial cell. This albumin-specific receptor 
mediated process involves the binding of albumin to a specific receptor (gp60) on the intralumminal endothelial 
cell membrane, resulting in activation of a protein (caveolin-1), which initiates an internalization process in the 
endothelial cell through the formation of caveolae, with transport of the intact albumin-bound chemotherapeutic 


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complex via these caveolae to the underlying tumor interstitium (Desai et al, 2004). A protein specifically secreted 
by the tumor (SPARC) binds albumin, allowing release of the hydrophobic drug to the tumor cell membrane (Desai 
et al, 2004). ABRAXANE is the first biologically interactive nanoparticle product leveraging this gp-60/caveolin-
1/caveolae/SPARC pathway to increase intra-tumoral concentration of the drug and reducing toxic effects in 
normal tissue. 
INDICATION 
In the United States, ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable 
suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic 
disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline 
unless clinically contraindicated. 
ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in 
combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 
PRECLINICAL STUDIES WITH ABRAXANE  
Preclinical studies comparing ABRAXANE to Taxol® (paclitaxel Cremophor® EL solvent-based, BMS) 
demonstrated lower toxicities, with an MTD approximately 50% higher for ABRAXANE compared to Taxol.  At 
equal doses there was less myelosuppression and improved efficacy in a xenograft tumor model of human 
mammary adenocarcinoma.  At equitoxic doses of paclitaxel, ABRAXANE treated groups showed more complete 
regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor 
paclitaxel area under the curve was 33% higher for ABRAXANE versus solvent based paclitaxel, indicating more 
effective intratumoral accumulation of ABRAXANE (Desai et al, 2006). 
CLINICAL STUDIES WITH ABRAXANE 
Every-Three-Week (Q3W) Schedule in Metastatic Breast Cancer 
In a phase I study, the maximum tolerated dose (MTD) of ABRAXANE was determined to be 300 mg/m2 by 30 
minute infusion Q3W, without premedication or G-CSF support (Ibrahim et al, 2002). No severe hypersensitivity 
reactions occurred with ABRAXANE despite the absence of premedication.  Dose-limiting toxicities included 
sensory neuropathy, stomatitis, and superficial keratopathy, which occurred at a dose of 375 mg/m2.  
Two multicenter phase II studies have evaluated 2 dose levels of ABRAXANE (300 mg/m2, n=63, and 175 mg/m2, 
n=43) in patients with metastatic breast cancer (Ibrahim et al 2005 and Investigator’s Brochure, respectively). The 
overall response rates in these 2 phase II trials were 40% (95% CI 25-54%) for the 175 mg/m2 dose, and 48% 
(95% CI 35-60%) for the 300 mg/m2 dose.  Of 39 patients receiving 300 mg/m2 as first-line therapy for metastatic 
breast cancer, 64% (95% CI 49-79%) responded.  This was contrasted with a 45% response rate in similar patients 
at the lower dose level. Grade 4 neutropenia was noted in 24% of patients at the higher dose level, occurred 
primarily during the first cycle and resolved rapidly.   
A Phase III trial in patients with metastatic breast cancer compared ABRAXANE 260 mg/m2 (n=229) to Taxol 175 
mg/m2 (n=225) given Q3W (Gradishar et al 2005).  Efficacy analyses were based on the ITT population. The ORR 
was significantly greater for ABRAXANE than for Taxol for all patients (33% v 19%, respectively; P = 0.001), 
patients who received first-line therapy (42% v 27%, respectively; P = 0.029), patients who received second-line 
or greater therapy (27% v 13%, respectively; P = 0.006), and patients who had received prior anthracycline therapy 
in either the adjuvant/metastatic setting (34% v 18%, respectively; P = 0.002) or the metastatic setting only (27% 
v 14%, respectively; P = 0.010). Tumor response rate was also significantly higher for ABRAXANE than for Taxol 
in patients with visceral dominant lesions (34% v 19%, respectively; P = 0.002) and in patients aged younger than 
65 years (34% v 19%, respectively; P < 0.001). ORR also was greater for ABRAXANE compared with standard 
paclitaxel in patients with nonvisceral dominant lesions (34% v 19%, respectively) and in patients  65 years old 
(27% v 19%, respectively), but the results did not reach statistical significance because of the small number of 
patients in these subsets. 
Median TTP was significantly longer with ABRAXANE than with Taxol for all patients (23.0 v 16.9 weeks, 
respectively; hazard ratio [HR] = 0.75; P = 0.006).   


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There was a trend for greater median survival for all patients treated with ABRAXANE than with Taxol (65.0 v 55.7 
weeks, respectively; P = 0.374). Although no difference in survival was observed in first-line patients, the difference 
was statistically significant in patients who received ABRAXANE, compared to Taxol, as second-line or greater 
therapy (56.4 v 46.7 weeks, respectively; HR = 0.73; P = .024) [Gradishar et al, 2005].  
The incidence of hypersensitivity reactions (any grade) was low for both arms (1% for ABRAXANE and 2% for 
Taxol). No severe (grade 3 or 4) treatment-related hypersensitivity reactions occurred in any of the patients in the 
ABRAXANE group despite the absence of premedication. In contrast, grade 3 hypersensitivity reactions occurred 
in the Taxol group despite standard premedication (chest pain, two patients; allergic reaction, three patients). Per 
protocol, corticosteroids and antihistamines were not administered routinely to patients in the ABRAXANE group; 
however, premedication was administered for emesis, myalgia/arthralgia, or anorexia in 18 patients (8%) in the 
ABRAXANE group in 2% of the treatment cycles, whereas 224 patients (> 99%) in the Taxol group received 
premedication in 95% of the cycles. 
Although the patients in the ABRAXANE group received an average paclitaxel dose-intensity 49% greater than 
that received by patients in the Taxol group, the incidence of treatment-related grade 4 neutropenia was 
significantly lower in the ABRAXANE group than in the Taxol group (9% v 22%, respectively; P < 0.001), with a 
higher mean neutrophil nadir (1.67 v 1.31x109/L, respectively; P = 0.046), suggesting that polyethylated castor oil 
may have contributed to this toxicity in patients who received standard (solvent-based) paclitaxel.  
As expected with a higher dose of paclitaxel, treatment-related grade 3 sensory neuropathy occurred more 
frequently in the ABRAXANE arm than in the Taxol arm (10% v 2%, respectively; P <  0.001); however, these 
episodes improved with interruption of treatment to grade 2 or 1 in a median 22 days and were easily managed 
with treatment interruption and dose reduction. By day 28 after its first occurrence, the number of patients with 
persistent grade 3 sensory neuropathy was the same (n = 4) in both study arms. No episodes of motor neuropathy 
or grade 4 sensory neuropathy were reported in either group.  
The only clinical chemistry value that was notably different between the two treatment arms was higher serum 
glucose levels in the Taxol–treated patients, who also had a higher incidence of hyperglycemia reported as an AE 
compared with ABRAXANE–treated patients (7% v 1% respectively;  P = 0.003).  
Subgroup analyses revealed that the safety profiles of ABRAXANE (n=97) and Taxol (n=30) in patients who 
received the drugs as first-line therapy were similar to those in the overall study population. In subgroup analyses 
by age, the reported AEs were similar in patients less than 65 years old and patients  65 years old in both groups. 
Of the patients  65 years old, the incidences of the following AEs were notably lower in the ABRAXANE group 
(n=30) than in the Taxol group (n=32): neutropenia (23% v 59%, respectively), leukopenia (10% v 31%, 
respectively), nausea (20% v 38%, respectively), hyperglycemia (0% v 19%, respectively), and flushing (0% v 
16%, respectively). These data indicate no additional safety concerns for ABRAXANE in patients  65 years old 
compared with younger patients.  
Six patients (3%) in the ABRAXANE group and eight patients (4%) in the standard paclitaxel group died during the 
study, all as a result of disease progression. No treatment-related deaths occurred in the ABRAXANE group; one 
patient (< 1%) in the Taxol group died of multiorgan failure, which was considered by the investigator to be possibly 
related to treatment but may also have been a result of sepsis and/or progressive disease. 
Weekly (QW) for 3 Weeks, Every 4 Weeks Schedule in Metastatic Breast Cancer  
Thirty-nine patients were enrolled into A Phase I study of ABRAXANE administered QW for 3 weeks followed by 
a 1 week rest in patients with advanced solid tumors (Nyman et al,  2005).  The MTDs for heavily and lightly pre-
treated patients were 100 and 150 mg/m2 respectively.  Dose limiting toxicities included grade 4 neutropenia and 
grade 3 sensory neuropathy.  Premedication was not required, and unexpected, non-taxane associated toxicities 
were not observed.   
In a Phase II trial in heavily pretreated patients with taxane-refractory metastatic breast cancer, objective antitumor 
responses occurred in 14% of women treated with ABRAXANE 100 mg/m2 QW schedule.  ABRAXANE weekly 
regimen was well tolerated; 91% of 106 patients were treated at the full dose of 100 mg/m2 of ABRAXANE without 
dose reductions. Based on the activity and low toxicity documented with this schedule, the study was expanded to 


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evaluate the efficacy and safety/tolerability of a higher dose of ABRAXANE 125 mg/m2 weekly regimen in 75 
additional patients. Results of this dose-finding study confirm the dose of ABRAXANE 100 mg/m2 as the 
appropriate dose for further study in this patient population (Blum et al, 2007). 45 
In a open-label, randomized, multicenter phase II study comparing the antitumor response and toxicity of  in two 
QW dosing regimens, ABRAXANE dosed Q3W, and Taxotere® (polysorbate solvent-based docetaxel  Sanofi-
Aventis] Q3W for the first-line treatment of metastatic breast cancer (Gradishar et al, EBCC 2008). Total of 300 
patients were randomized to one of four treatment arms: (A) ABRAXANE 300 mg/m2 IV Q3W, (n=76); (B) 
ABRAXANE 100 mg/m2 (n=76); (C) ABRAXANE 150 mg/m2 QW (n=74) QW every 28 days; or (D) Taxotere 100 
mg/m2 Q3W (n=74). The primary objective of the trial was to evaluate the antitumor activity and safety of three 
different ABRAXANE regimens to determine the optimal dose and frequency to be used. Secondary objectives 
included the comparisons of each treatment group with respect to efficacy and safety, specifically: ABRAXANE to 
Taxotere; ABRAXANE QW regimens to ABRAXANE Q3W regimen; and the two dose levels of QW ABRAXANE.  
Patients received ABRAXANE as a 30-minute IV infusion without premedication; Taxotere was administered as a 
60-minute infusion with corticosteroid premedication. The primary efficacy endpoint was ORR assessed every 8 
weeks in all treatment arms by using the RECIST* guidelines. The secondary efficacy endpoints included total 
response (ORR + SD >16 weeks) and PFS. Tumor response results underwent an evaluation by the investigators, 
as well as an Independent Radiology Review (IRR).  If a pre-set level of congruence was observed between the 
tumor responses described by the investigators and the IRR, only the tumor response assessed by investigators 
was reported. Total of 75% of all patients were post-menopausal with a mean age of 53.9 years at randomization.   
Both ORRs and total response rates were higher in all ABRAXANE arms compared to the Taxotere arm. The 
investigator-reported ORRs were 46%, 63%, 74%, and 39%, for arms A, B, C, and D, respectively. This difference 
was statistically significant for both QW dosing arms of ABRAXANE compared with Taxotere, (P = 0.002 for arm 
B v D, and P <0.001 for arm v D). The corresponding investigator-reported total response rates were 72%, 83%, 
91% and 69% for the four arms, respectively. This difference reached statistical significance for arms B and C 
compared to Taxotere (P = 0.009 for arm B v D, and p=0.005 for arm C v. D).  No significant difference in ORR 
was noted between the two weekly dosing arms (arm B vs. C, P = 0.24). A significant increase in PFS was observed 
in the 150 mg/m2 QW arm compared to the Taxotere arm (14.6 v 7.8 months, respectively, P = 0.012, hazard ratio 
0.57).  No significant difference in PFS was found between the ABRAXANE 300 mg/m2 Q3W arm and Taxotere 
arm (A and D). Similarly, PFS was not significantly different between arms A and C, or arms B and D. Figure I 
depicts the Kaplan-Meier curves comparing PFS for the four treatment arms.  
All three ABRAXANE arms demonstrated a favorable safety profile when compared with the Taxotere arm. Toxicity 
data occurring in >25% of patients is summarized in Table II. The most frequent hematologic adverse event was 
neutropenia, with significantly lower rates of Grade 3/4 neutropenia in all ABRAXANE arms (Grade 4, 5%, 5%, 
9%, 75% for arms A, B, C, D, respectively).  ABRAXANE also had lower rates of febrile neutropenia (1%, 1%, 1%, 
8% for arms A, B, C, D, respectively) and fatigue (Grade 3, 5%, 0%, 3%, 19% for arms A, B, C, D, respectively) 
compared to Taxotere. While the incidence of sensory neuropathy was similar in the ABRAXANE and Taxotere 
arms, the median time to improvement in patients with Grade 3 neuropathy was shorter in all three ABRAXANE 
arms (22, 22, 19 and 37 days in arms A, B, C and D, respectively).The ABRAXANE arms demonstrated improved 
safety and increased efficacy compared with Taxotere. All three ABRAXANE regimens produced lower rates of 
neutropenia, febrile neutropenia, and fatigue than Taxotere. 
Continuous Weekly (QW) Schedule in Neoadjuvant Breast Cancer 
The NSABP studied the administration of ABRAXANE in a neoadjuvant setting to patients with locally advanced 
breast cancer at a dose of 100 mg/m2 QW for 12 weeks, with no break (Robidoux et al, 2010).  Four cycles of 
FEC were administered sequentially based on patients’ HER2 status: HER2 negative patients received FEC-100 
(F: 500 mg/m2, E: 100 mg/m2, C: 500 mg/m2 Q3 weeks) and HER2 positive patients received weekly trastuzumab 
in addition to FEC-75 (F: 500 mg/m2, E: 75 mg/m2, C: 500 mg/m2 Q3 weeks).  Weekly trastuzumab was permitted 
during ABRAXANE and FEC-75 treatment at the discretion of the investigator.   The primary objective of the trial 
was to determine the pathologic complete response rate (pCR) in the breast.  At the time of initial report at SABCS 


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2006, 65 patients had been entered on study and were evaluable for cCR and safety.  Following 12 weeks of 
ABRAXANE, a clinical complete response rate (cCR) of 32% was noted.  The therapy was well tolerated, with 
48/65 patients receiving 12 doses in 12 weeks and 13/65 receiving 12 doses in 13-14 weeks.  The incidence of 
peripheral (sensory) neuropathy was low (11% grade 2, 5% grade 3) as was neutropenia (3% grade 3 and no 
grade 4). The authors concluded that the administration of ABRAXANE 100 mg/m2 QW x 12 was both effective 
and tolerable.  
At the time of this update, more than 20 abstracts and publications have been presented at major oncology 
conferences or published in medical journals related to ABRAXANE QW schedule in breast cancer, including 
completed and ongoing studies.    
ABRAXANE Toxicities  
Myelosuppression, nausea and vomiting, diarrhea, mucositis, infections, hypotension, abnormal ECG changes, 
cough, dyspnea, edema, sensory neuropathy, bilirubin/liver enzyme elevations, allergic reactions, alopecia, 
asthenia, arthralgia, and myalgia. During post marketing surveillance, rare cases of severe hypersensitivity 
reactions have occurred.  
Frequency
a 
of Important Treatment Emergent Adverse Events in the Randomized Study on an Q3W 
Schedule  
Percent of Patients  
  
ABRAXANE 260/30min
b (n=229) 
 
Paclitaxel Injection  175/3h
c,d 
 (n=225) 
Bone Marrow  
Neutropenia  
< 2.0 x 10
9/L  
< 0.5 x 10
9/L  
80  
9  
82  
22  
Thrombocytopenia  
< 100 x 10
9/L  
< 50 x 10
9/L  
2  
<1  
3  
<1  
Anemia  
< 11 g/dL  
< 8 g/dL  
33  
1  
25  
<1  
Infections  
24  
20  
Febrile Neutropenia  
2  
1  
Bleeding  
2  
2  
Hypersensitivity Reaction
e  
All  
4  
12  
Severe
f 
0  
2  
Cardiovascular  
Vital Sign Changes
g  
Bradycardia  
<1  
<1  
Hypotension  
5  
5  
Severe Cardiovascular Events
f 
3  
4  
Abnormal ECG  
All patients  
60  
52  
Patients with Normal Baseline  
35  
30  
Respiratory  
Cough  
7  
6  


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Dyspnea  
12  
9  
Sensory Neuropathy  
Any Symptoms  
71  
56  
Severe Symptoms
f 
10  
2  
Myalgia / Arthralgia  
Any Symptoms  
44  
49  
Severe Symptoms
f 
8  
4  
Asthenia  
Any Symptoms  
47  
39  
Severe Symptoms
f 
8  
3  
Fluid Retention/Edema  
Any Symptoms  
10  
8  
Severe Symptoms
f 
0  
<1  
Gastrointestinal  
Nausea  
Any symptoms  
30  
22  
Severe symptoms
f 
3  
<1  
Vomiting  
Any symptoms  
18  
10  
Severe Symptoms
f 
4  
1  
Diarrhea  
Any Symptoms  
27  
15  
Severe Symptoms
f 
<1  
1  
Mucositis  
Any Symptoms  
7  
6  
Severe Symptoms
f 
<1  
0  
Alopecia  
90  
94  
Hepatic (Patients with Normal Baseline)  
Bilirubin Elevations  
7  
7  
Alkaline Phosphatase Elevations  
36  
31  
AST (SGOT) Elevations  
39  
32  
Injection Site Reaction  
<1  
1  
Table 14
 
a Based on worst grade  
b ABRAXANE dose in mg/m
2/duration in minutes  
c paclitaxel injection dose in mg/m
2/duration in hours  
d paclitaxel injection 
pts received premedication  
e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that  
began on a day of dosing.  
f Severe events are defined as at least grade 3 toxicity  
g During study drug dosing.  
STUDY MEDICATION ADMINISTRATION 
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line filters during the 
administration of ABRAXANE. In any event, filters of pore-size less than 15 micrometers must not be used. 
ABRAXANE Premedication 
Patients do not require premedication prior to ABRAXANE administration, as hypersensitivity reactions are rare.  
Although the solubilizing agents Cremophor® EL and Tween® 80 have long been implicated in adverse events 
including hypersensitivity reactions due to their detergent-like nature and known ability to induce histamine release 
(Ten Tije et al, 2003), the administration of solvent-based taxanes (Taxol and Taxotere) requires premedication 
with corticosteroids and histamine receptor blocking agents to prevent the occurrence of hypersensitivity reactions. 
However, the hypersensitizing role of the taxane molecules themselves cannot be ruled out.   In the unlikely event 


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of a mild hypersensitivity reaction, premedication may be administered using the premedication regimen the 
institution typically uses for solvent based paclitaxel. 
In the rare event of a severe hypersensitivity reaction, discontinue ABRAXANE. 
Dose Modifications/Reductions 
Administration of Study Drug to Patients with Abnormal Hematologic Function 
ABRAXANE dosing should not be administered at the start of each cycle until the absolute neutrophil count returns 
to 1.5 x 109 cells/L and the platelet count returns to >100 x 109 cells/L.  For patients receiving weekly ABRAXANE, 
for each subsequent dose of ABRAXANE within a cycle (Days 8 and 15), patients must have an ANC  1.0 x 109 
cells/L and platelets > 75 x 109 cells/L.  If the ANC and platelets are not adequate for treatment on Day 8 and/or 
15, the dose will be omitted and the total cycle length remains the same.   
Administration of Study Drug to Patients with Abnormal Hepatic Function 
Study drug should only be administered if hepatic function is within the parameters established in the eligibility 
criteria.  Hepatic toxicity from taxanes may occur but it is uncommon.  Therefore, hepatic dysfunction that occurs 
while the patient is on study should prompt an evaluation to determine the cause, including the possibility of 
progressive metastatic disease and hepatotoxicity from concurrent medications. 
Dose Modification Table 
Use this table as a guideline to determine any necessary dose modifications.  The modification is dependant on the starting 
dose for the study.  The below modifications are aligned with the most recent data presented at the SABCS. 
Dose Modification                                            
 
 
 
 
 
 
               Table 15 
Dose Level 
ABRAXANE (mg/m2) 
1 
100 
-1 
80 
-2 
60 
Dose Reductions and guidelines for optional use of Growth Factors for Hematologic Toxicity. The table below provides a 
guideline for implementing dose reductions and optional use of growth factor treatment for hematologic toxicity: 
Use of G-CSF and Dose reductions for Hematologic Toxicity 
Adverse Event 
Occurrence 
Action to be Taken 
 
 
ANC < 500 cells/mm3 (nadir count) with 
neutropenic fever > 38° 
OR 
Delay of next cycle due to persistent 
neutropenia (ANC < 1000 cells/mm3) 
OR 
Neutropenia < 500 cells/mm3 for > 1 week 
Any 
Occurrence 
At the first occurrence of a hematological toxicity (as outlined 
in the Adverse Event column), the same dose is maintained 
and G-CSF is given as outlined below.  In the event that a 
hematological toxicity re-occurs in the face of G-CSF, dose 
reduction to the next lower level will be required for 
subsequent cycles once ANC is  1500 cells/mm3.  
 
If G-CSF will be given if needed concurrently with weekly 
ABRAXANE; its administration may begin the day after 
ABRAXANE is given and should stop at least 48 hours prior 
to when ABRAXANE is given the following week.   
Thrombocytopenia Grade 3 or Grade 4* 
1st Occurrence 
Dose reduction to next lower level 
Recurrence 
Dose reduction to next lower level 
Table 16 
*See NCI Toxicity Criteria Scale for definition of Grade 3 and Grade 4 events. 
G-CSF Administration. For QW study drug administration administer G-CSF 5 mcg/kg/day (rounded to the nearest 
vial size per investigator/institution’s standard of care) 24 hours after chemotherapy and hold 48 hours prior to the 
next dose 
Pegfilgrastim (Neulasta®) is not allowed. 
Sensory Neuropathy 
ABRAXANE should be withheld in patients who experience  Grade 3 sensory neuropathy.  Treatment may be 
resumed at the next lower dose level (see Table 14) in subsequent cycles after the sensory neuropathy improves 
to  Grade 1. The time to resolution to Grade  1 should be the adverse event duration used for adverse event 


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reporting.  In those patients who experience Grade 4 sensory neuropathy, study drug should be withheld, and 
treatment resumed at a reduction of 2 dose levels (Dose Level -2; see Table 14) in subsequent cycles after the 
sensory neuropathy improves to  Grade 1.  Note: the investigator may elect to dose modify for Grade 2 sensory 
neuropathy. 
Hypersensitivity Reactions 
Hypersensitivity reactions rarely occur.  If they do occur, minor symptoms such as flushing, skin reactions, 
dyspnea, lower back pain, hypotension, or tachycardia may require temporary interruption of the infusion.  
However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, 
angioedema or generalized urticaria require immediate discontinuation of study drug administration and 
aggressive symptomatic therapy.  Patients who experience a severe hypersensitivity reactions to ABRAXANE 
should not be re-challenged.  It is not recommended to administer ABRAXANE to patients with prior 
hypersensitivity to a taxane. 
Other Toxicities 
If toxicities are  grade 3, except for anemia, treatment should be withheld until resolution to  grade 1 or baseline 
if baseline was greater than grade 1, then reinstituted, if medically appropriate, at the next lower dose level (see 
Table 2). 
Concomitant Medications 
Supportive care, including but not limited to anti-emetic medications, may be administered at the discretion of the 
Investigator.  Concurrent treatment with bisphosphonates is allowed.  Erythropoietin and G-CSF may be 
administered at the discretion of the investigator, consistent with institutional guidelines.  
Packaging, Labeling, and Storage of Study Drug 
Availability ABRAXANE will be supplied by Celgene Corporation.  Each single-use vial contains 100 mg of 
paclitaxel and approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted suspension contains 
5 mg paclitaxel.  
Storage and Stability 
Storage: Store the vials in original cartons at 20º C to 25º C (68º F to 77ºF). Retain in the original package to 
protect from bright light.  
Stability: Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 
20ºC to 25ºC (68ºF to 77ºF), in the original package. Neither freezing nor refrigeration adversely affects the stability 
of the product.  
Stability of Reconstituted Suspension in the Vial  
Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for 
a maximum of 8 hours if necessary. If not used immediately, each vial of reconstituted suspension should be 
replaced in the original carton to protect it from bright light. Discard any unused portion.  
Stability of Reconstituted Suspension in the Infusion Bag  
The suspension for infusion prepared as recommended in an infusion bag should be used immediately, but may 
be stored at ambient temperature (approximately 25º C) and lighting conditions for up to 8 hours.  
Study Medication Administration 
ABRAXANE is injected into a vein [intravenous (I.V.) infusion] over 30 minutes.  The use of an in-line liter is not 
recommended.  
Reconstitution and use of ABRAXANE 
Calculate the patient’s body surface area at the beginning of the study and if the weight changes by > 10% by 
using the formula provided in the study manual. 
Calculate the total dose (in mg) to be administered by:  
Total Dose (mg) = BSA x (study dose mg/m2 ) 
Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 
                                            100 (mg/vial) 


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Round up the number of vials to be reconstituted to the next higher whole number when a fractional number of 
vials is obtained by the above formula (eg, if the total number of vials = 4.05 or 4.5, then 5 vials would be 
reconstituted).  Using sterile technique, prepare the vials for reconstitution. Swab the rubber stoppers with alcohol. 
Aseptically, reconstitute each ABRAXANE vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.  Slowly 
inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe 
directing the solution flow onto the inside wall of the vial. 
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution directly onto the lyophilized cake as this will 
result in foaming. 
Once the injection is complete, allow the vial to sit for a minimum of 5 (five) minutes to ensure proper wetting of 
the lyophilized cake/powder.   
Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder 
occurs.  Avoid generation of foam.  Rapid agitation or shaking will result in foaming. If foaming or clumping occurs, 
stand solution for at least 15 minutes until foam subsides. Each ml of reconstituted product will contain 5 mg of 
paclitaxel. Calculate the exact total dosing volume of 5 mg/ml suspension required for the patient: 
Dosing volume (ml) = Total dose (mg) / 5 (mg/ml) 
The reconstituted suspension should be milky and homogeneous without visible particulates.  If particulates or 
settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use.  Discard 
the reconstituted suspension if precipitates are observed.  Once the exact volume of reconstituted ABRAXANE 
has been withdrawn from the vials, discard any excess solution left over in accordance with standard operating 
procedures. Further dilution is not necessary. Inject the calculated dosing volume of reconstituted ABRAXANE 
suspension into an empty sterile, standard PVC IV bag using an injection port.  Inject perpendicularly into the 
center of the injection port to avoid dislodging plastic material into the IV bag.   Administer the calculated dosing 
volume of reconstituted ABRAXANE suspension by IV infusion over 30 minutes.  The use of in-line filters is not 
recommended because the reconstituted solution may clog the filter.  
Drug Distribution and Destruction 
Supplier 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ  07901 
Industry Contact: 
TBN 
Manager, Medical Operations 
Celgene Corporation 
400 Connell Drive, 7th Floor 
Connell Corporate Park 
Berkeley Heights, NJ 07922 
Mobile: 908-723-6919 
Fax: 908-673-2779 
Email: Mkennedy@celgene.com  
Drug Distribution 
ABRAXANE® will be distributed by Celgene Corporation.  No supplies will be shipped to any site until regulatory 
approval has been obtained.  Investigational sites will be supplied with ABRAXANE® upon identification and 
screening of a potential trial subject.   
Upon identification of a potential subject, sites must fax a completed Drug Request Form to Celgene Corporation.  
Allow at least 5 working days for drug shipment.  There are no shipments on Fridays or holidays. 
For re-supply of drug, please complete and fax the Drug Request Form to Celgene Corporation at 908-673-2779. 
Drug Return and Destruction 


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If the investigational site does not have a policy, procedure or SOP detailing the process to follow for study drug 
destruction, the study drug must then be returned to Celgene using the Drug Return Form provided in the package 
containing the study drug.  The following information must be recorded on the site’s pharmacy drug accountability 
log: quantity of vials to be returned, expiration date and lot number.  A copy of the Drug Return Form and the study 
drug should be returned to Celgene Clinical Supplies Dept. using the mailing address on the packaging slip that 
came with the original study drug order.  A copy of the Drug Return Form should be retained at the clinical site.  In 
the event of study completion or termination, a copy of all pharmacy records (drug dispensing log, drug 
accountability log and any destruction memos) must be mailed to Celgene Medical Operations. 
If the investigational site has a policy, procedure or SOP detailing the process to follow for study drug destruction, 
the pharmacist or designee can choose to destroy the study drug on site.  The following information must be 
recorded on the site’s pharmacy drug accountability log: quantity of vials destroyed, expiration date and lot number.  
The pharmacist must document that the study drug was destroyed in accordance with their institution’s drug 
destruction policy or SOP.  A drug destruction memo and the site’s drug destruction SOP/policy should be sent to 
Celgene Medical Operations Dept.  A copy of the drug destruction memo should be retained at the clinical site.  In 
the event of study completion or termination, a copy of all pharmacy records (drug dispensing log, drug 
accountability log and any destruction memos) must be mailed to Celgene Medical Operations. 
 
9.5 Paclitaxel General Infortmation46 
DRUG NAME: Paclitaxel  
SYNONYM(S): benzenepropanoic acid 
COMMON TRADE NAME(S): TAXOL®, ONXOL®  
CLASSIFICATION: antimicrotubule agent  
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.  
MECHANISM OF ACTION:  
Paclitaxel is a taxane. Paclitaxel binds to tubulin, the protein component of microtubules, simultaneously promoting 
their assembly and disassembly to form stable, nonfunctional microtubules. Although some reports indicate a 
cross-reactivity rate of 90% between docetaxel and paclitaxel, others suggest it does not occur consistently.  
Stabilization of microtubules blocks cells in the M phase of the cell cycle, inhibiting cell division and causing cell 
death.  Paclitaxel acts as a radiosensitizing agent by blocking cells in the G2phase.  Paclitaxel is an 
immunosuppressant. 
PHARMACOKINETICS: 
Distribution  
biphasic: initial distribution to peripheral compartment, then slow efflux from the peripheral compartment; widely 
distributed into body fluids and tissues
1,7; small changes in dose may lead to large changes in peak plasma 
concentrations and total drug exposure due to saturable, nonlinear pharmacokinetics 
cross blood brain barrier? 
no  
volume of distribution
  
67 L/m² for 1-6 h infusion; varies with dose and infusion time; 198-688 
L/m² for 24 h infusion  
plasma protein binding
  
88-98%  
Metabolism  
extensively metabolized in liver via CYP 2C8 (primarily) and CYP 3A4; activity of metabolites is unknown
  
metabolite(s)
  
67% as 6α-hydroxypaclitaxel via CYP 2C8;  37% as 3-p-hydroxypaclitaxel 
and 6α,3-p-dihydroxypaclitaxel via CYP 3A4  
Excretion  
primarily via bile
  
urine  
14% (1-13% as unchanged drug)  
feces  
71% (5% as unchanged drug)  
terminal half life
  
10 h; varies with dose and infusion time  
clearance
  
12 L/h/m²; varies with dose and infusion time  


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Children 
clearance: 19 to 260 L/m²                                                                                                                   Table 17 
     
USES: Primary uses:  
*Breast cancer, Lung cancer, small cell, *Lung cancer, non-small cell, Esophageal cancer , *Ovarian cancer  
Bladder cancer, *Kaposi’s sarcoma, Head and Neck cancer, Cervical cancer,  Endometrial cancer. 
SPECIAL PRECAUTIONS:  
Preexisting liver impairment may impair elimination of paclitaxel , dose reduction is suggested; see Dosage 
Guidelines.  
Special populations: Elderly patients may have more myelosuppression, neuropathy and cardiovascular 
toxicities 
Patients with AIDS-related Kaposi’s sarcoma may have more hematologic toxicities, infections and febrile 
neutropenia. 
Carcinogenicity: no information found  
Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test. Paclitaxel is clastogenic in 
human lymphocytes in vitro but not in other mammalian in vivo chromosome tests. 
Fertility: In animal studies, reduced fertility has been observed, with decreased pregnancy rates and increased 
embryo loss in females and testicular atrophy/degeneration in males. 
Pregnancy: FDA Pregnancy Category D.  There is positive evidence of human fetal risk, but the benefits from use 
in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or 
for a serious disease for which safer drugs cannot be used or are ineffective). Paclitaxel has shown to be 
embryotoxic and fetotoxic in animal studies; soft tissue and skeletal malformations have been reported. 
Breastfeeding is not recommended due to the potential secretion into breast milk. 
SIDE EFFECTS:  
The table includes adverse events that presented during drug treatment but may not necessarily have a causal 
relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event 
rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they 
were reported in more than 1% of patients in the product monograph or pivotal trials. 
ORGAN SITE  
SIDE EFFECT  
blood 
and 
lymphatic 
system/ 
febrile 
neutropenia  
anemia (62-78%, severe 6-16%) 
febrile neutropenia (2%) 
leukopenia (86-90%, severe 4-17%) 
neutropenia (87-90%, severe 27-52%) nadir 10-12 days, recovery 15-21 
days; may require dose reduction  
thrombocytopenia (6-20%, severe 1-7%); nadir 8-9 days
  
cardiac  
bradycardia (3-4%); first 3 h of infusion;  
cardiovascular events (severe 1-2%);  
ear and labyrinth  
hearing loss, tinnitus, vertigo, ototoxicity (<1%)  
eye  
optic nerve and/or visual disturbances, photopsia, visual floaters (<1%); 
generally reversible, may be dose-related  


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gastrointestinal  
emetogenic potential: low-moderate 
abdominal pain; with intraperitoneal administration
  
anorexia (25%) 
constipation (18%)
 
intestinal obstruction (4%) 
mucositis (20-31%); more common with 24 h infusion
  
nausea and vomiting (44-52%)  
taste changes 
general disorders and administration site 
conditions  
extravasation hazard: irritant 
edema (17-21%, severe 1%); localized under skin at no specific site  
fever (12%) 
injection site reactions (4-13%) 
immune system  
hypersensitivity reactions (5-42%, severe 1-2%)  
infections and infestations  
infections (18-30%, severe 1%); primarily urinary tract and upper respiratory 
tract 
injury, poisoning, and procedural complications  radiation recall dermatitis 
investigations  
ECG abnormalities (8-14%, severe <1%);  
alkaline phosphatase, elevated (18-22%, severe 1%)
  
AST, elevated (18-19%, severe 1%) 
bilirubin, elevated (4-7%, severe 1%)
  
musculoskeletal and connective tissue  
arthralgia/myalgia (54-60%, severe 8-12%);  
nervous system  
autonomic neuropathy, resulting in paralytic ileus and orthostatic hypotension 
(<1%)  
motor neuropathy, with resultant minor distal weakness (<1%)  
peripheral neuropathy (52-64% severe 2-4%) 
respiratory, thoracic and mediastinal  
dyspnea (2%) 
radiation recall pneumonitis
  
skin and subcutaneous tissue  
alopecia (87-93%); usually complete, generally occurs 14-21 days after 
administration of paclitaxel; onset sudden, often occurring in a single day // nail 
discoloration (2%) //r ash (12-14%) 
vascular  
hypotension (11-24%); during first 3 h of infusion 
phlebitis
  
   Table 18  
Hypersensitivity reactions typically occur within the first 10 minutes of the first two cycles. Reactions are caused 
by either a histamine release in response to polyoxyl 35 castor oil (Cremophor® EL), or a non-IgE mediated 
reaction to the taxane moiety. Frequent, minor hypersensitivity reactions include: flushing (28%), rash (12%), 
hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). Chills, abdominal pain, and back pain 
are more rare.  Severe hypersensitivity reactions include: dyspnea requiring bronchodilators, hypotension requiring 
treatment, flushing, chest pain, tachycardia, angioedema, and generalized urticaria. Severe reactions rarely occur 
after the third cycle of treatment.  The incidence and severity of hypersensitivity reactions are reduced with 
premedication although rare, fatal reactions may occur despite premedication.  A single IV dexamethasone dose 
with an antihistamine and an H2-antagonist reduces the incidence of hypersensitivity reactions from 40% to 2-3%.  


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The frequency and severity of hypersensitivity reactions are not affected by the dose or duration of infusion of 
paclitaxel.  For management of hypersensitivity reactions. 
Rechallenge after a severe hypersensitivity reaction:  
The occurrence of hypersensitivity reactions does not preclude rechallenge with paclitaxel. In the event of a 
hypersensitivity reaction, the patient may be rechallenged the same day after additional premedication, slowing 
the rate of infusion, and close monitoring.  Subsequent cycles may benefit from a regimen of oral dexamethasone 
given 12 and 6 hours before paclitaxel, plus antihistamines and H2-antagonists given 30 minutes to 1 hour before 
paclitaxel.  Consider substituting paclitaxel with docetaxel or implementing a desensitization protocol if a patient 
develops a reaction following a rechallenge. For management of  
Arthralgia/myalgia may be severe in some patients; however, there is no consistent correlation between 
cumulative dose and infusion duration of paclitaxel and frequency or severity of the arthralgia/myalgia. Symptoms 
are usually transient, occurring within 2 or 3 days after paclitaxel administration, and resolving within days.  If 
arthralgia/myalgia is not relieved by adequate doses of ibuprofen, or short-term, low-dose dexamethasone or 
prednisone,  gabapentin may be tried.  Dose reducing paclitaxel may lessen the severity of arthralgias/myalgias; 
however, there is no data on efficacy of reduced doses in a curative setting. Dose reduction should be considered 
only if symptom severity precludes continuing paclitaxel. 
Peripheral sensory neuropathy presents with numbness and tingling in a stocking-and-glove distribution, perioral 
numbness, and hyperesthesia. Onset of symptoms can be within days following infusion. Frequency of symptoms 
increases with repeated exposure and cumulative dose.  Pre-existing neuropathies from prior therapies are not a 
contraindication for treatment with paclitaxel; however, the incidence of neuropathy appears to be increased in this 
patient population. A dose reduction of 20% is recommended for all subsequent cycles of paclitaxel for patients 
who experience severe peripheral neuropathy. Sensory neuropathy usually improves or resolves within months of 
paclitaxel discontinuation. 
Cardiovascular effects present as bradycardia, hypotension and ECG changes. Bradycardia and hypotension 
typically occur during the first 3 hours of infusion; however, they are usually asymptomatic and do not require 
treatment. Paclitaxel administration may require interruption or discontinuation in some cases. Frequency of 
hypotension and bradycardia is not influenced by dose, schedule or prior anthracycline therapy. Common ECG 
changes are non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia, and premature beats. 
Among patients with normal ECG at baseline, prior therapy with anthracyclines did not influence the frequency of 
ECG abnormalities. Severe cardiovascular effects are rarely reported, including cases of atrial fibrillation, 
supraventricular tachycardia, myocardial infarction, congestive heart failure, and thromboembolic events. When 
reported, these patients had underlying disease or previous radiotherapy or chemotherapy which was thought to 
have contributed to the event. 
INTERACTIONS: 
AGENT 
EFFECT 
MECHANISM 
MANAGEMENT 
cisplatin 
may 
increase 
neutropenia 
when 
paclitaxel is given 
after cisplatin  
paclitaxel clearance is decreased by 25-33% 
when given after cisplatin  
preferred method is to give 
paclitaxel 
first 
when 
administering as sequential 
infusions  
dexamethasone 
does not affect protein binding of paclitaxel  
diphenhydramine 
does not affect protein binding of paclitaxel  
disulfiram
  
development 
of 
acute 
alcohol 
intolerance 
reactions  
inhibition of aldehyde dehydrogenase by 
disulfiram, leading to development of toxic 
metabolites of ethanol (found in the solution)  
avoid disulfiram concurrently 
with paclitaxel administration  
doxorubicin 
may 
increase 
cardiac toxicity from 
doxorubicin clearance is decreased leading to 
increased plasma levels of doxorubicin and 
monitor 
for 
increased 
cardiotoxicity  


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doxorubicin 
when 
given 
concurrently 
with paclitaxel  
doxorubicinol  
metronidazole 
and 
derivatives 
development 
of 
acute 
alcohol 
intolerance 
reactions; the risk for 
most 
patients 
appears slight  
inhibition of aldehyde dehydrogenase by 
metronidazole, leading to development of toxic 
metabolites of ethanol (found in solution)  
avoid metronidazole and its 
derivatives concurrently with 
paclitaxel administration  
vaccines, live 
enhanced 
viral 
replication 
may 
increase the risk of 
disseminated 
disease  
decreased immune response allows live 
vaccine to produce infection  
avoid live vaccines during 
treatment  
warfarin 
may 
increase 
anticoagulant effect 
of warfarin when 
given 
concurrently 
with paclitaxel  
paclitaxel may displace warfarin from plasma 
protein binding sites when given concurrently  
monitor INR and adjust 
warfarin dosing accordingly; 
consider use of LMWH with 
chemotherapy          
                              Table 19 
Paclitaxel is a substrate of CYP 3A4 and CYP 2C8 isoenzymes. Strong inhibitors of CYP 3A4 or 2C8 may decrease 
paclitaxel metabolism resulting in increased plasma levels and toxicity. Avoid concurrent use if possible; if 
unavoidable, consider reducing the paclitaxel dose.  Strong inducers of CYP 3A4 or 2C8 may increase paclitaxel 
metabolism, potentially resulting in a reduced therapeutic effect of paclitaxel. 
SUPPLY AND STORAGE:  
Paclitaxel (TAXOL) will be considered standard of care and will be provided by the insurance company for those 
patients randomized for the control arm. Biolyse Pharma produce paclitaxel as 30 mg and 100 mg single dose 
vials and a 300 mg multi-dose vial in a concentration of 6 mg/mL. Refrigerate. Do not freeze. Potency is not affected 
when transported or stored for up to 2 months at room temperature. Non-medicinal ingredients per mL of solution: 
527 mg Cremophor® EL (polyethoxylated castor oil) and 49.7%(v/v) alcohol.  
Adults: 
3 weeks 80 mg/m
2 IV for one dose on days 1, 8 and 15 (total dose per cycle 240 mg/m2), for atotal of 12 weeks 
Concurrent radiation: has been given 
Dosage in dialysis:  
No dosage adjustment required for creatinine clearance less than 50 mL/min Dosage in myelosuppression:     
modify according to protocol by which the patient is being treated.                               
                
                 Table 20 
Dosage in renal failure hemodialysis: no significant removal; may give standard dose before or after hemodialysis 
chronic ambulatory peritoneal dialysis(CAPD): no significant removal; may give standard dose before or after 
CAPD 
Bristol-Myers Squibb supplies paclitaxel as 30 mg, 100 mg and 300 mg vials in a concentration of 6 mg/mL. Store 
at room temperature. Product may precipitate if refrigerated; precipitate redissolves at room temperature. Non-
medicinal ingredients per mL of solution: 527 mg Cremophor® EL (polyethoxylated castor oil) and 49.7%(v/v) 
ethanol. 
Healthcare supplies paclitaxel as 30 mg, 100 mg, 150 mg, and 300 mg multi-use vials in a concentration of 6 
Dosage in hepatic 
failure 
Suggested guidelines for first course; subsequent courses should be based on individual tolerance 
ALT or AST  
bilirubin  
dose  
<10 X ULN  
and  
≤1.25 X ULN  
175 mg/m²  
<10 X ULN  
and  
1.26-2 X ULN  
135 mg/m²  
<10 X ULN  
and  
2.01-5 X ULN  
90 mg/m²  
≥10 X ULN  
or  
>5 X ULN  
not recommended  


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mg/mL. Store at room temperature. Protect from light. If refrigerated, product may precipitate; precipitate 
redissolves at room temperature. Non-medicinal ingredients per mL of solution: 527 mg Cremophor® EL 
(polyethoxylated castor oil) and 46.5%(v/v) alcohol. 
SOLUTION PREPARATION AND COMPATIBILITY:  
Additional information:  
Concentrated solution must be diluted prior to IV infusion.  To prevent extraction of plasticizer DEHP from 
container, prepare solutions in non-PVC (or non-DEHP) containers and administer using non-PVC administration 
sets. 
PARENTERAL ADMINISTRATION: 
Intermittent infusion over 1-3 h 
Continuous infusion has been given 
Intraperitoneal infuse into abdominal cavity as rapidly as possible by gravity 
DOSAGE GUIDELINES:  
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, 
response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count 
(ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to 
cytotoxic/radiation therapy or with other toxicities.  
 
10. 
Prohibited concomitant therapy 
Anti-neoplastic therapies 
Treatment with systemic anticancer agents (chemotherapy, hormone therapy, targeted or biologic agents) other 
than the protocol treatment is not permitted until disease progression is documented per RECIST1.1.  
 
 
11. 
Visit schedule and assessments 
11.1 
Study flow and visit schedule


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Table 21 
Visit evaluation schedule Arm 1 
 


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Table 22 
Visit evaluation schedule Arm 2 
 


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12. 
Assessment types 
Tests and procedures should be done on schedule, but visit windows of ± 2 days are allowed (except as 
otherwise specified) occasionally for holidays, vacations, and other administrative reasons. If extenuating 
circumstances prevent a patient from beginning treatment or completing a scheduled assessment within this 
time frame, the patient may continue in the study only with written permission of the medical monitor. 
Additional schedules that specify study days on which these assessments are to be performed will be 
provided in the study manual as needed. 
Screening:  Within 28 days prior to the Cycle 1, Day 1 dose of    Trastuzumab   or Trastuzumab Emtansine 
Base line:   Within 3 days prior to the Cycle 1, Day 1 dose of Trastuzumab  or Trastuzumab Emtansine. Only 
screening procedures not performed within 3 days of dosing are required at baseline. Treatment cycles are 
to be repeated every 28 days.   
    The Biological window (BW) will be covered by targeted therapy only (Trastuzumab Emtansine 3.6 mg/kg    
IV every three weeks plus Lapatinib 750 mg/daily p.o for a total of six (6) weeks) ( in Arm 1 only). 
The Biological window (BW) will be covered by targeted therapy only (Trastuzumab 4 mg/kg IV load followed 
by 2 mg/kg IV weekly  plus Lapatinib 750 mg/daily p.o for a total of six (6) weeks)( in Arm 2 only) 
The baseline symptom- directed medical history and physical examination are not required if the screening 
medical history and physical examination were conducted within 3 days prior to the Cycle 1, Day 1. 
Vital signs (blood pressure, heart rate, and oral temperature) measurements will be obtained during 
screening and baseline and before every infusion. 
A 12-lead ECG will be performed during screening/before start treatment, at week 12 and EOT.  In all patients 
enrolled in the study, MUGA or echocardiogram to be performed at screening and week 12 or when clinically 
indicated.  MUGA or echo also required for all patients with history of cardiac dysfunction.  Same method 
(ECHO or MUGA) must be used throughout the duration of the study. 
A blood sample for complete blood count (CBC) with platelet count and differential white blood cell (WBC) 
count will be obtained during screening/baseline, and on day one, eight, and fifteen (1, 8, 15) of every chemo 
dose [±1 day], and every three weeks during the biological window, EOT and if clinically indicated.  If a 
patient is found to have an absolute neutrophil count (ANC) <500/mm3 or a platelet count < 25,000/mm3, or 
both, the CBC with differential should be repeated at least every other day until the ANC and platelet count 
have exceeded these values on at least 2 occasions.   
A blood sample for the clinical chemistry panel (sodium, potassium, carbon dioxide, chloride, magnesium, 
blood urea nitrogen [BUN], creatinine, total bilirubin, uric acid, LDH, alkaline phosphatase, aspartate 
transaminase [AST/SGOT], alanine transaminase [ALT/SGPT]) will be obtained at screening/baseline, and 
on day one, eight, and fifteen (1, 8, 15) of every chemo dose [±1 day],  and every three weeks during the 
biological window. EOT and if clinically indicated. Glucose and albumin are to be obtained at baseline only. 
For women of childbearing potential, the results of a serum -hCG pregnancy test must be negative within 
7 days before the first dose of treatment is administered.  If the screening serum -hCG pregnancy test is 
performed more than 7 days before dosing, it must be repeated at baseline, with results known to be negative 
prior to first dose of study drug.  To be repeated as clinically indicated. 
Mammography and Ultrasound at baseline and before surgery,  chest X-ray at baseline only or when clinically 
indicated, CT scans, abdomen at discretion of the treatment physician, or as a clinically indicated.  Bilateral 
breast MRI at baseline, after the biological window before the first cycle of chemotherapy and at the end of 
the study before surgery. Main tumor site  biopsy will be completed during screening (within 56 days of Cycle 
1, Day 1 is acceptable)  In patients with accessible tumor, biopsies will be conducted at baseline, and before 
the third infusion of Trastuzumab,  and if the patient progresses while in treatment a new biopsy will be taken 
before the patient start the new treatment. 
Banked tumor tissue obtained as part of the patient’s standard care and additional biopsies, will be evaluated 
for  HER2 expression levels, PTEN, PI3K and possibly other candidate markers related to the drug’s 
mechanism of action, tumor biology or the improvement of diagnostic assays.  


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 Arm 1; Trastuzumab Emtansine 3.6 mg/kg IV every three weeks plus Lapatinib 750 mg/daily p.o for a total   
 of six (6) weeks, after this biological window patients will continue the same targeted therapy plus  weekly    
Abraxane  100 mg/m2 for a further 12 weeks, up to definitive surgery. 
Arm 2: Trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly plus Lapatinib 750 mg/daily for a total 
of 6 weeks, after this biological window, patients will continue on the same targeted therapy plus weekly 
paclitaxel 80 mg/m2 for a further 12 weeks, up to definitive surgery.  
Serious adverse events (SAEs) will be captured from the time of informed consent through 30 days from the 
last dose of   treatment. SAEs occurring beyond 30 days from last dose that are attributed to study treatment 
or any study patient death should be reported also. 
*. Patients will be treated until completion of 4 cycles with the chemo agent then a local therapy (surgery).   
Following surgery, patients will complete one year of anti-HER2 therapy with trastuzumab.  Hormone positive 
patients will continue hormonal therapy.  Chemotherapy and radiation will be given at the discretion of the 
treating physician. 
Clinical evaluation will include a record of the date and site(s) of recurrence, subsequent breast cancer 
treatment administered, and late treatment-related toxicity. 
The duration of patient participation in the study will be a total of six(6) to seven (7) months from the start of 
treatment. Follow-up for all patients will include: ·Medical history update (30 days after the last dose of the 
study drug) Evaluate subjects who discontinue the protocol for reasons other than disease progression (AEs) 
every 4 weeks until progression or until they receive additional anti-cancer therapy. 
 
12.1 
CRITERIA FOR RESPONSE 
The main endpoint in this study is to determine the pathologic complete response rate (pCR) in the breast, 
when TDM-1 is given in combination with Lapatinib and Abraxane in patients with Her 2 Neu over-expressed  
Breast carcinoma and who are candidates for pre-operative chemotherapy. 
 
12.2 
RECIST Criteria 
The clinical tumor response will be assessed using RECIST criteria at baseline and before surgery.  
RECIST criteria offer a simplified, conservative, extraction of imaging data for wide application in clinical trials. 
They presume that linear measures are an adequate substitute for 2-D methods and register four response 
categories47  
 
CR (complete response) = disappearance of all target lesions  
 
PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions  
 
PD (progressive disease) = 20% increase in the sum of the longest  diameter of target lesions  
 
SD (stable disease) = small changes that do not meet above criteria  
 
12.3 
Withdrawal of subjects from study 
Withdrawal 
Subjects must be withdrawn from the trial (treatment and procedures) for the following reasons:  
 
Subject withdraws consent from study treatment and study procedures.  A subject must be removed 
from the trial at her own request or at the request of her legally acceptable representative.  At any 
time during the trial and without giving reasons, a subject may decline to participate further.  The 
subject will not suffer any disadvantage as a result. 
 
Subject is lost to follow-up. 
 
Death. 
Subjects may be withdrawn from the study for the following reasons: 
 
The subject is non-compliant with study drug, trial procedures, or both; including the use of anti-
cancer therapy not prescribed by the study protocol. 


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 
Pregnancy.  Pregnancy will be reported as an SAE.  (Note: subjects who have been withdrawn from 
treatment with study drug because of pregnancy should not undergo CT scans [with contrast]/MRI or 
bone scans while pregnant.) 
 
If, in the investigator's opinion, continuation of the trial would be harmful to the subject's well-being. 
 
Severe allergic reaction to Everolimus (such as stomatitis or Grade 3 or 4 hypersensitivity reaction). 
 
The development of a second cancer.  
 
Development of an intercurrent illness or situation which would, in the judgment of the investigator, 
significantly affect assessments of clinical status and trial endpoints. 
 
Deterioration of ECOG performance status to 4. 
 
Use of illicit drugs or other substances that may, in the opinion of the investigator, have a reasonable 
chance of contributing to toxicity or otherwise skewing trial result. 
Any subject removed from the trial will remain under medical supervision until discharge or transfer is medically 
acceptable. In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's medical 
records. 
12.4 
Pregnancy and assessments of fertility 
Pregnancy testing is required at screening or whenever pregnancy is suspected.  Serum pregnancy testing 
should be performed at screening and at the end of the study or if clinically indicated.  
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must 
use highly effective contraception during the study and for 8 weeks after stopping treatment. Highly effective 
contraception is defined as either: 
 
Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception] 
 
Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment 
 
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in 
the ejaculate). [For female subjects on the study, the vasectomised male partner should be the sole partner 
for that subject]. 
 
Use of a combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, implanted or other hormonal methods of contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository 
 
In case of use of oral contraception, women should have been stable on the oral agent before taking study 
treatment. 
Sexually active males must use a condom during intercourse while taking the drug and for 8 weeks after 
stopping treatment and should not father a child in this period. 
A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal 
fluid. 
Female partners of male patients must also be advised to use one of the following contraception methods: 
Use of (1) oral, injected, implanted or other hormonal methods of contraception, or (2) intrauterine device (IUD) 
or intrauterine system (IUS), or (3) prior male/female sterilization. 
 
13. 
Safety monitoring and reporting 
Information about all adverse events, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be collected and 
recorded and followed as appropriate. 


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13.1 
Adverse events 
13.1.1 
Definitions and reporting 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse Events CRF. 
Conditions that were already present at the time of informed consent should be recorded in the Medical History 
page of the patient’s CRF. Adverse event monitoring should be continued for at least 30 days (or 5 half-lives, 
whichever is longer) following the last dose of study treatment. Adverse events (including lab abnormalities 
that constitute AEs) should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom should 
be reported as a separate Adverse Event. 
The occurrence of adverse events should be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the patient during or 
between visits or through physical examination, laboratory test, or other assessments. As far as possible, each 
adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates or if continuing at the Safety Follow-up Visit) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)  
4. Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, hospitalized, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, concomitant 
medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved with 
sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 14. 
All adverse events should be treated appropriately. Such treatment may include changes in study drug 
treatment including possible interruption or discontinuation, starting or stopping concomitant treatments, 
changes in the frequency or nature of assessments, hospitalization, or any other medically required 
intervention. Once an adverse event is detected, it should be followed until its resolution, and assessment 
should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study drug, the interventions required to treat it, and the outcome. Information about 
common side effects already known about the investigational drug can be found in the [Investigators’ 
Brochure]. This information should be included in the patient informed consent and should be discussed with 
the patient during the study as needed. Adverse event monitoring should be continued for at least 30 days 
following the last dose of study treatment 
 
13.1.2 
Laboratory test abnormalities 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes in study 
treatment), should be recorded on the Adverse Events CRF. Whenever possible, a diagnosis, rather than a 
symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory abnormalities that meet the 
criteria for Adverse Events should be followed until they have returned to normal or an adequate explanation 
of the abnormality is found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. Laboratory abnormalities, that do not meet the definition of an adverse event, should not be reported 
as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE unless 
it meets the definition of serious as defined below and/or as per investigator’s discretion. A dose hold or 
medication for the lab abnormality may be required by the protocol and is still, by definition, an adverse event. 


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14. 
Serious Adverse Events 
14.1 
Definitions 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 
is fatal or life-threatening 
 
results in persistent or significant disability/incapacity 
 
constitutes a congenital anomaly/birth defect 
 
requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: 
 
routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition (specify what this includes) 
 
elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under 
study and has not worsened since the start of study drug 
 
treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE 
given above and not resulting in hospital admission 
 
social reasons and respite care in the absence of any deterioration in the patient’s general condition 
 
is medically significant, i.e., defined as an event that jeopardizes the patient or may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
14.1.1 
Reporting 
The principal investigator has the obligation to report all related and unexpected adverse events to the local, 
IRB.  To ensure patient safety, every SAE, regardless of suspected causality, occurring: 
 
after the patient has provided informed consent and until atleast 30 days after the patient has stopped 
study treatment/participation 
 
after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind treatment, 
etc.) and 30 days after the patient has stopped study treatment 
 
after the start of any period in which the study protocol interferes with the standard medical treatment 
given to a patient (e.g., treatment withdrawal during washout period, change in treatment to a fixed dose 
of concomitant medication) and until 30 days after the patient has stopped study treatment must be 
reported to the institutional IRB  within 24 hours of learning of its occurrence ; This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths 
during treatment or within 30 days following completion of active protocol therapy must be reported within 
5 working days. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. A SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.  The end date of the first event must be provided. 
Each re-occurrence, complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not (if applicable), and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator Brochure or Package Insert (new occurrence) and 
is thought to be related to the study drug, may urgently require further information from the investigator to the 
local IRB. The Investigator and the local IRB may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been reported. Suspected Unexpected 
Serious Adverse Reactions (SUSARs) will be collected and reported to the competent authorities.  For 
Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse experiences will be 
forwarded to the comapartor drug company by the investigator. The following categories and definitions of 
causal relationship to study drug should be considered for use for this clinical study. 


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 
Certain: There is a known causal relationship between the study drug and the SAE. The event responds 
to withdrawal of study drug (dechallenge), and recurs with rechallenge when clinically feasible. (>95% 
certainty) 
   Probable: There is reasonable causal relationship between the study drug and the SAE. The event 
responds to dechallenge. Rechallenge is not required. (65%-95% probability) 
   Possible: There is reasonable causal relationship between the study drug and the SAE. Dechallenge 
information is lacking or unclear. (35%-65% probability of relatedness) 
   Not likely: There is temporal relationship to study drug administration, but there is not a reasonable causal 
relationship between the study drug and the SAE. (5-35% probability of relatedness) 
   Not related: There is not a temporal relationship to study drug administration (too early, or late, or study 
drug not taken), or there is known causal relationship between the SAE and another drug, concurrent 
disease, or other circumstance. (<5% chance of relatedness) 
 
Adverse events classified as “serious” require expeditious handling and reporting to Houston  Methodist 
Cancer Center (TMHCC) and local IRB to comply with regulatory requirements.  
 
All related or unexpected AEs of any of the study drugs  must be immediately reported to local IRB  by 
the investigator or designee within 24 hours of becoming aware of the event. If only limited information 
is initially available, follow-up reports are required.  The original SAE form must be kept on file at the 
study site. 
 
Report SAE to Celgene Drug Safety within 24 hours via email or fax.   
Celgene Corporation 
Global Drug Safety and Risk Management  
Connell Corporatke Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ 07922 
Fax 908-673-9115. Email  
Email:  drugsafety@celgene.com 
All SAEs should be faxed or emailed to  
Houston Methodist Cancer Center at: 
Research@tmhs.org 
Fax Number: 713-793-1642 
 
For studies conducted under an Investigator IND expecion , any event that is both related and  
unexpected must be reported to the local IRB as soon as possible and, in no event, later than 7  days 
(death or life-threatening event) or 15 days (all other SAEs) after the investigator’s or  institution’s initial 
receipt of the information.  
14.1.2 
Pregnancy 
Preclinical data regarding reproductive toxicity is described in the most recent Investigator Brochure. The 
potential reproductive risk for humans is unknown.  Women of childbearing potential should be advised to use 
highly effective contraception methods while they are receiving everolimus and up to 8 weeks after treatment 
has been stopped.   
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported 
to the local IRB/CELGENE/GSK within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
The newborn will be followed for at least 12 months. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the local 
IRB/CELGENE/GSK Drug Safety and Epidemiology Department (DS&E). Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to the study 


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treatment and any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form. 
 
15. 
Statistical methods 
15.1 
Sample Size. 
Two parallel arms (arm 1: Trastuzumab Emtansine plus Lapatinib followed by Abraxane and arm 
2:  Trastuzumab plus Lapatinib followed by paclitaxel) will be evaluated and a two-stage optimum Simon’s 
design will be employed to perform interim analysis for each arm of the trial. The null hypothesis is that 
pathological complete response rate is equal to 50% versus an alternative hypothesis equal to 70%.  A sample 
of 15 patients will be enrolled in each arm during the first stage.  Decisions on how to proceed with the trial 
after enrollment has been completed in the first stage will involve all three parties (CELGENE, GSK, and 
HMRI).  For the experimental arm only, a two-stage Simon’s design with 80% power and 5% alpha level patient 
accrual will be terminated if 8 or fewer patients achieve pCR; otherwise decisions on how to proceed with  the 
trial will involve all three parties.  The interim analysis results will be treated as confidential as long as the study 
is ongoing, and may not be released to anyone other than those specified in the interim analysis plan 
(CELGENE, GSK, and HMRI).     pCR rates will be estimated in each arm along with exact 95% confidence 
intervals. The safety profiles of the study will be assessed through summaries of adverse events (AEs), serious 
adverse events (SAEs), AEs leading to treatment discontinuation, and treatment-related death. All patients 
who receive at least 1 dose of treatment will be included in the analysis for safety. The safety analysis will 
report the frequency of all AEs and laboratory abnormalities, as well as the frequency of dose interruptions, 
dose reductions, and treatment discontinuation for toxicity. Toxicity rates will be presented using the worst NCI 
CTCAE (V4) grade per patient. Blocked randomization will be used to randomly assign patients either to arm 
1 or arm 2.  Other secondary clinical outcomes will be summarized including clinical response rate, % tumor 
shrinkage, changes in imaging, operability and type of surgery, disease-free interval and time to progression.  
All subjects who received study drug will be included in the safety analysis.  
 
16. 
Protocol amendments, or changes in study conduct 
Any change or addition to this protocol requires a written protocol amendment that must be reviewed by the 
local IRB and the investigator before implementation. Amendments significantly affecting the safety of 
subjects, the scope of the investigation or the scientific quality of the study require additional approval by the 
IRB at each study center.  Examples of amendments requiring such approval are: 
1. increases in drug dose or duration of exposure of subjects, 
2. significant changes in the study design (e.g. addition or deletion of a control group), 
3. increases in the number of invasive procedures, 
4. addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being taken by the 
investigator in the interests of preserving the safety of all patients included in the trial.  If an immediate change 
to the protocol is felt to be necessary by the investigator and is implemented for safety reasons must be notified 
to the IRB and other centers must be informed immediately.   Amendments affecting administrative aspects of 
the study do not require formal protocol amendments. Amendments affecting administrative aspects of the 
study will require IRB approval.  


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17. 
References: 
1. Trastuzumab Emtansine IB& protocol 
2. Holbro T, Beerli RR, Maurer F, et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 
requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A 2003; 100:8933-8938. 
3. Kim HH, Sierke SL, Koland JG. Epidermal growth factor-dependent association of phosphatidylinositol 3-
kinase with the erbB3 gene product. J Biol Chem 1994; 269:24747–24755. 
4. Baselga J and Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev 
Cancer 2009; 9:463-475. 
5. Hellyer NJ, Cheng K and Koland JG. ErbB3 (HER3) interaction with the p85 regulatory subunit of 
phosphoinositide 3-kinase. Biochem J 1998; 333:757-63. 
6. Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: 
implications for targeted therapy. Cancer Res 2008; 68:5878-5887. 
7. Sergina NV, Rausch M, Wang D, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the 
kinase-inactive HER3. Nature 2007; 445:437-41. 
8. Konecny GE, Pegram MD, Venkatesan N, et al.  Activity of the dual kinase inhibitor lapatinib (GW572016) 
against HER-2-overexpressing and trastuzumab-treated breast cancer cells.  Cancer Res 2006; 66:1630-
1639. 
9. Rusnak DW, Lackey K, Affleck K, et al.  The effects of the novel, reversible epidermal growth factor 
receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cel 
lines in vitro and in vivo.  Mol Cancer Ther 2001; 1(2):85-94. 
10. Ritter CA, Perez-Torres M, Rinehart C, et al. Human breast cancer cells selected for resistance to 
trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent 
on the ErbB receptor network. Clin Cancer Res 2007; 13:4909-4919. 
11. Rabindran SK, Discafani CM, Rosfjord EC, et al.  Antitumor activity of HKI-272, an orally active, irreversible 
inhibitor of the HER-2 tyrosine kinase.  Clin Cancer Res 2004; 64(11):3958-3965. 
12. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, A functional genetic approach identifies 
the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.Cancer Cell. 2007 
Oct;12(4):395-402. 
13. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Hortobagyi GN, PTEN activation contributes to 
tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer 
Cell. 2004 Aug;6(2):117-27. 
14. Abraxane package insert. 
15. Abraxane plus Lapatinib in the Neo-adjuvant setting data 
16. Yardley D, Burris H 3rd, Peacock N, et al A pilot study of adjuvant nanoparticle albumin-bound (nab) 
paclitaxel and cyclophosphamide, with trastuzumab in HER2-positive patients, in the treatment of early-
stage breast cancer. 2010 Sep;123(2):471-5. doi: 10.1007/s10549-010-1047-0. Epub 2010 Jul 24. 
17. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-
positive breast cancer. N Engl J Med 353:1673-84, 2005 
18. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in 
HER2-positive breast cancer. N Engl J Med 353:1659-72, 2005 
19. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-
positive breast cancer. N Engl J Med 353:1673-84, 2005 
20. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in 
HER2-positive breast cancer. N Engl J Med 353:1659-72, 2005 
21. Riese DJ, 2nd, Stern DF: Specificity within the EGF family/ErbB receptor family signaling network. 
Bioessays 20:41-8., 1998 
22. Amundadottir LT, Leder P: Signal transduction pathways activated and required for mammary 
carcinogenesis in response to specific oncogenes. Oncogene 16:737-46, 1998 
23. Okano J, Gaslightwala I, Birnbaum MJ, et al: Akt/protein kinase B isoforms are differentially regulated by 
epidermal growth factor stimulation. J Biol Chem 275:30934-42., 2000 


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24. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against 
HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-92., 2001 
25. Rusnak DW, Affleck K, Cockerill SG, et al: The characterization of novel, dual ErbB-2/EGFR, tyrosine 
kinase inhibitors: potential therapy for cancer. Cancer Res 61:7196-203., 2001 
26. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast 
cancer. N Engl J Med 355:2733-43, 2006 
27. Blackwell K, Kaplan E, Franco S, et al: A phase II, open-label, multicenter study of GW572016 in patients 
with trastuzumab-refractory metastatic breast acncer. Proc Am Soc Clin Onco 23:196 (abstract 3006), 
2004 
28. Dees EC, Burris H, Hurwitz H, et al: Clinical summary of 67 heavily pre-treated patients with metastatic 
carcinomas treated with GW572016 in a phase Ib study. Proc Am Soc Clin Onco 22:3188, 2004 
29. Agus DB, Gordon MS, Taylor C, et al: Phase I clinical study of pertuzumab, a novel HER dimerization 
inhibitor, in patients with advanced cancer. J Clin Oncol 23:2534-43, 2005 
30. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N 
Engl J Med 367:1783-91, 2012 
31. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in 
women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a 
randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012 
32. Baselga J, Bradbury I, Eidtmann H, et al: Lapatinib with trastuzumab for HER2-positive early breast cancer 
(NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379:633-40, 2012 
33. Nagata Y, Lan KH, Zhou X, et al: PTEN activation contributes to tumor inhibition by trastuzumab, and loss 
of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117-27, 2004 
34. Berns K, Horlings HM, Hennessy BT, et al: A functional genetic approach identifies the PI3K pathway as 
a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395-402, 2007 
35. Xia W, Mullin RJ, Keith BR, et al: Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks 
EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21:6255-63., 2002 
36. Dave B, Migliaccio I, Gutierrez MC, et al: Loss of phosphatase and tensin homolog or phosphoinositol-3 
kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-
overexpressing locally advanced breast cancers. J Clin Oncol 29:166-73, 2010 
37. Mohsin SK, Weiss HL, Gutierrez MC, et al: Neoadjuvant trastuzumab induces apoptosis in primary breast 
cancers. J Clin Oncol 23:2460-8, 2005 
38. Rimawi MF, Mayer IA, Forero A, et al: Multicenter phase II study of neoadjuvant lapatinib and trastuzumab 
with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 
2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 31:1726-31, 2013 
39. Ding L, Getz G, Wheeler DA, et al: Somatic mutations affect key pathways in lung adenocarcinoma. Nature 
455:1069-75, 2008 
40. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 
455:1061-8, 2008 
41. Trastuzumab Emtansine Investigator Brochure 
42. Trastuzumab  Investigator Brochure 
43. Lapatinib Investigator Brochure, protocol temaplete & Package insert 
44. Abraxane Investigator Brochure & protocol temaplete 
45. Andre Robidoux,Aman U. Buzdar, et al A Phase II Neoadjuvant Trial of SequentialNanoparticle Albumin-
Bound Paclitaxel Followedby 5-Fluorouracil/Epirubicin/Cyclophosphamide in Locally Advanced Breast 
Cancer Clinical Breast Cancer, Vol. 10, No. 1, 81-86, 2010; DOI: 10.3816/CBC.2010.011 
46. Paclitaxel Investigator Brochure 
47. National Cancer Institute RECIST Guidelines and criteria. 
 
 


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18. 
Appendices  
Appendix A: ECOG/ Karnofsky Performance Status Criteria 
 
 
 
 
 
 
 
 


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Appendix B: New York Heart Association (NYHA) Classifications 
 
This table is an excerpt from the Oxford Textbook of Medicine, 2nd ed. Oxford; New York: Oxford University Press, 1987, p. 2228. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C: Version 4.0 (dated June-14-2010) 


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CTCAE Files 
NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 data files and related documents 
are published here. The most current release files appear in this directory:  
Files: Booklet 
 
Content 
CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
Most recent release of core terminology: PDF document, 
traditional small booklet format. 
 
 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix D: WOCBP & Determination of Menopausal Status 
 
WOCBP 
Women of childbearing potential and men must agree to use adequate contraception (one of the following 
listed below) prior to study entry, for the duration of study participation and up to 90 days following completion 
of therapy.  Additionally, male subjects (including those who are vasectomized) whose partners are pregnant 
or might be pregnant must agree to use condoms for the duration of the study and for 90 days following 
completion of therapy. 
● Total abstinence from sexual intercourse (minimum one complete menstrual cycle). 
● Vasectomized male subjects or vasectomized partner of female subjects. 
● Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug 
administration. 
● Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal 
jellies or cream). 
● Intrauterine device (IUD). 
 
 
The following criteria will be used in this trial to define postmenopausal: 
 
Age 56 or older with no spontaneous menses for at least 12 months prior to study entry;  
Or 
 
Age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., 
spontaneous or secondary to hysterectomy) and with a documented estradiol level in the 
postmenopausal range according to local institutional/laboratory standard;  
Or 
 
Documented bilateral oophorectomy. 
 
Women failing to meet one of these criteria will be classified as pre-menopausal. 
 
 
 
 


Apendix E:  Lapatinib Liver Toxicity guidelines 
 
LIVER TOXCIITY DISCONTINUATION AND FOLLOW-UP CRITERIA 
a. Bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject meets the criterion of total bilirubin >2.0 × 
ULN, then the event should still be reported as an SAE and actions taken as described 
b. the appearance or worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia 
c. Hold Lapatinib and TDM-1 if grade 2(>3.0-5.0 x ULN) or grader  ALT, until resolve, return to baseline or ≤ grade 1 (whichever is greater), once liver 
chemistries resolve, or return to baseline, then continue monitoring per the protocol assessment schedule, retest within 3 days from the first occurrence 
and then weekly to determine if ALT elevation persists 


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Apendix E continuation: Liver Chemistry Follow up Criteria 
For all subjects who meet any of the liver chemistry criteria described above, make every attempt to carry out the liver event follow up assessments described below:  
a. Viral hepatitis serology including: 
b. Hepatitis A IgM antibody; 
c. Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  
d. Hepatitis C RNA;  
e. Cytomegalovirus IgM antibody;   
f. 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);   
g. Hepatitis E IgM antibody (if subject resides or has traveled outside USA or Canada in past 3 months); 
h. Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
i. 
Complete blood count with differential to assess eosinophilia;  
j. 
Pharmacokinetic (PK) testing for measurement of lapatinib concentrations" 
k. Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever, or rash as relevant on the AE report form; 
l. 
Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form; 
m. Record alcohol use on the liver event alcohol intake case report form. 


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Appendix F: Algorithm for the management of diarrhea in subjects treated with 
lapatinib-based therapy 
 
For Grade 1 diarrhea that persists for 2 weeks or longer, refer to Section 9.3 
For Grade 2 diarrhea that persists longer than 3 days/72 hours, refer to Uncomplicated Diarrhea Section 9.3 
For recurrent diarrhea, refer to Uncomplicated Diarrhea Section 9.3 for further management guidelines 
 
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 
 Medications (Prescription; OTC; herbal supplements) and dietary profile 
UNCOMPLICATED 
Grade 1 or Grade 2 with no complicating 
signs or symptoms 
ADDED RISK 
FACTORS 
COMPLICATED 
Grade 3 or 4 diarrhea or Grade 1 or 2 with 
≥ 1 of these signs or symptoms: 
• Cramping (moderate/severe) 
• Nausea/vomiting (≥ Grade 2) 
• Decreased performance status 
• Fever 
• Sepsis 
• Neutropenia 
• Frank bleeding 
• Dehydration 
 MANAGEMENT 
• Subjects should be instructed to administer loperamide and notify physician 
• 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 Resolving 
• Continue instructions for dietary 
modification 
• Gradually add solid food to diet 
• Discontinue standard anti-
diarrheal after 12-hour diarrhea-
free interval 
• If applicable resume treatment 
with lapatinib and chemotherapy 
Diarrhea Unresolved 
 Continue  loperamide 
 Continue dietary modifications 
 Evaluate for  possible infection 
(Grade 2) 
Reassess 24 hours later 
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 
 MANAGEMENT 
• Subject must call physician immediately 
• Grade 3: hold lapatinib and chemotherapy (if applicable) 
• Grade 4:hold all study treatment (lapatinib + 
chemotherapy) 
• Evaluate for possible infection  
• Consider hospitalization   
SUGGESTED TREATMENT 
• Administer loperamide  
• Hydration (i.v. fluids as needed) 
• Consider need for antibiotics and consider second line anti-
diarrheals  
Diarrhea Free for 24 hours 
 Discontinue diarrhea intervention 
For Grade 3 
 Reintroduce lapatinib at a reduced 
dose (if dose was >750mg) and 
chemotherapy (if applicable) 
 Consider dose reduction for 
chemotherapy 
For Grade 4 
Evaluate risk benefit, continue treatment 
at physician’s discretion. 


 TMHRI&TMHCC                                             TDM-1 + Lapatinib + Abraxane Clinical Protocol                                                     Page 71 
          
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Appendix G: Inducers and Inhibitors’ list 
 
 
 


 TMHRI&TMHCC                                             TDM-1 + Lapatinib + Abraxane Clinical Protocol                                                     Page 72 
          
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 TMHRI&TMHCC                                             TDM-1 + Lapatinib + Abraxane Clinical Protocol                                                     Page 73 
          
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Appendix H : Trail Support and Development 
 
 
 
 
 
We have recently created the Consortium for the Advancement of Research Excellence (CARE) with seven 
(7) major academic medical and research institutions committed to translational and clinical cancer research. 
 
CARE represent a consortium of clinical and laboratory investigators/Institutions with the primary objective as 
development of translational research studies incorporating innovative molecular diagnostics, targeted 
therapeutic interventions and utilizing advanced statistical design. The overall goal is to expedite the 
translational of laboratory research into the clinic and to develop a model for the implementation of effective 
personalized therapy.  In this effort we will work closely with the Industry, the NCI, other federal and private 
funding agencies and advocate organizations. 
  
Our Members are:  
  
1) 
Massimo Cristofanilli, MD – Thomas Jeferson Philadelphia (PA) 
2) 
Jenny Chang MD – The Methodist Hospital-Houston (TX) 
3) 
Lyndsay Harris, MD- Case Comprehensive Cancer Center- Cleveland (OH)  
4) 
Linda T Vahdat, MD- Weill Cornell Medical Center, NY (NY) 
5) 
Stefan Gluck, MD- Sylvester Cancer Center Miami (FL) 
6) 
Ruth O'Regan, MD-Georgia Cancer Center Emory University (GA) 
7) 
Sunil Sharma, MD– Huntsman Cancer Institute University of Utah 
 
 
Key Milestones: 
FPFV / First Dose: With documented invasive disease and eligible for neo-adjuvant therapy 
LPLV / Last Subject completed:   Sep/2015 
Database Lock: March/2016 
Final Report: June/2016 
 
Sponsoring Department: TMHCC &TMHRI  
 
Prepared by: _________________________________ 
Date ___________ 
 
 
SM