Single Arm Phase II Study of Docetaxel and Lapatinib in Metastatic Transitional Cell Carcinoma in Bladder as Second Line Treatment
Phase: PHASE2
Conditions: Recurrent Bladder Cancer, Stage III Bladder Cancer, Stage IV Bladder Cancer, Transitional Cell Carcinoma of the Bladder
Sponsor: University of Southern California

 
 
Local Protocol #: 4B-10-4 
Protocol Title: Single Arm Phase II Study of Docetaxel and 
Lapatinib in Metastatic Transitional Cell Carcinoma in Bladder as 
Second-Line Treatment. 
 
Protocol version date: 5/9/2013 
 
ClinicalTrialsgov #: NCT01382706 
 
 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
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PROTOCOL NUMBER: 4B-10-4 
TITLE:  
Single Arm Phase II study of Docetaxel and Lapatinib in Metastatic Transitional Cell 
Carcinoma in Bladder as Second Line Treatment 
 
 
 
STUDY PHASE: Phase II 
 
 
STUDY ARMS: Single Arm 
 
 
IND OR IDE #: 
 
Version date: 5/9/2013 
 
PRINCIPAL INVESTIGATOR: 
 
NAME: DAVID QUINN, MD, PHD  
USC / Norris Comprehensive Cancer Center 
ADDRESS: 1441 EASTLAKE AVE. LOS ANGELES, CA 90033 
TELEPHONE: 3238653956 
FAX: 3238650061 
 
STATISTICIAN: 
 
Dongyun Yang, PhD 
USC / Norris Comprehensive Cancer Center 
1441 Eastlake Ave. Rm 3419 
Los Angeles, CA  90033 
 
CO-INVESTIGATORS: 
Sujie Tang, MD MS 
Amir Goldkorn, MD 
Tanya Dorff, MD 
Jacek Pinski, MD, PhD 
James Hu, MD 
Barbara Gitlitz, MD 
Monica Averia-Suboc, ONP 
Anne Schuckman, MD (Urology) 
Michael Press MD (Pathology) 
 
 
 
Financial Supporter:  
GlaxoSmithKline (GSK) 
 
PARTICIPANTS/LOCATONS:  
LAC-USC Medical Center  
University of Southern California University Hospital/Norris Comprehensive Cancer Center 
 
USC University Hospital 
 
 
 
 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
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LIST OF ABBBREVIATIONS: 
 
CTC                 = 
Circulating tumor cells 
EGFR 
= 
Epidermal growth factor receptor  
GC 
= 
Gemcitabine plus cisplatin  
IHC 
= 
Immunohistochemistry  
ITT 
= 
Intent-to-treat  
MTD 
= 
Maximum tolerated dose  
MVAC 
= 
Methotrexate, cisplatin, doxorubicin and vinblastine  
NCI-CTC 
= 
National Cancer Institute Common Toxicity Criteria  
OS 
= 
Overall survival  
PFS 
= 
Progression free survival  
RECIST 
= 
Response Evaluation Criteria in Solid Tumors 
SAE  
= 
Serious Adverse Events  
TCC 
 
= 
Transitional cell carcinoma 
TTP 
= 
Time to progression  
TURBT 
= 
Transurethral resection of bladder tumor  
 
 
Summary of Amendments: 
 
Amendment dated 5/9/2013 
This amendment clarifies the dosing of docetaxel in the study after 6 patients were treated 
at a starting dose of 60mg/m2 and did not experience unacceptable toxicity. All 
subsequent patients are to be treated with docetaxel 75mg/m2 intravenously every 3 
weeks and lapatinib 1250mg orally daily from the first cycle.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
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TABLE OF CONTENTS 
 
 
1.0 BACKGROUND 
2.0 OBJECTIVES 
2.1 Primary Objectives 
2.2 Secondary Objectives  
2.3 Exploratory Objectives 
3.0 Study Design 
3.1 Study Design 
3.2 Study Schema 
4.0 DRUG INFORMATION 
4.1 Docetaxel 
4.2 Lapatinib 
5.0  SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 Subject registration 
5.2 Inclusion Criteria 
5.3 Exclusion Criteria  
5.4 Restrictions 
5.5 Criteria for discontinuation from the study 
6.0 DESCRIPTIVE FACTORS and STRATIFICATION SCHEME 
7.0 STUDY AGENTS ADMINISTRATION AND TOXICITY MANAGEMENT PLAN 
 
8.0 ASSESSMENT OF EFFICACY AND SAFETY 
9.0 ADVERSE EVENT REPORTING  
10.0 
CLINICAL AND LABORATORY EVALUATIONS 
11.0 
 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
11.1.1 RECIST 1.1 Evaluation 
11.1.2  Outcome Parameters / Analytical Endpoints 
12.0 
DATA COLLECTION AND MONITORING 
13.0 
STATISTICAL CONSIDERATIONS  
14.0 
REGISTRATION GUIDELINES 
15.0 
CONTAINMENT 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
17.0 
PROCESSING AND HANDLING OF RESEARCH BLOOD AND TISSUE 
SAMPLES  
18.0 
APPENDIX  
19.0 
REFERENCES 
 
 
 
 
 
 
 
 
 

David Quinn, MD,PhD ;  
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1.0 
BACKGROUND  
Transitional cell carcinoma (TCC) is the fifth most common malignancy in the United 
States. The surveillance epidemiology and end results from national cancer institute 
estimated 70,980 new cases, and 14,330 deaths from cancer of the urinary bladder in 
2009(1, 2).  
 
Yet advanced TCC has seen few significant advances in the last decade. Standard of care 
in the United States consists of a cisplatin based upfront therapy (gemcitabine plus 
cisplatin (GC), or methotrexate, cisplatin, doxorubicin and vinblastine (MVAC). Once 
patients progress through one of these regimens, there is no second-line standard of care. 
Many agents, including docetaxel, paclitaxel and ifosfamide, have shown single agent 
responses (between 10-20%, which improve with combination therapy), yet no 
randomized trial has shown the benefit of one over another (3-6). In fact, no second-line 
trial has demonstrated improved survival with any chemotherapy agent.  
 
With the wider application of chemotherapy and standard care of cisplatin based 
chemotherapy, GC or MVAC, the proportion of metastatic cancer patients with cisplatin 
refractory disease is increasing (7),  along with the concern of treating a patient 
population with depleted bone marrow and impaired renal function. Because of this lack 
of a gold standard, and above concerns related to cisplatin, practice patterns differ 
although taxanes therapies are the most commonly used second line treatment (either in 
combination or as single agents). Please see the attached Table 2, which summarized 
second line therapy outcomes in TCC. 
 
A study by Chow N, et al. showed the epidermal growth factor receptors (epidermal 
growth factor receptor) and ErbB2 (HER2) expression were detected in 72.2% and 44.5% 
of bladder cancer cases, respectively. Co- Expression of EGFR and HER2 was 33.9%(8). 
A study by Wulfing C, et al. showed EGFR overexpression in 30 (52%), HER2 over 
expression in 25 (44%), and co-expression of EGFR and HER2 in 13 (22%)(9) (Table 3). 
Previously several studies proved that over-expression of HER2, and co-expression of 
EGFR-HER2 in bladder TCC are associated with a poor prognosis (8, 10-13).  These data 
suggest that EGFR and HER2 are of potential importance in TCC and represetnt potential 
therapeutic targets. Given the poor outcomes for patients with advanced, refractory 
metastatic TCC, the addition of Lapatinib, a dual inhibitor of EGFR and HER2 tyrosine 
kinases encompasses a rational approach to improve the response of metastatic TCC as a 
second line treatment compared with docetaxel alone.  
 
A phase 3, randomized study in breast cancer has showed that the addition of lapatinib to 
capecitabine was associated with a 51% reduction in the risk of disease progression (14). 
A pre-clinical study investigated the potential utility of lapatinib as an adjunct to 
chemotherapy gemcitabine and cisplatin in human bladder cancer cell lines. The study 
suggests that lapatinib cooperates with clinically relevant cytotoxic agents and may have 
therapeutic utility in the management of metastatic bladder cancer(15). 
 
A single-arm, multicenter, open-label phase 2 study of single-agent lapatinib as second or 
third-line treatment of patients with locally advanced or metastatic transitional cell 
carcinoma who had progressed after platin-based chemotherapy did not meet the primary 
endpoint of an overall response rate (ORR) >10% (one patient with PR, ORR 1.7%; 
[95% CI], 0.0%-9.1%). However, nearly one-third of patients (32%, n=19) experienced 
clinical benefit with non-progressing disease for at least 8 weeks. The median time to 
progression (TTP) and median overall survival (OS) are 8.6 weeks and 17.9 weeks, 

David Quinn, MD,PhD ;  
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respectively. The subset of patients with EGFR-over-expressing and/or HER-2–over-
expressing tumors demonstrated a significant prolongation of median OS (30.3 weeks; 
95% CI, 17.6 weeks-49.9 weeks) compared with the intent-to-treat (ITT) patient 
population, which comprised all patients who enrolled in the study and received the study 
drug, (17.9 weeks; 95% CI, 13.1 weeks-30.3 weeks), or patients with low expression of 
EGFR or HER-2 (10.6 weeks; 95% CI, 5.0 weeks-17.6 weeks) (9). These data suggest 
that lapatinib has biological activity in transitional cell carcinoma and that benefit from 
this drug may accrue preferentially to patients whose tumor tissue over-expresses EGFR 
or HER2 or both. EGFR and HER2 over-expression was determined by 
immunohistochemistry in archival paraffin-embedded tumor material. The expression of 
EGFR (PharmDx) and HER-2 (HercepTest) were detected by Immunohistochemistry 
(IHC) using DakoCytomation kits (DakoCytomation, Carpinteria, Calif). The testing was 
performed centrally in a blinded, independent manner using archival paraffin-embedded 
tissue taken from primary and/or metastatic tumor sites. EGFR/HER-2-negative tumor 
was defined as the absence of membranous staining above background in all tumor cells. 
EGFR/HER-2-positive tumor (1+, 2+, and 3+) was defined as any membranous staining 
of the cell above background level of the cell in >10% of the tumor cells. A tumor with 
an intensity score of 2+ or 3+ was classified as an EGFR- or HER-2-overexpressing 
tumor. The major toxicities in the study were diarrhea (39%, ≥grade 3 in 3%), nausea 
(27%), vomiting (22%; ≥grade 3 in 7%), acne (14%), asthenia (12%) and fatigue (10%). 
Dehydration and hyponatremia ≥grade 3 were each seen in 3% of patients. Asymptomatic 
LVEF decline to 27% was seen in one patient after 8 weeks of lapatinib therapy. 
 
The Lapatax trial, a phase I design was used to evaluated Lapatinib plus docetaxel in 
patients with HER2+ (ErbB2+) locally advanced breast cancer in the neoadjuvant setting 
to determine the maximum tolerated dose (MTD) based on the observed safety profile. 
HER2+ was defined by immunohistochemistry, fluorescent in situ hybridization, and/or 
chromogenic in situ hybridization in tumor tissue. Patients had had no prior 
chemotherapy for their cancer. A stepwise, dose escalation regimen of lapatinib was 
administered in combination with docetaxel. The MTD, defined during cycle 1 was: any 
grade 3-4 non hematological toxicity, ANC<0.5 G/L lasting for 7days or more, Febrile 
neutopenia or thrombocytopenia <25 000 cell per microliter, and without administration 
of G-CSF, was reached at dose level 4 - lapatinib 1250mg daily orally and docetaxel 85 
mg/m2 every 3 weeks (16).   
 
LoRusso and colleagues undertook a phase I trial of lapatinib and docetaxel every 3 
weeks in solid tumors with regulated G-CSF given prophylactically 24 hours after 
docetaxel (17). In this context the “optimal therapeutic dose” was lapatinib 1250mg daily 
and docetaxel 75mg/m3 every 3 weeks. There was no pharmacokinetic interaction 
between the drugs.  
 
Given the mechanism of the action of lapatinib, we propose a single arm phase II trial 
investigate the efficacy of the combination of lapatinib and docetaxel as a second line 
treatment for metastatic bladder cancer with an endpoint of progression free survival 
(PFS). This trial chooses docetaxel since there is no standard of care in relapsed, 
refractory metastatic TCC and docetaxel is a widely-used option in this situation. 
Docetaxel given every three weeks is the current control “backbone” for a randomized 
phase II trial of testing docetaxel and vandetanib led by colleagues at the Dana Farber 
Cancer Center (DFCI) to which USC has accrued 10 patients. The results of PFS from 
groups, docetaxel only group and docetaxel + vandetanib group, will be presented at the 
2011 Genitourinary Cancers Symposium. DFCI colleagues have agreed to provide de-

David Quinn, MD,PhD ;  
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identified but annotated data on the docetaxel only patients from that trial to compare to 
patients given docetaxel with lapatinib in this proposal. The data and the result of PFS at 
12 weeks of the docetaxel only group from DFCI study will be available before this 
proposed study is completed.  
 
Lapatinib 1250 mg daily and docetaxel 75mg/m2 were chosen based on phase I studies of 
lapatinib and docetaxel in breast cancer and solid tumors as mentioned above, which was 
the optimal therapeutic dose (16, 17). Dosage reduction will permitted in cases of drug-
related toxicity grade 3 as defined by National Cancer Institute Common Toxicity 
Criteria (NCI-CTC) (version 4.0), Lapatinib related toxicity reduced dosage will be 1000 
mg/day; Docetaxel related toxicity reduced dosage will be 60mg/m2.  
 
Detection of circulating tumor cells (CTC) in metastatic cancer represents a novel 
prognostic strategy in patients with metastatic cancers and may serve as a surrogate 
marker for prospective therapeutic clinical trials (18, 19). Studies have shown that CTC 
baseline number and change in response to therapy provide predictive and prognostic 
information in patient with metastatic breast, colorectal and prostate cancer (18, 20-24). 
Previous studies in metastatic breast cancer have shown evidence of a strong correlation 
between CTC results and radiographic disease progression in patients receiving 
chemotherapy or endocrine therapy (19). A study in serial monitoring of circulating 
melanoma cells during neoadjuvant biochemotherapy for melanoma showed monitoring 
CTCs in blood may be useful for prediction of outcome of patients receiving treatment 
for metastatic melanoma (25). In a study to detect the circulating tumor cells in thirty-
three patients with urothelial cancer, fourteen of them (44%; 95% confidence interval 
27% to 59%) had a positive assay (range 0-87 cells/7.5 ml of blood) with 10 patients 
(31%) having five or more CTCs (26).  
 
In this proposed study, a platform which captures live CTCs on a parylene-C slot 
microfilter will be used for CTC detection and characterization (27). The circulating 
tumor cells will be tested for expression of EGFr and Her2 expression by cytochemistry 
(28-30). CTC numbers will be monitored prior and post chemotherapy to evaluate CTC 
as a predictor for the disease progression and indicator for response of treatment in 
bladder cancer in the setting of combination therapy of lapatinib and docetaxel. These 
assessments are not intended to be definitive but will provide data for further more 
definitive assessment in future studies.  
 
Lapatinib is a selective inhibitor of both epidermal growth factor receptor (EGFR) and 
HER-2 tyrosine kinases. Pre-clinical studies further characterize lapatinib activity and 
analyze whether EGFR and HER-2 expression or changes induced in the activation of 
EGFR, HER-2, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug 
activity in breast cancer and gastrointestinal cell lines. Studies showed that response to 
lapatinib was significantly correlated with HER-2 and EGFR expression and its ability to 
inhibit HER-2, EGFR, and AKT/ERK phosphorylation (31-35). In this study, three 
antibodies targeting HER2, AKT and ERK, will be added on the CTCs to evaluate the 
phosphorylation of AKT and ERK. These will be collected using slot filter technology 
from a single sample. We will evaluate the effect of lapatinib in human circulating 
urothelial tumor cells at the molecular level by targeting the phosphorylation activity of 
the AKT/ERK on pathway on CTC prior and during the lapatinib treatment.   
 
USC is currently involved in a phase II study with zactima (vandetanib) given in 
combination with docetaxel compared with the efficacy of docetaxel combined with 

David Quinn, MD,PhD ;  
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placebo in prolonging progression-free survival of subjects with metastatic, previously 
treated TCC, which was led by colleagues at the Dana Farber Cancer Center as 
mentioned before. As targeting therapy is a potential future in bladder cancer, a 
comparison of efficacy of these two trials in the same institution, one with zactima and 
docetaxel, the other is lapatinib and doxetaxel, is intriguing. More saliently, the proposed 
study will use the control arm of placebo and docetaxel in USC as a historical control 
group for comparison at the time of statistical analysis. 
 
2.0 
OBJECTIVES 
2.1 
Primary Objectives:  
2.1.1 
To assess the efficacy of 1250 mg of lapatinib given in combination with 
docetaxel in prolonging progression-free survival of subjects with metastatic, previously 
treated TCC relative to historical controls.  
2.2 
Secondary Objectives:  
2.2.1 
To assess the efficacy of 1250 mg of Lapatinib given in combination with 
docetaxel in the objective response rates and overall survival. 
2.2.2 
To study the tolerability and safety of 1250 mg of lapatinib given in combination 
with docetaxel by assessing the incidence and nature of Grade 3, 4 and serious 
adverse events (AEs). 
2.3 
Exploratory Objectives 
2.3.1 
To assess the expression status of EGFR or HER-2 in tumor tissue and/or CTCs 
as potential predictors of response to therapy. 
2.3.1 
To evaluate the number of circulating tumor cells present in 7.5mLs of peripheral 
blood as a predictor for disease progression and response of treatment in bladder 
cancer in the setting of combination therapy of lapatinib and docetaxel. 
2.3.3 
To evaluate the effect of lapatinib in human at molecular level by targeting the 
phosphorylation activity of the AKT/ERK on pathway prior and during the 
treatment with lapatinib.   
 
3.0 
STUDY DESIGN  
3.1 
Study Design 
This is a single arm 2-stage phase II clinical trial, with a progression-free survival 
rate at 12 weeks as the primary endpoint. A total of 40 subjects will be enrolled. 
One interim analysis will be used to assess efficacy. 
Treatment will continue until RECIST 1.1 progression, toxicity, or withdrawal. 
3.2 
Study Schema 
 
 
 
 
 
 
 
 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
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All eligible patients will be evaluated for HER2 and EGFR status with tissue available. At the 
first stage, we will recruit 14 patients; we will then analyze the patient groups based on the 
markers for non-progression at 12 weeks. We will continue recruit 6 more patients (2 per 4 
weeks) during the 12 weeks until the interim analysis for the 14 patients (first stage) is done. 
After the first stage interim analysis, if one group or groups appear to benefit more relative to 
the recent historial contol group with docetaxel alone arm, which is from the randomized 
phase II trial of testing docetaxel and vandetanib led by colleagues at the Dana Farber Cancer 
Center, will consult GSK to determine the value of accruing an additional cohort of around 
26 with that marker profile at second stage. Otherwise, we will recruit all eligible patients 
regardless EGFR/HER2 status if patients reach primary end point at first stage. It is intended 
to examine the EGFr /HER2 at this point for subsequent planning. It is exceeding unlikely 
that accrual will be curtailed or defined based on the profile at the first interim assessment. A 
more likely scenario is that patterns of disease control and response are defined based on the 
current two-stage cohort. If after the completion of the total planned accrual there is a 
potential pattern, there is provision for further amendment of the protocol to accrue another 
26 patients with entry based on the biomarker.  
 
If the patient signs the informed consent form for the clinical trial but does not qualify for the 
treatment by eligibility criteria after screening, the patient will have the choice to allow the 
use of his/her tumor block for EGFR and HER-2 expression testing, and his/her one time 
blood draw for circulation tumor cells collection and the testing of HER-2, AKT and ERK 
expressions on the circulating tumor cells, so that we could have better understanding of 
EGFR and HER2 expression both on tumor block and circulating tumor cells on this patients’ 
population.   The tissue testing from patients who are not eligible will defer to the protocol 
OS-11-5 study “Circulating tumor cell collection from cancer patients”, Primary Investigator 
Dr. Amir Goldkorn. A separate informed consent form for the OS 11-5 study needs to be 
signed by the patients. We will include the results of these testing into the statistical analysis 
in this study. 
 
 
4.0 DRUG INFORMATION  
 
4.1 Docetaxel: 
Name and chemical Information 
Chemical name: 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1, 7β, 10β-trihydroxy-9-oxotax-
11-ene-13α-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate 
Empirical formula: C43H53O14N 
Molecular weight: 807.9 
 
Eligible  
Patients 
 
Off Study;  
Follow-up 
Survival 
Docetaxel  
75 mg/m2 q 3 wks 
+  
Lapatinib  
1250 mg daily 
Follow up for the 
primary end point:  
Progression-Free 
Survival 
Treatment until 
RECIST 1.1 
progression or 
unacceptable toxicity 
HER2/EGFR 
status and 
CTCs are 
evaluated 
Patient withdrawal from study 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
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Appearance: White powder 
 
Mechanism of action 
In vitro, docetaxel promotes tubulin assembly into microtubules and inhibits 
depolymerization thus stabilizing microtubules, which is different from the action of 
other spindle poisons in clinical use. This can lead to bundles of microtubulesin the cell, 
which by blocking cells in the M phase of the cell cycle, results in the inability of the 
cells to divide. 
Comparing docetaxel and paclitaxel using the "tubulin in vitro assay", the concentration 
required to provide 50% inhibition of microtubule disassembly (orIC50) is 0.2 μM for 
docetaxel and 0.4 μM for paclitaxel.  
 
Toxicology  
The major toxic effect of docetaxel, which limits dose, is neutropenia, which may be 
associated with fever and infection. Other toxic effects, which may be seen, include 
leukopenia, thrombocytopenia, anemia, asthenia, dysgeusia, myalgia, arthralgia, nail 
changes and conjunctivitis. Severe anaphylactoid reactions, characterized by a flush 
associated with hypo- or hypertension, with or without dyspnea, mayoccur requiring 
immediate discontinuation of the docetaxel infusion andaggressive therapy. All patients 
should be premedicated with an oralcorticosteroid prior to the initiation of the infusion of 
docetaxel. If minor reactions such as flushing or localized skin reactions occur, 
interruption of therapy is not required. Other toxicities include cutaneous reactions (e.g., 
skin rash, desquamation following localized pruriginous maculopapular eruption, 
skinerythema with edema), hypersensitivity reactions (flushing, pruritis, fever, chills, 
rigors, lower back pain), dyspnea with restrictive pulmonary syndrome, pleural effusions, 
arrhythmias, pericardial effusions, fluid retention syndrome, ascites, myopathy, digestive 
tract toxicities (nausea, vomiting, oral mucositis, diarrhea, anorexia), alopecia, 
extravasation reaction (erythema, swelling, tenderness, pustules), reversible peripheral 
phlebitis, peripheral edema, reversible increase in liver function tests, hepatic failure and 
neurotoxicity (reversible dysesthesias or paresthesias, peripheral neuropathy, seizure, 
headache, lethargy orsomnolence). Patients with SGOT (AST) > 1.5 times normal and 
alkalinephosphatase > 2.5 times normal appear to have decreased docetaxel clearance and 
appear to be more likely to suffer severe toxicity, including drug-related death. 
Disseminated intravascular coagulation often in association with sepsis or multiorgan 
dysfunction has been reported. Rare cases of congestive heart failure have been reported 
with docetaxel used in combination with other chemotherapy agents. Very rare cases of 
myeloid leukemia or myelodysplasia have occurred in docetaxel, doxorubicin, and 
cyclophosphamide treated patients. 
Please refer to the package insert for complete product instructions and toxicity. 
Potential Drug Interactions: In in vitro screening assays, docetaxel was asignificant 
inhibitor of CYP3A4 and a moderate to weak inhibitor of CYP2D6, 2C19, 2C9 and 1A2. 
These preliminary data indicate that there may be some potential for interactions with co-
administered drugs that are metabolized bythese isozymes although the results should be 
treated with caution until definitive studies are conducted. 
 
Pharmocology, Handeling, Disposal, Preparation, Administration, And Storage 
Preparation and Administration  
TAXOTERE is a cytotoxic anticancer drug and, as with other potentially toxic 
compounds, caution should be exercised when handling and preparing TAXOTERE 
solutions. The use of gloves is recommended. Please refer to Handling and Disposal 
section. 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
10 
If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for 
infusion should come into contact with the skin, immediately and thoroughly wash with 
soap and water. If TAXOTERE Injection Concentrate, initial diluted solution, or final 
dilution for infusion should come into contact with mucosa, immediately and thoroughly 
wash with water. 
Contact of the TAXOTERE concentrate with plasticized PVC equipment or devices used 
to prepare solutions for infusion is not recommended. In order to minimize patient 
exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from 
PVC infusion bags or sets, the final TAXOTERE dilution for infusion should be stored in 
bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and 
administered through polyethylene-lined administration sets. 
TAXOTERE Injection Concentrate requires two dilutions prior to administration. Please 
the preparation instructions provided below. Note: Both the TAXOTERE 
Injection Concentrate and the diluent vials contain an overfill to compensate for liquid 
loss during preparation. This overfill ensures that after dilution with the entire contents 
of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL 
docetaxel. 
The table below provides the fill range of the diluent, the approximate extractable volume 
of diluent when the entire contents of the diluent vial are withdrawn, and the 
concentration of the initial diluted solution for TAXOTERE 20 mg and TAXOTERE 80 
mg. 
Product 
Diluent 13% (w/w) 
ethanol in water for 
injection Fill Range 
(mL) 
Approximate 
extractable volume 
of 
diluent 
when 
entire contents are 
withdrawn (mL) 
Concentration of the 
initial diluted 1.1.1 
solution 
(mg/mL 
docetaxel) 
Taxotere 
20 mg/0.5mL 
1.88 - 2.08 mL 
1.8 mL 
10 mg/mL 
Taxotere 
80 mg/2 mL 
6.96 – 7.70 mL 
7.1 mL 
10 mg/mL 
 
Preparation and Administration 
1. TAXOTERE vials should be stored between 2 and 25°C (36 and 77°F). If the vials are 
stored under refrigeration, allow the appropriate number of vials of TAXOTERE 
Injection Concentrate and diluent (13% ethanol in water for injection) vials to stand at 
room temperature for approximately 5 minutes. 
2. Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 
1.8 mL for TAXOTERE 20 mg and approximately 7.1 mL for TAXOTERE 80 mg) into 
a syringe by partially inverting the vial, and transfer it to the appropriate vial of 
TAXOTERE Injection Concentrate: If the procedure is followed as described, an initial 
diluted solution of 10mg docetaxel/mL will result. 
3. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure 
full mixture of the concentrate and diluent. Do not shake. 
4. The initial diluted TAXOTERE solution (10 mg docetaxel/mL) should be clear; 
however, there may be some foam on top of the solution due to the polysorbate 80. 
Allow the solution to stand for a few minutes to allow any foam to dissipate. It is not 
required that all foam dissipates prior to continuing the preparation process. 
The initial diluted solution may be used immediately or stored either in the refrigerator or 
at room temperature for a maximum of 8 hours. 
B. Final Dilution for Infusion 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
11 
1. Aseptically withdraw the required amount of initial diluted TAXOTERE solution 
(10mg docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or 
bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a 
final concentration of 0.3 to 0.74 mg/mL. 
If a dose greater than 200 mg of TAXOTERE is required, use a larger volume of the 
infusion vehicle so that a concentration of 0.74 mg/mL TAXOTERE is not exceeded. 
2. Thoroughly mix the infusion by manual rotation. 
3. As with all parenteral products, TAXOTERE should be inspected visually for 
particulate matter or discoloration prior to administration whenever the solution and 
container permit. If the TAXOTERE initial diluted solution or final dilution for infusion 
is not clear or appears to have precipitation, these should be discarded. 
The final TAXOTERE dilution for infusion should be administered intravenously as a 1- 
hour infusion under ambient room temperature and lighting conditions. 
Stability: TAXOTERE infusion solution, if stored between 2 and 25°C (36 and 77°F) is 
stable for 4 hours. Fully prepared TAXOTERE infusion solution (in either 0.9% Sodium 
Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 
1 hour i.v. administration). 
HOW SUPPLIED 
TAXOTERE Injection Concentrate is supplied in a single-dose vial as a sterile, 
pyrogenfree, non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic, 
Diluent (13% ethanol in water for injection) vial. The following strengths are available: 
TAXOTERE 80 MG/2 ML (NDC 0075-8001-80) 
TAXOTERE (docetaxel) Injection Concentrate 80 mg/2 mL: 80 mg docetaxel in 2 mL 
polysorbate 80 and Diluent for TAXOTERE 80 mg (13% (w/w) ethanol in water for 
injection). Both items are in a blister pack in one carton. 
TAXOTERE 20 MG/0.5 ML (NDC 0075-8001-20) 
TAXOTERE (docetaxel) ) Injection Concentrate 20 mg/0.5 mL: 20 mg docetaxel in 0.5 
mL polysorbate 80 and diluent for TAXOTERE 20 mg (13% (w/w) ethanol in water for 
injection). Both items are in a blister pack in one carton. 
This drug is commercially available for purchase by a third party.  
Storage: Store between 2 and 25°C (36 and 77°F). Retain in the original package to 
protect from bright light. Freezing does not adversely affect the product. 
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs 
should be considered. Several guidelines on this subject have been published. There is no 
general agreement that all of the procedures recommended in the guidelines are necessary 
or appropriate. 
 
 
 
4.2 Lapatinib  
Name and chemical Information 
Chemical 
Name: 
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-
(methylsulfonyl)ethyl]amino}methyl)-2 furyl]-4-quinazolinamine, 
 

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12 
Lapatinib is a yellow solid, and its solubility in water is 0.007 mg/mL and in 0.1N HCl is 
0.001 mg/mL at 25° C. 
Each 250 mg tablet of LAPATINIB contains 405 mg of lapatinib ditosylate monohydrate, 
equivalent to 398 mg of lapatinib ditosylate or 250 mg lapatinib free base. 
The inactive ingredients of LAPATINIB are: Tablet Core: Magnesium stearate, 
microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Orange film-coat: 
FD&C yellow No. 6/sunset yellow FCF Aluminum Lake, hypromellose, macrogol/PEG 
400, polysorbate 80, titanium dioxide. 
Mechanism of Action 
Dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 or HER2 
tyrosine kinases: 
Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase 
domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human 
Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated Kiapp values of 3nM 
and 13nM, respectively) with a dissociation half-life of ≥ 300 minutes. Lapatinib inhibits 
ErbB/HER-driven tumor cell growth in vitro and in various animal models. 
An additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the 
active metabolite of capecitabine) were used in combination in the 4 tumor cell lines 
tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-
conditioned cell lines. Lapatinib retained significant activity against breast cancer cell 
lines selected for long-term growth in trastuzumab-containing medium in vitro. These in 
vitro findings suggest non-crossresistance between these two agents. 
Pharmacokinetics 
Absorption: Absorption following oral administration of LAPATINIB is incomplete and 
variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 
1.5 hour). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 
hours after administration. Daily dosing of LAPATINIB results in achievement of steady 
state within 6 to 7 days, indicating an effective half-life of 24 hours. 
At the dose of 1,250 mg daily, steady state geometric mean (95% confidence interval) 
values of Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 
mcg.hr/mL (23.4 to 56 mcg·hr/mL). 

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13 
Divided daily doses of LAPATINIB resulted in approximately 2-fold higher exposure at 
steady state (steady state AUC) compared to the same total dose administered once daily. 
Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC 
values were approximately 3- and 4-fold higher (Cmax approximately 2.5- and 3-fold 
higher) when administered with a low fat (5% fat-500 calories) or with a high fat (50% 
fat-1,000 calories) meal, respectively. 
Distribution: Lapatinib is highly bound (> 99%) to albumin and alpha-1 acid 
glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters 
breast cancer resistance protein (BCRP, ABCG2) and P-glycoprotein (Pgp, ABCB1). 
Lapatinib has also been shown in vitro to inhibit these efflux transporters, as well as the 
hepatic uptake transporter OATP 1B1, at clinically relevant concentrations. 
Metabolism: Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and 
CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated 
metabolites, none of which accounts for more than 14% of the dose recovered in the feces 
or 10% of lapatinib concentration in plasma. 
Elimination: At clinical doses, the terminal phase half-life following a single dose was 
14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours. 
Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with 
negligible ( < 2%) renal excretion. Recovery of parent lapatinib in feces accounts for a 
median of 27% (range 3 to 67%) of an oral dose. 
Effects of Age, Gender, or Race: Studies of the effects of age, gender, or race on the 
pharmacokinetics of lapatinib have not been performed. 
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 freebase 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). 
 
Route of Administration: Oral on an empty stomach (either 1 hour before or 1 hour after 
meals). 
 
Kool-Aid Flavored Suspension: Prepare Lemonade or Tropical Punch Kool-Aid as 
directed on the package.  Place 2 or 4 oz of Kool-Aid (room temperature or refrigerated) 
in a glass container, then add six 250 mg lapatinib tablets to the container.  Cover the 
container, let it stand for 5 minutes, and then stir the mixture intermittently for 10-20 

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14 
minutes or until the tablets are completely broken up.  Stir the container for 5 seconds 
then administer.  Rinse the container with a 2 oz aliquot of water and administer (total of 
4-6 oz of liquid is dispensed). 
Suspension in Water: Place 4 oz of water in a glass container, and then add six 250 mg 
lapatinib tablets to the container.  Cover the container, let it stand for 5 minutes, and then 
stir the mixture intermittently for 10-20 minutes or until it is fully dispersed.  Stir the 
container for 5 seconds then administer.  Rinse the container with a 2 oz aliquot of water 
and administer (total of 6 oz of liquid is dispensed). 
Lapatinib Prohibited Medication List 
Gastric pH Modifiers. 
GSK is no longer prohibiting gastric pH modifiers (i.e. H2 blockers and PPIs).  This is 
based on collection of concurrent med use and the observation that PK was no different 
between pts on gastric pH modifiers and those not taking gastric pH modifiers. 
 
Lapatinib is a substrate for CYP3A4.  Inducers and inhibitors of CYP3A4 may alter the 
metabolism of lapatinib.  The following list of CYP3A4 inducers and inhibitors are 
prohibited from screening through discontinuation from study. 
 
Drug Class 
Agent 
Wash-
out1 
CYP3A4 Inducers 
Antibiotics 
all rifamycin class agents (e.g., 
rifampicin, rifabutin, rifapentine) 
14 days 
Anticonvulsants 
phenytoin, carbamezepine, 
barbiturates (e.g., phenobarbital) 
Antiretrovirals 
efavirenz, nevirapine 
Glucocorticoids 
(oral) 
cortisone (>50 mg), hydrocortisone 
(>40 mg), prednisone (>10 mg), 
methylprednisolone (>8 mg), 
dexamethasone (>1.5 mg)2 
 
Other 
St. John’s Wort, modafinil 
 
CYP3A4 Inhibitors 
Antibiotics 
clarithromycin, erythromycin, 
troleandomycin 
7 days 
Antifungals 
itraconazole, ketoconazole, 
fluconazole (>150 mg daily), 
voriconazole 
Antiretrovirals, 
Protease Inhibitors 
delaviridine, nelfinavir, amprenavir, 
ritonavir, indinavir, saquinavir, 
lopinavir, atazanvir 
Calcium channel 
blockers 
verapamil, diltiazem 
Antidepressants 
nefazodone, fluvoxamine 
GI Agents 
cimetidine, aprepitant 
Other 
grapefruit, star fruit, pomegranate, 
papaw and their juices 
 

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15 
amiodarone  
6 months 
Miscellaneous 
Antacids 
Mylanta, Maalox, Tums, Rennies 
Excluded 
1 hour 
before 
and after 
dosing 
Herbal or dietary 
supplements 
ginkgo biloba, kava, grape seed, 
valerian, ginseng, echinacea, evening 
primrose oil, and St John's Wort 
14 days 
 
At the time of screening, if a patient is receiving any of the above listed 
medications/substances, the medication or substance must be discontinued (if clinically 
appropriate) for the period of time specified prior to administration of the first dose of 
lapatinib and throughout the study period in order for the patient to be eligible to 
participate in the study. 
Glucocorticoid daily doses (oral) ≤ 1.5 mg dexamethasone (or equivalent) are allowed.  
Glucocorticoid conversions are provided in parentheses. 
 
TOXICITY 
Clinical Trials Experience: 
The safety of lapatinib (LAPATINIB) has been evaluated in more than 3,500 patients in 
clinical trials. The efficacy and safety of lapatinib in combination with capecitabine in 
breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. Adverse 
reactions which occurred in at least 10% of patients in either treatment arm and were 
higher in the combination arm are shown in Table 1. 
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in practice. 
The most common adverse reactions ( > 20%) during therapy with lapatinib plus 
capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic 
(palmarplantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common 
adverse reaction resulting in discontinuation of study medication. 
The most common Grade 3 and 4 adverse reactions (NCI CTC v3) were diarrhea and 
palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 
2. 
Table 1. Adverse Reactions Occurring in 10% of Patients 
  
Lapatinib 1,250 mg/day + Capecitabine 
2,000 mg/m2/day 
(N = 198) 
Capecitabine 
2,500 mg/m2/day 
(N = 191) 

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Reactions 
All Grades* 
% 
Grade 3 % 
Grade 4 % All 
Grades* 
% 
Grade 
3 % 
Grade 4 
% 
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 
Skinand subcutaneous tissue disorders 
Palmar-
plantar 
erythrodysest
hesia 
53 
12 
0 
51 
14 
0 
Rash† 
28 
2 
0 
14 
1 
0 
Dry skin 
10 
0 
0 
6 
0 
0 
General disorders and administrativesite 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 

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Insomnia 
10 
<1 
0 
6 
0 
0 
*National Cancer Institute Common Terminology Criteriafor Adverse Events, version3.  
†Grade 3 dermatitis acneiform was reportedin <1% of patientsin LAPATINIB plus 
capecitabine group.  
Table 2. Selected Laboratory Abnormalities 
Parameters 
Lapatinib 1,250 mg/day + 
Capecitabine 2,000mg/m2/day 
Capecitabine 2,500 
mg/m2/day 
All 
Grades* 
% 
Grade3% 
Grade 
4% 
All 
Grades* 
% 
Grade 
3% 
Grade 
4% 
Hematologic 
Hemoglobin 
56 
<1 
0 
53 
1 
0 
Platelets 
18 
<1 
0 
17 
<1 
<1 
Neutrophils 
22 
3 
<1 
31 
2 
1 
Hepatic 
Total Bilirubin 
45 
4 
0 
30 
3 
0 
AST 
49 
2 
<1 
43 
2 
0 
ALT 
37 
2 
0 
33 
1 
0 
*National Cancer Institute Common Terminology Criteriafor Adverse Events, 
version 3. 
Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with 
HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week 
intervals. LVEF decreases were defined as signs or symptoms of deterioration in left 
ventricular cardiac function that are ≥ Grade 3 (NCI CTCAE), or a ≥ 20% decrease in left 
ventricular cardiac ejection fraction relative to baseline which is below the institution's 
lower limit of normal. Among 198 patients who received lapatinib/capecitabine 
combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse 
reactions (NCI CTC 3.0).  
QT Prolongation 

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18 
The QT prolongation potential of lapatinib was assessed as part of an uncontrolled, open-
label dose escalation study in advanced cancer patients. Eighty-one patients received 
daily doses of lapatinib ranging from 175 mg/day to 1,800 mg/day. Serial ECGs were 
collected on Day 1 and Day 14 to evaluate the effect of lapatinib on QT intervals. 
Thirteen of the 81 subjects were found to have either QTcF (corrected QT by the 
Friedericia method) > 480 msec or an increase in QTcF > 60 msec by automated 
machine-read evaluation of ECG. Analysis of the data suggested a relationship between 
lapatinib concentration and the QTc interval. 
Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial 
lung disease and pneumonitis in monotherapy or in combination with other 
chemotherapies 
Warning and Precautions: 
Decreased Left Ventricular Ejection Fraction 
Lapatinib has been reported to decrease LVEF. In the randomized clinical trial, the 
majority ( > 60%) of LVEF decreases occurred within the first 9 weeks of treatment; 
however, data on long-term exposure are limited. Caution should be taken if 
LAPATINIB is to be administered to patients with conditions that could impair left 
ventricular function. LVEF should be evaluated in all patients prior to initiation of 
treatment with LAPATINIB to ensure that the patient has a baseline LVEF that is within 
the institution's normal limits. LVEF should continue to be evaluated during treatment 
with LAPATINIB to ensure that LVEF does not decline below the institution's normal 
limits. 
Hepatotoxicity 
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:  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. 
Other hepatic events should be documented as an AE or an SAE as appropriate. 
 
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 
Fram
e 
Document
s 
Time 
Frame 
Documen
ts 

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Version date: 5/9/2013 
 
 
19 
All SAEs 
24 
hours 
“SAE” 
data 
collection 
tool 
24 hours 
Updated 
“SAE” 
data 
collection 
tool  
Pregnancy 
2 
Week
s 
Pregnancy 
Notificatio
n Form 
2 Weeks 
Pregnanc
y Follow 
up Form 
Liver 
chemistry 
abnormalities
: 
 
 
 
 
ALT >3 × 
ULN and 
bilirubina >2 
× ULN (35% 
direct) 
24 
hours 
CRF 
24 hours 
CRF 
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 
Patients with Severe Hepatic Impairment 
If Lapatinib is to be administered to patients with severe pre-existing hepatic impairment, 
dose reduction should be considered. In patients who develop severe hepatotoxicity while 
on therapy, lapatinib should be discontinued and patients should not be retreated with 
lapatinib. 
Diarrhea 
Diarrhea, including severe diarrhea, has been reported during treatment with lapatinib. 
Proactive management of diarrhea with anti-diarrheal agents is important. Severe cases of 
diarrhea may require administration of oral or intravenous electrolytes and fluids, and 
interruption or discontinuation of therapy with LAPATINIB. 
Interstitial Lung Disease/Pneumonitis 
Lapatinib has been associated with interstitial lung disease and pneumonitis in 
monotherapy or in combination with other chemotherapies. Patients should be monitored 
for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Lapatinib 
should be discontinued in patients who experience pulmonary symptoms indicative of 
interstitial lung disease/pneumonitis which are ≥ Grade 3 (NCI CTCAE). 
QT Prolongation 
QT prolongation measured by automated machine-read evaluation of ECG was observed 
in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer 
patients. Lapatinib should be administered with caution to patients who have or may 
develop prolongation of QTc. These conditions include patients with hypokalemia or 
hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic 

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20 
medicines or other medicinal products that lead to QT prolongation, and cumulative high-
dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior 
to lapatinib administration. The prescriber should consider baseline and on-treatment 
electrocardiograms with QT measurement. 
Pregnancy 
Pregnancy Category D 
LAPATINIB can cause fetal harm when administered to a pregnant woman. In a study 
where pregnant rats were dosed with lapatinib during organogenesis and through 
lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical 
exposure based on AUC), 91% of the pups had died by the fourth day after birth, while 
34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 
20 mg/kg/day (approximately equal to the human clinical exposure based on AUC). 
Lapatinib was studied for effects on embryo-fetal development in pregnant rats and 
rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects; 
however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious 
ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day 
(approximately 6.4 times the human clinical exposure based on AUC). In rabbits, 
lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 
0.07 and 0.2 times the human clinical exposure, respectively, based on AUC) and 
abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body 
weights and minor skeletal variations. 
There are no adequate and well-controlled studies with LAPATINIB in pregnant women. 
Women should be advised not to become pregnant when taking LAPATINIB. If this drug 
is used during pregnancy, or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to the fetus.   
Supplier: This drug is supplied by GSK as investigation drug.  
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 Subject registration 
Screening studies will be performed as described in the “Required Data for registration 
and follow up work flow” table in Section 10.0. Informed consent will be obtained and an 
eligibility checklist will be completed prior to subject registration.  
 
5.2 Inclusion Criteria 
1. Histologically or cytologically confirmed transitional cell carcinoma of the urothelium 
(also called urothelial cancer). Mixed histologies are allowed as long as the predominant 
histology is TCC. In addition, tumor tissue must be available for evalautuon for EGFR 
and HER2/neu status.  
2. Locally recurrent or advanced, non-resectable or stage IV transitional cell carcinoma. 
3. Patient must have had prior platinum salt-based chemotherapy for TCC. Other prior 
systemic chemotherapeutic or investigational treatment regimens for TCC are allowed. 
The patient may have had up to three lines of chemotherapy for advanced disease. 
Patients may have had paclitaxel provided their cancer did not progress while on it; and it 

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21 
was part of an adjuvant or neoadjuvant regimen. Prior targeted or biological therapy is 
permitted except for drugs targeting EGFR and/or HER2.  
Specifically, subjects must meet one or more of the following criteria: 
a. Progression after treatment with a regimen that includes a platinum salt (e.g. – 
carboplatin or cisplatin) for Stage IV or recurrent disease. 
OR 
b. Disease recurrence within two years (from the date of last dose of chemotherapy 
or surgery until day the informed consent is signed) of neoadjuvant or adjuvant 
treatment with a regimen that includes a platinum salt. 
4. Measurable or evaluable disease, as defined by RECIST 1.1 (detail in section 6). If all 
sites of measurable or evaluable disease have been irradiated, one site must have 
demonstrated growth after irradiation. 
5. A left ventricular ejection fraction (LVEF) within normal range as measured by 
echocardiogram or MUGA scan. 
6. Adequate contraceptive method for subjects with reproductive potential (females with 
reproductive potential must have a negative serum pregnancy test within 7 days of study 
entry). 
7. ECOG performance status 0 or 1 (ECOG criteria are listed in Appendix A) 
8. A signed written informed consent (Informed consent form is attached with protocol)  
9. Age > / = 18 years old 
10. Due to the experimental nature of lapatinib, female subjects must be one year 
postmenopausal, surgically sterile, or using an acceptable method of contraception (oral 
contraceptives, barrier methods, approved contraceptive implant, long-term injectable 
contraception, intrauterine device or tubal ligation.) Male subjects must be surgically 
sterile or using an acceptable method of contraception during their participation in this 
study. 
 
5.3 Exclusion Criteria  
1. History of treatment of TCC (in any setting – neoadjuvant, adjuvant or for metastatic 
disease) with Docetaxel. 
2. History of treatment with an EGFR or HER2 targeted agent.  
3. Laboratory results: 
a. Serum bilirubin > 1.5 x the upper limit of normal (ULN) except in patients with 
diagnosis of Gilbert’s disease. 
b. Creatinine clearance < 20 mL/minute (calculated by the Cockcroft-Gault formula 
or other formulas on the basis of serum creatinine levels.), Patient is not eligible if on 
hemodialysis, or clinically symptomatic due to uremia.  
C. Potassium, less than institutional normal level despite supplementation; serum 
calcium (ionized or adjusted for albumin,) or magnesium below lower limits or 
normal despite supplementation.  
d. Baseline liver function test including SGOT (AST) or SGPT (ALT) > 2.5 x                       
institutional upper limits of normal. 
If the patient has bone metastases (which may result in serum alkaline phosphatase 
elevation independent of liver function) then the patient will be ineligible if the AST 
or ALT exceed 5 times the upper limit of normal (ULN).  
e. ANC < 1500/uL 
f. Platelets < 100/uL 
4. Evidence of severe or uncontrolled systemic disease or any concurrent condition which 
in the Investigator’s opinion makes it undesirable for the subject to participate in the trial 
or which would jeopardize compliance with the protocol. 

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22 
5. An abnormal left ventricular ejection fraction (LVEF) as measured by echocardiogram 
or MUGA scan or other suitable technique. 
6. Clinically significant cardiac event such as myocardial infarction; New York Heart 
Association (NYHA) classification of heart disease >2 (see Appendix F) within 3 months 
before entry; or presence of cardiac disease that, in the opinion of the Investigator, 
increases the risk of ventricular arrhythmia. 
7. History of arrhythmia (multifocal premature ventricular contractions (PVCs), 
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is 
symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained 
ventricular tachycardia. Atrial fibrillation controlled on medication is not exclusion nor 
are infrequent or unifocal ectopic beats. 
8. Current QTc prolongation as a result of medication will require discontinuation of that 
medication. The patient can be reassessed after discontinuation, provided this is 
medically appropriate, after 2 weeks or five half-lives of the drug have past which ever is 
longer. 
9. Congenital long QT syndrome or 1st degree relative with unexplained sudden death 
under 40 years of age. 
10. Presence of left bundle branch blocks (LBBB.) 
11. QTc with Bazett’s correction that is unmeasurable, or exceeds 480 msec on screening 
ECG. If a subject has QTc > 480 msec on screening ECG, the screen ECG may be 
repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs 
must be <480 msec in order for the subject to be eligible for the study. 
12. Any concomitant medication that may cause QTc prolongation, induce Torsades de 
Pointes (see Appendix D) or induce CYP3A4 function (see Appendix E) 
13. Hypertension not controlled by medical therapy. 
14. Currently active diarrhea. 
15. Women who are currently pregnant or breast feeding. 
16. Receipt of any investigational agent, chemotherapy or radiation therapy within 21 
days prior to Study Day 1 
17. Any unresolved non-hematologic toxicity greater than CTCAE grade 1 from previous 
anti-cancer therapy (other than alopecia) 
18. Major surgery within 4 weeks or incompletely healed surgical incision before starting 
study therapy 
19. Grade 2 or greater peripheral neuropathy 
20. Previous or current malignancies within the last 3 years, with the exception of in situ 
carcinoma of the cervix, adequately treated carcinoma of the skin, small renal masses, 
and adequately treated localized prostate cancer. Other cancers that are highly likely to be 
cured (cure rate of 75% or greater) may be included at the discretion of the Principal 
Investigator.  
21. History of severe hypersensitivity reaction to drugs formulated with polysorbate 80. 
22. Patients with brain metastasis can only be included if they were treated > 4 week 
prior to enrollment. Subjects with treated brain metastases must have a post treatment 
brain MRI showing no further progression of prior lesions AND no new metastatic 
lesions. Subjects will be ineligible if they have any ongoing symptoms from brain 
metastases or if there continues to be radiographic evidence of cerebral edema 
 
5.4 Restrictions 
Subjects who are blood product donors should not donate blood products during the trial 
and for 3 months following their last dose of trial treatment. 
 
5.5 Criteria for discontinuation from the study: 

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23 
Subjects may discontinue from the study at any time, for any reason. Other reasons may 
include (but are not limited to): 
o Disease progression 
o Death 
o Unacceptable toxicity 
o Physician decision 
o Subject decision 
o Inability to follow protocol-based guidelines 
o Study closure 
 
The reason for study discontinuation must be documented if possible. All subjects will be 
followed for PFS at 12 weeks, PFS and OS after discontinuation. This includes patients 
who choose to discontinue the study and change chemotherapy regimens. The only 
exception to this is if the subject specifically chooses to withdraw consent in which case 
the patient will be censored at last contact.   
 
6.0 
DESCRIPTIVE FACTORS and STRATIFICATION SCHEME 
 
 
For the purposes of this study, subjects should be evaluated initially after 6 weeks (2 
cycles), then 2 cycles later at 12 weeks from commencement then every 9 weeks (3 
cycles) thereafter with appropriate imaging studies for response evaluation. Response 
will be monitored as per the RECIST 1.1 criteria, described below. Patients will have a 
bone scan or suitable alternative to assess for metastatic osseous involvement. If the 
baseline bone assessment is negative it need not be repeated at each re-imaging session 
but should be repeated if clinically indicated. 
 
Biomarkers study: 
Tissue must be available for analysis of EGRF and HER2 at trial commencement. This 
tissue will be sourced from formalin fixed parrrfin embedded archival sources from 
transurethral resection of bladder tumor (TURBT), fine needle biopsy with tissue block 
or cystectomy or nephrectomy or other biopsy. If the patient has a malignant lesion that is 
readilty amenable to FNA biopsy and tissue block production without imaging guidance 
then the physician and patient may decide to undertake this to provide tissue for analysis 
only if it is deemed clinically diagnostically appropriate for the patients’ general cancer 
care. Expression of EGFR and HER2 will be evaluated by immunohistochemistry (IHC). 
All samples with a 2+ or 3+ HER2 over-expression are evaluated by fluorescent in situ 
hybridization (FISH). We will then analyze the patient groups based on these markers for 
non-progression at 12 weeks. 
 
As an exploratory evaluation, HER2 expression on CTC will be analysed before 
treatment. CTC counts will be monitored and compared before and during treatment at 
day 1, Day 7, week 7, week 10, and at progression, in an attempt to evaluate an 
association with response to treatment. The molecular effects of lapatinib on human 
target cells will be evaluated by measuring the phosphorylation activity of the AKT/ERK 
on pathway (targets of lapatinib) in CTC captured before and during treatment with 
lapatinib. 
 
Over-expression of EGFR and HER-2 will be categorized into 3 groups: both positive, 
one positive, both negative. The CTC counts will be classified into 2 categories, <5 and 
≥5 /7.5 mL.  We hypothesize that patients with both EGFR and HER-2 over-expression 
are more likely to benefit from the treatment, and patients with CTC ≥5 per 7.5 mL of 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
24 
bood after first cycle (3 weeks) of treatment are less likely to benefit. About 35% of 
patients with TCC have both EGFR and HER-2 over-expression. Approximately 30% of 
patients are projected to have CTC ≥5 7.5 mL after one cycle of treatment. The 
association between overexpression of EGFR and HER-2, CTC, and tumor response will 
be tested using Fisher’s exact test at a significance level of 0.05. The association between 
overexpression of EGFR and/or HER-2, CTC, and PFS and OS will be examined using 
the Kaplan Meier curves and the log-rank test at a significance level of 0.05. With a small 
sample size in this Phase II trial, we will not have 80% power to detect small or moderate 
differences in the endpoints by EGFR and HER-2 over-expression and CTC. The 
molecular effects of lapatinib on human target cells by measuring the phosphorylation 
activity of the AKT/ERK on pathway (targets of lapatinib) in CTC captured before and 
during treatment with lapatinib will be evaluated by descriptive data. 
 
The purpose of including the biomarkers in this trial is to generate the hypotheses and to 
suggest which biomarkers will be tested in future trials of similar regimens. 
 
At the first stage, we will recruit 14 patients, and then analyze the patient groups based on 
HER2 or EGFr expression for non-progression at 12 weeks. We will continue to recruit 6 
more patients (2 per 4 weeks) during the 12 weeks until the interim analysis for the 14 
patients (first stage) is done. If 7 or more patients of the first 14 are alive with non-
progression at 12 weeks then we will continue to acrrue until a total of 40 assessible 
patients. If one group or groups based on biomarker expression appear to benefit more 
relative to the recent historial contol group treated with docetaxel alone, which is from 
the randomized phase II trial of testing docetaxel and vandetanib led by colleagues at the 
Dana Farber Cancer Center, we will consult GSK to determine the value of accruing an 
additional cohort of around 26 patients with that marker profile as a further stage. 
Otherwise we will recruit all eligible patient regardless EGFR/HER2 status. It is intended 
to examine the EGFr /HER2 at this point for subsequent planning. It is exceeding 
unlikely that accrual will be curtailed or defined based on the profile at the first interim 
assessment. A more likely scenario is that patterns of disease control and response are 
defined based on the current two-stage cohort. If all 40 patients are accrued and a marker 
profile suggests benefit in a given group discussion with the sponsor, GSK is planned to 
determine whether accrual of further subjects might be beneficial to explore the marker – 
therapy link.  
 
7.0  
STUDY AGENTS ADMINISTRATION AND TOXICITY MANAGEMENT PLAN  
Docetaxel  
Docetaxel will be given once every 21 days intravenously, starting at a dose of 75 
mg/square meter. It should be given over approximately one hour. Premedication the day 
prior to infusion and the day of infusion is recommended (dexamethasone 8 mg PO 12 
hours prior to treatment, 1-3 hours prior to treatment, and 4-6 hours after treatment, 
although other similar institutional regimens are acceptable). The patients will all receive 
premedication with 5HT-3 modulator such as ondansetron, granisetron or dolasetron 
before docetaxel admininstration. Longer acting agents should not be used because of the 
risk of QT prolongation. Other premedications may be administered as per the 
institutional standard.  
 
In the early part of the trial, six patients were treated and assessable with a reduced 
dose of docetaxel 60mg/m2 for the first cycle and did not experience unacceptable 
toxicity as defined in Section 13.0 of the protocol. Therefore, as of Amendment  
dated 5/9/2013 all patients will commence on docetaxel 75mg/m2 intravenously and 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
25 
lapatinib 1250mg daily orally every 3 weeks from cycle 1 onwards an then be 
subject to the dose modifications detailed in Section 8.0 of this protocol.   
 
Dose reduction instruction for docetaxel after full dose due to toxicity is list in section 
8.0.  
 
 
 
Lapatinib 
Lapatinib: 1250 mg per day continuously, each and every day. 
 
Concomitant therapy 
Concomitant therapy with other chemotherapy and radiopharmaceuticals is not allowed. 
If clinically indicated, concomitant radiation therapy may be allowed after discussion 
with the Principal Investigator.  
Therapy with bisphosphonates is allowed at the discretion of the investigator.  
Use of hematological growth factors is permitted but G-CSF will not be given 
prophylactically on the first cycle. If a patient develops febrile neutropenia then G-CSF 
may be used and subsequent prophylaxiz should be consistent with ASCO guidelines. To 
maintain dose intensity, if the patient has absolute neutrophil count <=1000 on any day 1 
then recovery should be waited until ANC > 1000, and the next cycle supported with G-
GSF. Erythropoeitin may be used within institutional and ASCO guidelines. Transfusion 
with blood products is allowed. 
Premedication the day prior to docetaxel infusion and the day of docetaxel infusion are 
recommended. The preferred regimen is dexamethasone 8 mg PO 12 hours prior to 
treatment; 1-3 hours prior to treatment, and 4-6 hours after treatment, but other similar 
alternatives are acceptable.  
Nausea, vomiting, or both may be controlled with antiemetic therapy. 5HT-3 antagonists 
may prolong QTc interval risk. Increased monitoring is suggested and discussed below. 
Concomitant uses of the known potent inducers and inhibitors of CYP3A4 (see E) are 
not allowed during the study.  
Oral and IV glucocorticoids (e.g. – dexamethasone) are allowed as part of a pre-
medication strategy for docetaxel infusion. 
Concomitant use of medications generally accepted as having a risk of causing Torsades 
de Pointes (see Appendix D) are not allowed during study. 
The following medications can be taken by subjects, but require additional monitoring: 
Co-administration of drugs that in some reports might be associated with Torsades de 
Pointes, but at this time lack substantial evidence, should be avoided if possible (see 
Appendix D). However, these drugs will be allowed, at the discretion of the Investigator, 
if considered absolutely necessary. In such cases, the subject must be closely monitored 
including regular checks of QTc and electrolytes. The ECG must be checked within 24 
hours of commencing the concomitant medication and then at least once per week while 
the subject remains on the medication. The frequency of ECG monitoring could revert to 
the standard schedule if no ECG prolongation has been noted during 4 weeks of 
coadministration of a drug from Appendix D Table 2. Electrolytes should be maintained 
within the normal range using supplements if necessary. 
 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
_____  
 
 
There are several general guidelines for toxicity management that apply to all specific 
toxicities: 
1. Neither docetaxel nor lapatinib should be re-escalated if reduced. 

David Quinn, MD,PhD ;  
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26 
2. If dose reduction for docetaxel is mandated below dose level –2 or if docetaxel is held 
for more than 3 weeks from its scheduled date, docetaxel should be permanently 
discontinued (the subject should stay on lapatinib until disease progression or 
unacceptable toxicity related to lapatinib). 
3. If dose reduction for lapatinib below dose level –1 is mandated or lapatinib is held for 
more than 6 weeks (or 3 weeks, in the case of QTc prolongation), Lapatinib should be 
permanently discontinued (The subject should stay on docetaxel until disease progression 
or unacceptable toxicity of docetaxel). 
 
 
Dose Reduction for docetaxel and Lapatinib/Placebo 
 
 
Dose Levels for Docetaxel 
Dose Level 
Dose (mg/m2), given q 3 weeks 
0 
75 
-1 
60 
-2 
48 
 
Dose Levels for Lapatinib 
Dose Level 
Dose (mg) 
Tablets per Dose 
0 
1250, given every day 
5 
-1 
1000, given every day 
4 
 
 
Hematologic toxicities 
 
Blood counts on Day 1 of each cycle: 
ANC/uL 
 
Platelets/uL 
Docetaxel 
Lapatinib 
>/= 1000 
And 
>/ = 100,000 
No change 
No change 
< 1000 
OR 
< 100,000 
Hold * 
No change 
 
* Hold docetaxel. Repeat counts weekly and resume therapy when ANC >/= 1000/uL and 
platelets >/= 100,000/uL. For platelet < 100,000/uL, resume docetaxel at one reduced 
dose level for subsequent cycles. For ANC < 1000/uL, if therapy is held for one week or 
less, please institute growth factor support with the subsequent cycle. If therapy is held 
for more than one week (or growth factor support has already been instituted), resume 
docetaxel at reduced one dose level. 
 
Febrile neutropenia 
The occurrence of febrile neutropenia (Grade 4 neutropenia associated with an oral 
temperature of >/= 38.5 degrees Celsius) should result in the institution of growth factor 
support with subsequent cycles. If growth factor support has already been initiated (prior 
to the febrile neutropenia) please resume docetaxel at reduced one dose level. 
 
No Lapatinib dose or schedule change for hematologic toxicities. 
 
Hepatic toxicities 
Docetaxel should not be administered to subjects with a serum total bilirubin >1.5x ULN. 
If serum total bilirubin is >1.5x ULN, hold docetaxel until serum total bilirubin is </= 
1.5x ULN, then retreat with docetaxel at a dose which is reduced by one dose level. 
Lapatinib should not be held or dose adjusted for a Grade 1 total bilirubin elevation. For 
Grade 2, 3 or 4 total bilirubin elevation, Lapatinib should be held until resolution to 
Grade 1 or below, and then restarted at a reduced dose level. 

D a vi d Q ui n n, M D, P h D  ;  
V er si o n d at e: 5/ 9/ 2 0 1 3  
 
 
2 7  
 
D ose a dj ust me nts f or a b n or mal li ver f u ncti o n tests i n t he a bse nce of b o ne metastases:   
 
If A S T or A L T > 2. 5 u p per li mit of n or mal ra n ge, will re d uce D oceta xel o ne d ose le vel, 
n o c ha n ge i n La pati ni b. If A S T or A L T > 5. 0 u p per li mit of n or mal ra n ge we  will h ol d 
b ot h D oceta xel a n d La pati ni b.  
 
* H ol d b ot h mea ns h ol d d oceta xel a n d la pati ni b u ntil s u bject’s li ver f u ncti o n tests meet 
t he  eli gi bilit y  criteria;  t he n  res u me  d oceta xel  at  re d uce d  d ose  le vel.  N o  c ha n ge  t o  
la pati ni b.  
 
If t he patie nt has b o ne metastases, t he n t he d oceta xel s h o ul d be hel d if t he A S T or A L T 
e xcee d 5 ti mes t he u p per li mit of n or mal u ntil res o ulati o n t o < 5 x U L N a n d t he d ose of 
d oceta xel s h o ul d be re d uce d o ne le vel. 
 
Ne ur ot oxicity  
F or Gra de 3 or 4 ne ur ot o xicit y, h ol d d oceta xel u ntil res ol ve d t o </ = Gra de 2, t he n res u me 
at decrease d o ne d ose le vel. D o n ot h ol d or c ha n ge la pati ni b.  
 
M a n a ge me nt of di arr he a  
Diarr hea  s h o ul d  be  treate d  wit h  sta n dar d  me dicati o ns  t o  a v oi d  d ose  m o dificati o n  or  
i nterr u pti o n, if p ossi ble. Electr ol yte s u p ple me ntati o n wit h re g ular la b orat or y m o nit ori n g 
s h o ul d  be  use d,  w he n  a p pr o priate,  t o  mai ntai n  electr ol ytes  wit hi n  n or mal  li mits  a n d  
pre ve nt a n i ncrease d ris k of Q Tc pr ol o n gati o n. 
 N o d ose m o dificati o ns will be ma de beca use of gra de 1 or 2 diarr hea. 
 If gra de 3 diarr hea de vel o ps, d oceta xel a n d la pati ni b s h o ul d be wit h hel d u ntil diarr hea 
res ol ves t o gra de 2 or bel o w. T he f oll o wi n g acti o ns s ho ul d be i nstit ute d:  
•  
S u bjects w h o are cli nicall y u nsta ble beca use of diarr hea or ot her i nterc urre nt me dical 
ill ness m ust be a d mitte d a n d e val uate d usi n g tele metr y, u ntil cli nicall y sta ble. 
•  
If st u d y t hera p y is hel d d ue t o diarr hea f or 3 wee ks or less, La pati ni b s h o ul d be d ose 
re d uce d o ne le vel. D oceta xel ca n be rei nstit ute d at sa me d ose le vel. 
•  
If st u d y t hera p y is hel d f or greater t ha n 3 wee ks, b ut less t ha n 6 wee ks, La pati ni b ca n 
be rei nstit ute d at  re d uce d d ose le vel  after c o ns ultati o n wit h t he O verall  Pri nci pal 
I n vesti gat or. D oceta xel ca n be rei nstit ute d at sa me d ose le vel. 
•  
If  gra de  3  or  4  diarr hea  rec urs  after  d ose  re d ucti o n  a n d  a p pr o priate  s u p p orti ve  
t hera p y, t he s u bject  m ust  per ma ne ntl y disc o nti n ue La pati ni b. D oceta xel  treat me nt 
ca n be rei nstit ute d at sa me d ose le vel. I n t his sit uati o n, d oceta xel s h o ul d be wit h hel d 
u ntil diarr hea res ol ves t o Gra de 1 or bel o w, a n d t he n restarte d at a sa me d ose le vel.  
•  
If st u d y t hera p y is hel d f or m ore t ha n 6 wee ks, s u bject s h o ul d be re m o ve d fr o m 
st u d y. 
 
M a n a ge me nt of ot her G astr oi ntesti n al ( GI) T oxicity 
Na usea, v o miti n g, or b ot h ma y be c o ntr olle d wit h a ntie metic t hera p y. 5 H T -3 a nta g o nists 
ma y  pr ol o n g  Q Tc  i nter val  ris k.  I ncrease d  m o nit ori n g  is  s u g geste d  a n d  disc usse d  i n  
secti o n 5. 0. F or Gra de 3 or 4 oral ulcerati o n, d ys p ha gia, na usea or v o miti n g, h ol d b ot h 
d oceta xel a n d La pati ni b. U p o n rec o ver y t o Gra de 1 or bel o w, treat me nt ma y res u me at a 
re d uce d d ose le vel of b ot h d oceta xel a n d La pa bi ni b 
 
M a n a ge me nt of fl ui d rete nti o n  
T here is n o d ose or sc he d ule c ha n ge t o eit her treat me nt f or fl ui d rete nti o n. Fl ui d rete nti o n 
s h o ul d be ma na ge d wit h di uretics. 
 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
28 
Management of Skin Toxicity 
It is strongly recommended that all subjects follow a program of sun protective measures 
while receiving study therapy and for 3-4 weeks after discontinuing study therapy. The 
aim is to reduce the risk of development of skin rash, minimize the severity of skin rash, 
and to minimize the requirement for dose reduction of study therapy. 
If a subject develops a skin rash, the following actions are recommended to the 
Investigator for the management of this reaction: 
• 
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. 
• 
The rash should be graded/assessed by a physician as soon as possible according to 
the CTCAE cutaneous toxicity criteria and documented accordingly. 
• 
If a rash of CTCAE grade 2 or higher is detected, immediate symptomatic treatment 
should be provided. 
• 
If a rash of CTCAE grade 3 or higher is detected, Lapatinib and docetaxel should be 
withheld until recovery to grade 2 or below.  
The following actions should be instituted: 
a. If study therapy is held due to severe skin toxicity for 3 weeks or less, 
Lapatinib should be dose reduced one level. Docetaxel can be reinstituted at 
same dose level. 
b. If study therapy is held for greater than 3 weeks, but less than 6 weeks, 
Lapatinib can be reinstituted at reduced dose level after consultation with the 
Overall Principal Investigator. Docetaxel can be reinstituted at same dose level. 
c. If severe cutaneous toxicity recurs after this dose reduction, the subject must 
permanently discontinue Lapatinib. Docetaxel treatment can be reinstituted at 
same dose level. In this situation, docetaxel should be withheld until skin toxicity 
resolves to Grade 2 or below, and then restarted at a same dose level. 
d. If study therapy is held for more than 6 weeks, subject should be removed 
from study. 
 
QTc Prolongation 
Subjects will have ECGs performed to monitor QTc interval (using Bazett’s correction, 
Appendix G) as outlined in the study plan. 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
29 
 
 
For this study, QTc prolongation is defined as: 
A single QTc value of > = 550 msec or an increase of > = 100 msec from baseline;  
OR  
Two consecutive ECG measurements, within 48 hours of one another, in which either of 
the following criteria are met for both QTc values (the second being the mean of 3 
consecutive ECGs): 
A QTc interval > = 500 msec but <550 msec OR 
An increase of > = 60 msec, but <100 msec, from baseline QTc to a QTc value > 
= 480 msec. The baseline will be the average of the screening and Day 1 pre-dose 
QTc values. 
 
Management of Subjects with QTc Prolongation 
For a single QTc value of ≥550 msec or an increase of ≥100 msec from baseline, 
Lapatinib must be withheld. ECGs and electrolytes should be followed 3 times a week 
until QTc falls below 480 msec or baseline, whichever is higher. Lapatinib treatment may 
be resumed at a lower dose level after the QTc recovers to <480 msec or baseline. 
 
For a QTc interval ≥500 msec, but <550 msec, or an increase of ≥60 msec but <100 msec 
from baseline QTc to a QTc value ≥480 msec, Lapatinib may be continued but a repeat 
ECG (in triplicate) must be obtained within 48 hours. If QTc prolongation is confirmed, 
Lapatinib should be withheld. ECGs and electrolytes should be checked 3 times a week 
until QTc falls below 480 msec or baseline, whichever is higher.Lapatinib treatment may 
be resumed at a lower dose level after the QTc recovers to <480 msec or baseline. If the 
subject does not meet the criteria for QTc prolongation at the repeat ECG, then the 
subject should continue treatment and resume the ECG schedule as outlined in the Study 
Plan. 
 
If Lapatinib is restarted after the QTc prolongation has resolved, ECGs should be 
performed 1, 2, 4, 7, 10 weeks and then every 3 months after treatment is restarted. If 
Lapatinib must be withheld for >3 weeks to allow for QTc prolongation to recover to 
<480 msec or baseline, the subject will not be restarted on Lapatinib. If QTc prolongation 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
30 
recurs after the dose reduction as detailed, the subject must permanently discontinue 
treatment with study medication. 
There are no changes to the dose and schedule of docetaxel due to QTc prolongation. 
 
Management of Decreased left ventricular ejection 
Lapatinib should be discontinued in patients with a decreased left ventricular ejection 
fraction (LVEF) that is grade 2 or greater by NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the 
institution’s lower limit of normal. Lapatinib may be restarted at a reduced dose (1,000 
mg/day) after a minimum of 2 weeks if the LVEF recovers to normal and the patient is 
asymptomatic. 
 
Concomitant admistration of strong inhibitors or inducers of CYP3A4: 
Concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib 
concentrations significantly. Dose adjustment of lapatinib should be considered for 
patients who must receive concomitant strong inhibitors or concomitant strong inducers 
of CYP3A4 enzymes: Lapatinib will not be adjusted by AUC without inhibitors/inducers. 
Lapatinib dosage without inhibitors/inducers was decided by phase I studies as 
mentioned in this protocol.  
 
Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 
inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, 
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). 
Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If 
patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic 
studies, a dose reduction to 500 mg/day of lapatinib is predicted to adjust the lapatinib 
AUC to the range observed without inhibitors and should be considered. However, there 
are no clinical data with this dose adjustment in patients receiving strong CYP3A4 
inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 
week should be allowed before the lapatinib dose is adjusted upward to the indicated 
dose.  
Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers 
should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital, St. John's Wort). If patients must be coadministered a strong 
CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be 
titrated gradually from 1,250 mg/day up to 4,500 mg/day based on tolerability. This dose 
of lapatinib is predicted to adjust the lapatinib AUC to the range observed without 
inducers and should be considered. However, there are no clinical data with this dose 
adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is 
discontinued the lapatinib dose should be reduced to the indicated dose.  
Management of hypersensitivity reactions 
Subjects who experienced Grade 3 or 4 of hypersensitivity which felt due to docetaxel 
should permanently discontinue docetaxel. These patients may be eligible for continue 
Lapatinib alone.  
Management of Grade 1 or 2 hypersensitivity reactions secondary to docetaxel should be 
managed as per local standard of care.   
 
Surgery 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
31 
For subjects who require surgery while on study, it is recommended that all study 
treatment be discontinued at least 3 weeks prior to surgery. Re-initiation of protocol 
therapy should be discussed with primary investigators, Dr. David Quinn and Dr. Sujie 
Tang.  
 
Management of all other toxicities 
Docetaxel and Lapatinib should be held for any other CTCAE Grade 3 or 4 toxicity 
(other than alopecia, hemoglobin, and fatigue or if covered above) until resolved to Grade 
2 or less (or the subject’s baseline). If the toxicity is felt to be related to study treatment; 
that treatment can be reduced one dose level. 
 
9.0 Adverse Event Reporting 
Quality Assurance Committee (QAC) in USC will monitor the safety/toxicity from the 
chemotherapy (Lapatinib + Doxetaxel) in this study. USC financial supporter, GSK, will 
monitor safety/toxicity as well. Primarily, the monitoring will come from the QAC.  
Definitions 
The definitions of Adverse Events (AEs) and Serious Adverse Events (SAEs) are given 
below. It is of the utmost importance that all staff involved in the study be familiar with 
the content of this section. The Principal Investigator is responsible for ensuring this. 
Adverse Event 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not considered to 
be related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests. 
Serious Adverse Event 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that: 
• 
Results in death 
• 
Life-threatening: Life-threatening means that the person was at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a 
reaction which hypothetically might have caused death had it occurred in a 
more sever form. 
• 
Require or prolong inpatient hospitalization (i.e., the event required at least a 
24-hour hospitalization or prolonged a hospitalization beyond the expected 
length of stay). Hospitalization admissions and/or surgical operations 
scheduled to occur during the study period, but planned prior to study entry 
are not considered SAEs if the illness or disease existed before the person 
was enrolled in the trial, provided that it did not deteriorate in an unexpected 
manner during the trial (e.g., surgery performed earlier than planned). 
Results in persistent or significant disability/incapacity. Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
Is a congenital anomaly or birth defect; or 
• 
Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
32 
in an emergency room or at home; blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse. 
Events not considered to be serious adverse events are hospitalizations for: 
o Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures 
o Elective or pre-planned treatment for a pre-existing condition that did not worsen 
o Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
o Respite care 
Expectedness 
Adverse events can be 'Expected' or 'Unexpected.' 
Expected adverse event 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, 
the package insert or is included in the informed consent document as a potential risk. 
Unexpected adverse event 
For the purposes of this study, an adverse event is considered unexpected when it varies 
in nature, intensity or frequency from information provided in the current adverse event 
list, the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk. 
Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
Procedures for AE and SAE Recording 
Adverse events will be assessed at each study visit. CTCAE Version 4.0 will be used to 
assess and describe AEs. AEs will be collected and reported from the time of beginning 
study treatment. The following adverse events will be recorded on the case report forms: 
1. All SAEs 
2. All Grade 3 and 4 adverse events, including Grade 3 and 4 laboratory AEs. 
3. All adverse events resulting in a treatment interruption, dose reduction, or withdraw 
from the study. 
Should a pregnancy occur during study participation, it must be reported to the principal 
investigator. Pregnancy in itself is not regarded as an AE unless there is a suspicion that 
an investigational product may have interfered with the effectiveness of a contraceptive 
medication. 
Reporting Responsibilities 
The conduct of the study will comply with FDA and all local safety reporting 
requirements. Each participating investigator is responsible for evaluating all adverse 
events to determine whether criteria for “serious” as defined above or according to local 
reporting requirements are present. 
Each investigative site will be responsible to report SAEs that occur at that institution to 
their respective IRB. It is the responsibility of each participating investigator to report 
serious adverse events to the study sponsor and/or others as described below. 
Non-Serious Adverse Event Reporting 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
33 
Non-serious adverse events will be reported to the Principal Investigator on the toxicity 
Case Report Forms. 
Serious Adverse Events Reporting 
All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported to the Overall 
Principal Investigator. This includes events meeting the definition of Serious Adverse 
Events as defined above, as well as the following: 
o Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
Unexpected and Possibly, Probably or Definitely Related/Associated with the 
intervention. 
o ALL Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
o ALL Grade 5 (fatal) Events – When participant is enrolled and actively 
participating in the trial OR when occurs within 30 days of the last study 
intervention. 
Note: If participant is in Long Term Follow Up, death is reported at the time of 
continuing review. 
 
All SAEs, regardless of “expectedness” or “causality” must be reported to the Overall 
Principal Investigator within 24 hours of learning of the event. In the event that the 
participating investigator does not become aware of the serious adverse event 
immediately (e.g., participant sought treatment elsewhere), the participating investigator 
is to report the event within 24 hours after learning of it and document the time of his or 
her first awareness of the adverse event. All SAEs should be recorded on a MedWatch 
3500a form. Please fax all supporting documentation as it becomes available. 
 
If a non-serious adverse event becomes serious, this and other relevant follow-up 
information must also be provided to Principal Investigator.  
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether 
the event has resolved or continues, if and how the event was treated, and whether the 
participant will continue or discontinue study participation. 
 
Reporting to the Institutional Review Board (IRB) 
All serious adverse events will be reported directlyto the Human Research Studies 
offices.  
 
Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating investigator 
assesses them as stable, or the participating investigator determines the event to be 
irreversible, or the participant is lost to follow-up. The presence and resolution of AEs 
and SAEs (with dates) should be documented on the appropriate case report form and 
recorded in the participant’s medical record to facilitate source data verification. 
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy 
report). 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
34 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the Principal Investigator and their respective IRB of any unanticipated death or 
adverse event occurring after a participant has discontinued or terminated study 
participation that may reasonably be related to the study. 
 
Reporting to FDA 
As the sponsor-investigator, the Principal Investigator is required to notify the FDA of 
any serious adverse event that is unexpected and assessed by the investigator to be 
possibly related to the study treatment in accordance with the reporting obligations of 21 
CFR 312.32. 
SAE reports of fatal or life-threatening events must be telephoned or faxed to the FDA 
within 7 calendar days of first learning of the event. SAE reports of unexpected events 
(not fatal or life-threatening) must be telephoned or faxed to the FDA within 15 calendar 
days of first learning of the event. 
 
  IND Safety Reports 
In accordance with 21 CFR 312.32, GSK shall be responsible for notifying the 
Overall Principal Investigator via an IND Safety Report of the following information: 
1. Any AE associated with the use of the study drug in this study or other studies that is 
both serious and unexpected. 
2. Any finding from tests in the laboratory animals that suggests a significant risk to 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
3. Serious adverse events that do not require expedited reporting to the FDA will be 
reported to GSK on a monthly basis and under no circumstance less frequently than 
quarterly. 
 
Report to GSK: 
All serious adverse events, in addition to being reported to the FDA by the investigator, 
must be reported by facsimile within 24 hours to GlaxoSmithKline. 
Oncology MDC Fax:      (610) 917-6715 
For medical emergencies contact:  
Yasir Nagarwala, MD, Director, 
 
Office: 610-917-6068 
Mobile: 610-906-5035 
or 
Michael Arbushites; Assistant Director 
Office: 610-917-4039 
Mobile: 610-331-9395 
Toll Free Number: (800) 877-7074, ext. 5731 or 6862 
After Hours or Weekends: (800) 366-8900, ask for physician on call 
GlaxoSmithKline UP4420 
1250 S. Collegeville Road, 
P.O. Box 5089 
Collegeville, PA  19426-0989 
 
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. 
 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
35 
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, and 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. 
 
10.0 CLINICAL AND LABORATORY EVALUATIONS 
Required Data for registration and follow up work flow 
 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
36 
 
Cycle 
(21 days in 
length) 
Screening 
Cycle 1 
Cycle 2 
Cycle 
3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 
7 
Cycle 
8 
Follow up 
Week 
 
Week1 
Week2 
Week4 
Week6 
Week7 
Week1
0 
Week 
12 
Week 
13 
Week1
5 
Week 
16 
Week 
19 
Week 
22 
 
Day 
-28 to -1  
1 
C1D1 
8a 
C1D7 
22a 
C2D1 
 
43a 
C3D1 
64a 
C4D1 
 
85a 
C5D1 
 
106a 
C6D1 
127 a 
C7D1 
148 a 
C8D1 
 
Informed 
consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Vital signs 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
ECG c, d 
(see Section 
7.0) c, d 
And MUGA 
Scan 
Xb 
Xc 
Xd 
 
 
 
Xbd 
 
Xd 
 
 
Xd 
 
 
Hematology 
clinical 
Chemistryg  
Xi 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Pregnancy 
test 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
CTCs 
and tissue 
collectionh 
Xh 
Xh 
Xh 
Xh 
 
 
Xh 
 
 
 
 
 
 
Xh 
ECOG 
Performance 
Status 
Xm 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Imaginge, 
Xe 
 
 
 
Xf 
 
 
Xf 
 
 
 
Xf 
 
 
Lapatinib 
dispensing 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Docetaxel 
infusion 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
AE 
reporting 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Xj 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
37 
a. +/- 3 days 
b. 12-lead ECG must be performed within 28 days before first dose. Up to 3 ECGs may be 
obtained at screening, and the mean QTc value used to determine eligibility. MUGA scan (or 
echocardiogram, or other suitable technique) must be performed within 28 days before first dose 
and at week 10.  Additional MUGA scan (or echocardiogram or other suitable technique) will be 
done if clinically suspect that patient develops heart failure during treatment.  
c. On day 1, cycle 1, 12-lead ECGs are to be performed pre-dose. Baseline QTc will be 
determined by the average of no less than 3 consecutive ECGs (within 5-10 minutes of one 
another) on day 1. If the screening QTc is obtained with 3 consecutive ECGs within 3 days before 
day 1, then the screening QTc will be considered to be the baseline, and repeat ECGs will not be 
necessary on day 1. 
d. ECGs must be performed at week 2 (C1D8), week 10 (C4D1), week 13 (C5D1), then every 4 
cycles. When possible, ECGs should be performed at the same time throughout the study 
(performed 4-8 hours after the subject takes their oral medication lapatinib, - therefore patients 
may take their Day 1 dose of drug in the morning to ensure the ECG is appropriately timed. If 
patient is on the schedule for blood draw for CTC, patient may draw blood in the morning, take 
the oral medication lapatinib right after blood draw, then perform ECG 4-8 hours later). 
Moreover, increased ECG monitoring is needed in the setting of certain concomitant medications 
that may prolong the QTc (see Appendix D and Section 5.0). The ECG must be checked within 
24 hours of commencing the concomitant medication and then at least once per week while the 
subject remains on the medication. The frequency of ECG monitoring could revert to the standard 
schedule if no ECG prolongation has been noted during 4 weeks of co-administration of a drug 
from Appendix D Table 2. 
e. Screening imaging must be performed within 35 days before first dose Must include 
chest/abdominal /pelvic CT scans (with IV and PO contrast if not contraindicated). MRI may be 
substituted for CT scan. Bone scan or other bone maging modality will be performed, subsequent 
restaging bone imaging only it there are bone metastases at baseline or if clinically indicated. 
f. Imaging to be performed prior to cycles 3 and 5 (6 week intervals) then prior to cycle 8 and 11 
(9 week intervals).  
g. To include electrolytes, BUN, creatinine, liver function tests, calcium, magnesium, 
phosphorus, and CBC with differential. 
h. CTC will be captured and analyzed from patient blood before the treatment on cycle 1, day 1, 
and during treatment at cycle 1 day 1 (4-6 hours after treatment (patient takes lapatinib in the 
morning, Docetaxel infusion needs to schedule in the morning as well)), Day 7 (before lapatinib 
dose, (patient may take the lapatinib right after the blood draw for CTC in the morning)), cycle 2 
day 1 (before lapatanib dose (patient may take the lapatinib right after the blood draw for CTC in 
the morning)), cycle 4 day 1 (before lapatanib dose (patient may take the lapatinib right after the 
blood draw for CTC in the morning)), and at progression, in an attempt to evaluate an association 
with response to treatment. 
Evaluate tissue from previous TURBT or tumor biopsy for correlative studies at study entry. This 
will be in the form of actual frozen tissue, blocks, or unstained slides. See section 17.0 for 
processing and handling of research tissue. 
i. Baseline labs performed within 3 days of start date will not need to be repeated. 
j. During Follow-up, AE reporting must continue for 30 days following last dose of study drug 
(please see section 8.0 for AE reporting guidelines). 
k. Follow for survival information every 6 months (±1 month) until death, up to 2 years after 
discontinuing therapy, or patient lost to follow-up 
l. Pregnancy test is required for woman of childbearing potential.  
m. ECOG performance status evaluation is requried at screening. Re-evaluation within 72 hour 
before treatment is needed if the ECOG performance stautus screening is out of the 72 hours 
window.  

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
38 
 
11 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
11.0 RECIST 1.1 Evaluation 
11.0.1 Measurability of Tumors at Baseline 
Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of:  
10mm by CT scan (irrespective of scanner type) and MRI (no less than double 
the slice thickness and a minimum of 10mm)  
10mm caliper measurement by clinical exam (when superficial)  
20mm by chest X-ray (if clearly defined and surrounded by aerated lung)  
 
11.0.2 Non-measurable Lesions 
Lesions considered truly non-measurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, and inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses /abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques. 
 
11.0.3 Assessment of Lymph Nodes 
Definitions provided for  
Normal: short axis < 10 mm 
Measurable (Target): short axis ≥ 15 mm 
Non-measurable: short axis 10 to < 15 mm 
Target nodes measured in the short axis (perpendicular to longest diameter) : 
More reproducible and predictive of malignancy 
Short axes of target nodes to be added to the sum of longest diameters  
 
11.0.4 Bone Lesion Measurability 
Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or 
MRI, can be considered as measurable lesions if the soft tissue component 
otherwise meets the definition of measurability previously described. 
Blastic bone lesions are non-measurable  
 
11.0.5 Cystic Lesions 
Lesions that meet radiographic criteria for simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable)  
Radiographically indeterminate, complex "cystic" lesions should be considered 
non-measurable lesions 
"Cystic Lesions" thought to be cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability. However, if non-cystic 
lesions are present in the same patient, these should be preferably selected for 
assessment.  
 
11.0.6 Prior Local Treatment of Lesions 
Tumour lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion. 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
39 
Study protocols should detail the conditions under which such lesions 
would be considered measurable. 
11.0.7 Baseline Documentation of Target Lesions 
All lesions up to a maximum of five lesions total (and a maximum of two 
lesions per organ) representative of all involved organs should be 
identified as target lesions 
It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest 
lesion which can be measured reproducibly should be selected. 
 
11.0.8 Documentation of Non-target Lesions 
It is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case record form (e.g. “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”) 
11.0.9 Definition of CR 
Target Lesions: Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm 
(the sum may not be “0” if there are target nodes) 
Non-target Lesions: disappearance of all non - target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm 
short axis)  
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
11.0.10 Definition of PD 
Target Lesions: > 20% increase in the SLD taking as reference the smallest SLD 
recorded since the treatment started (nadir) and minimum 5 mm increase over the 
nadir  
When sum becomes very small, increases within measurement error (2-3 mm) 
can lead to 20% increase 
 
11.0.11 Definition of Unequivocal Progression 
Unequivocal progression of existing non-target lesions defined as:  
Overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy 
In the absence of measurable disease, change in non-measurable disease 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease. 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread 
 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
40 
11.0.12 Too Small to Measure 
All target lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very 
small (e.g. 2mm)  
However, if target lesions or lymph nodes become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report 
them as being ‘too small to measure’ and a default value of 5mm should be 
assigned  
 
11.0.13 Lesions that Split or Coalesce 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented 
portions should be added together to calculate the target lesion sum 
Similarly, as lesions coalesce, a plane between them may be maintained that 
would aid in obtaining maximal diameter measurements of each individual 
lesion. If the lesions have truly coalesced such that they are no longer separable, 
the vector of the longest diameter in this instance should be the maximal longest 
diameter for the ‘coalesced lesion’ 
11.0.14 New Lesions 
Finding of a new lesion should be unequivocal: i.e. not attributable to differences 
in scanning technique, change in imaging modality or findings thought to 
represent something other than tumor. This is particularly important when 
patient’s baseline lesions show PR or CR 
When in doubt, subsequent timepoint should be evaluated 
Lesion seen in anatomical region which was not imaged at baseline = new lesion 
 
11.0.15 PET 
PET scanning will not be used routinely in this study as it is not standard of 
care for patients with ruothelial cancer.  
11.0.16 Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the 
patient is not evaluable (NE) at that time point. If only a subset of lesion 
measurements are made at an assessment, usually the case is also considered NE 
at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned 
time point response 
 
11.0.17 Overall Response Table, Subjects With Measurable Disease 
 
RECIST 1.1:  
Target 
Non-target 
New 
Overall Response 
CR 
CR 
No 
CR 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
41 
CR 
Non-CR / non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
. 
11.0.18 Best Overall Response 
Overall Response 
First Timepoint 
Overall Response 
Subsequent Timepoint 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, OR PR 
CR 
SD 
SD provided minimum criteria for SD 
duration are met. Otherwise PD 
CR 
PD 
SD provided minimum criteria for SD 
duration are met. Otherwise PD 
CR 
NE 
SD provided minimum criteria for SD 
duration are met. Otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
42 
duration are met. Otherwise PD 
PR 
NE 
SD provided minimum criteria for SD 
duration are met. Otherwise NE 
NE 
NE 
NE 
 
 
11.0.19 Lesion Reappearance 
In the setting of PR (or SD), if a lesion disappears and reappears at a subsequent 
time point it should continue to be measured. Response will depend upon the 
status of his/her other lesions. The lesion should simply be added into the sum.  
In the setting of CR, reappearance of a lesion would be considered PD.  
Most lesions do not actually ‘disappear’ but are not visualized because they are 
beyond the resolving power of the imaging modality employed. 
 
11.1 Outcome Parameters / Analytical Endpoints 
 
 
The primary endpoint is progression-free survival (PFS) rate at 12 weeks. PFS is defined as the 
time period from the start of treatment and documented progression or death without 
documentation of progression; patients who are alive and without evidence of progression will be 
censored at the date of last response evaluation. The binary endpoint the PFS at 12 weeks is 
defined as yes if patients have progressed or died within 12 weeks (PFS ≤ 12 weeks) or no if 
patients are alive and free of progression at 12 weeks (PFS > 12 weeks) since starting treatment. 
Patients who have progressed or died within 12 weeks of treatment (PFS ≤ 12 weeks) will be 
counted in the number of patients with PFS ≤ 12 weeks. Patients who remain alive and 
progression-free at 12 weeks (PFS > 12 weeks) will be counted in the number of patients with 
PFS > 12 weeks. Patients who discontinue treatment due to toxicity prior to 12 weeks without 
documented progression will be counted in the number of patients with PFS ≤ 12 weeks. Patients 
who withdraw the study or start another treatment not due to progression or toxicity prior to 12 
weeks (follow-up ≤ 12 weeks) will not be counted in the decision of continuing or stopping the 
trial. 
 
Secondary endpoints are: PFS; objective response rates, with response defined as a confirmed 
overall PR or CR; overall survival, defined from date of starting treatment to date of death or 
censored at the date the patient was last known alive; and toxicity. 
 
The primary and secondary endpoints of all patients registered in this study, will be reported.  
Patients who complete the first course of treatment and receive at least 50% of the doses, or who 
have experienced a DLT, will be evaluable for toxicity.   All patients who complete the first cycle 
of treatment will be included in the assessment of response; patients who do not complete the first 
cycle of treatment for reasons of toxicity due to the treatment or early progression, will also be 
included in the assessment of response. 
 
Patient baseline demographic and clinical characteristics will be described. 
 

David Quinn, MD,PhD ;  
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43 
Toxicities observed will be summarized in terms of type (organ affected, laboratory 
determination), severity (by CTC and nadir or maximum values for the laboratory measures), 
time of onset, duration, and reversibility or outcome. Tables will be created to summarize these 
toxicities and side effects by cycle of therapy.  
 
The overall response rate will be calculated as the ratio of the number of evaluable patients who 
experienced a confirmed CR or PR (by RECIST) divided by the total number of evaluable 
patients; 95% confidence intervals will be constructed.  Progression-free survival and overall 
survival will be summarized with Kaplan-Meier curves. The median PFS and OS will be 
estimated using a non-parametric method.  
 
12.0 
DATA COLLECTION AND MONITORING 
12.1 Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from a 
patient or a patient’s legal representative before any study related procedures are 
performed. The Investigator will provide an informed consent in compliance with ICH 
GCP and U.S. FDA guidelines (21 CFR 50). A summary of these guidelines can be found 
in Appendix C. The informed consent document must clearly describe the potential risks 
and benefits of the trial and each prospective participant must be given adequate time to 
discuss the trial with the Investigator or site staff and to decide whether or not to 
participate. The informed consent must be approved by the IRB prior to being presented 
to a potential patient. 
 
12.2. Use and completion of case report forms (CRFs) 
The Investigator will prepare and maintain adequate and accurate CRFs to record all 
observations and other data pertinent to the clinical investigation. All CRFs will be 
completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. Should a correction be made, the information to be modified must not be 
overwritten or erased. The corrected information will be transcribed next to the previous 
value, initialed and dated by the authorized person. The investigator is to maintain an up 
to date sheet bearing an example of the signatures of all persons authorized to enter data 
on the CRF. 
 
12.3. Confidentiality 
It is the responsibility of the Investigator to ensure that the confidentiality of all patients 
participating in the trial and all of their medical information is maintained. Case report 
forms must never contain the name of a trial patient. All case report forms and any 
identifying information must be kept in a secure location with access limited to the study 
staff directly participating in the trial. Personal medical information may be reviewed by 
representatives of the IRB or of regulatory authorities in the course of auditing the trial. 
Every reasonable effort will be made to maintain such information as confidential. 
 
12.4 Confidentiality Agreement 
All goods, materials, information (oral or written) and unpublished documentation 
provided to the Investigator by GlaxoSmithKline (or any company acting on their 
behalf), including the Investigators’ Brochure are the exclusive property of GSK. They 
may not be given or disclosed by the Investigator or by any person within his authority 
either in part or in totality to any unauthorized person without the prior written formal 
consent of GSK. 
 
12.5 Record Retention 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
44 
The Investigator must maintain all study records, patient files and other source data for 
the duration of the trial and as per FDA and institutional requirements. 
 
13.0 
STATISTICAL CONSIDERATIONS  
This is a single arm two-stage phase II trial to assess the efficacy of 1250 mg lapatinib daily 
given in combination with docetaxel with regard to the 12-week progression-free survival 
rate.  
 
Study Design 
 
There are no standard regimens of chemotherapy for patients with TCC who have progressed 
after receiving a first line therapy. We do not consider a randomized phase II design to compare 
the efficacy between docetaxel alone vs. the combination of docetaxel and lapatinib because a 
multi-center randomized study of docetaxel +/- ZD6474 in metastatic TCC has completed 
recently.  Dana Farber Cancer Institute colleagues have submitted an abstract to the 2011 
Genitourinary Cancers Symposium (Feb 17-19, 2011). The results of PFS from both groups, 
docetaxel only group and docetaxel + vandetanib group, will be presented at the 2011 
Genitourinary Cancers Symposium.  The data and the result of PFS at 12 weeks and median PFS 
of the docetaxel only group from DFCI study will be available before this proposed study starts.  
The patients in control arm of the trial receive docetaxel 75 mg/m2 q 3 wks + placebo. Based on 
the published previous studies for patients on second line chemotherapy, the progression-free 
survival rate at 12 weeks after starting treatment (a binomial outcome) will be the primary 
endpoint. The landmark time of 12 weeks is selected because tumor response is evaluated every 2 
cycles (6 weeks). A two-stage Phase II design (Simon 1989) will be used to estimate a 
progression-free survival rate at 12 weeks (36). The median progression-free survival in patients 
with chemotherapy-refractory TCC treated with chemotherapy was around 8-10 weeks. 
Therefore, 60% patients remain alive and free of progression at 12 weeks (translates to a median 
progression-free survival of around 16 weeks) will be considered important and indicative that 
this regimen warrants further study; a progression-free rate of 40% or less at 12 weeks (translates 
to a median progression-free survival of 9 weeks) would be considered background and 
disappointing.  
 
In the first stage, we will enroll and treat 14 patients. If ≤ 6 of the first 14 evaluable patients 
treated with the combination of docetaxel and lapatinib are alive and free of progression at 12 
weeks or ≥ 8 patients have progressed within 12 weeks, then accrual will be terminated with 
conclusion that the regimen is not promising.  If ≥ 7 patients are alive and remain free of 
progression at 12 weeks, then accrual will continue until a total of 40 evaluable patients have 
been treated and are followed.  If ≤ 19 of the 40 patients are alive and free of progression at 12 
weeks or ≥ 21 patients have progressed within 12 weeks, then we will conclude that no activity is 
observed for this regimen in these patients.  20 or more patients are alive and free of progression 
at 12 weeks will be taken as evidence that this regimen has some activity in these patients.   
 
Primary Endpoint Evaluation 
 
The primary endpoint is progression-free survival (PFS) rate at 12 weeks. PFS is defined as the 
time period from the start of treatment and documented progression or death without 
documentation of progression; patients who are alive and without evidence of progression will be 
censored at the date of last response evaluation. The binary endpoint the PFS at 12 weeks is 
defined as yes if patients have progressed or died within 12 weeks (PFS ≤ 12 weeks) or no if 
patients are alive and free of progression at 12 weeks (PFS > 12 weeks) since starting treatment. 
Patients who have progressed or died within 12 weeks of treatment (PFS ≤ 12 weeks) will be 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
45 
counted in the number of patients with PFS ≤ 12 weeks. Patients who remain alive and 
progression-free at 12 weeks (PFS > 12 weeks) will be counted in the number of patients with 
PFS > 12 weeks. Patients who discontinue treatment due to toxicity prior to 12 weeks without 
documented progression will be counted in the number of patients with PFS ≤ 12 weeks. Patients 
who withdraw the study or start another treatment not due to progression or toxicity prior to 12 
weeks (follow-up ≤ 12 weeks) will not be counted in the decision of continuing or stopping the 
trial. Patients who are not evaluable for the primary endpoint will be replaced. 
 
Interim analysis 
 
An interim analysis will be conducted when the first 14 patients have been evaluated for the 
primary endpoint: PFS at 12 weeks. Patient enrollment will not been stopped (up to an additional 
6 patients, for a total of 20, will be permitted) when the first 14 evaluable patients have been 
treated, but the decision to stop accrual is pending because of insufficient follow-up time in some 
patients. As soon as ≥8 of the first 14 evaluable patients have PFS ≤ 12 weeks, the accrual will be 
suspended for analysis.  
 
Sample size justification 
 
If the true progression-free survival rate at 12 weeks is 40%, there is a < 10% chance (type I error 
rate) that we will conclude that the regimen is promising.  If the true progression-free survival 
rate at 12 weeks is 60% (translates to a 79% improvement in median PFS), there is an 82% 
chance (power) that we will observe an activity.  If the true progression-free survival rate at 12 
weeks is 40%, there will be a 69% chance that the accrual will be terminated early because of 
lack of activity. With 40 patients, we will be able to estimate the objective tumor response rate, 
the secondary endpoint, with 95% confidence intervals having a half-width of ±15.5% or less 
 
Analysis of Endpoints 
 
The initial analysis of outcome (PFS at 12 weeks, PFS, objective response rate, and OS) will 
include all patients who begin treatment.  A secondary analysis (response rate) will include 
patients who have received at least one cycle of treatment and whose tumor response has been 
evaluated; patients whose treatment is terminated too early to have tumor response evaluated due 
to drug-related toxicity or disease progression will also be included in the calculations.  
 
The secondary clinical endpoints include PFS, OS, and drug-related toxicity. PFS and OS will be 
summarized using the Kaplan-Meier curves. The first 6 patients accrued will be dosed with 
docetacel 60mg/ m2 for cycle 1, and then escalated to 75mg/ m2 at cycle 2 and subsequent cycles, 
ensuring safety and tolerability of lapatinib and docetaxel in bladder cancer. If one or fewer of the 
first 6 experience any Grade 4 clinical or non-hematologic abnormalities lasting more than 7 days 
in the first cycle, then subsequent patients will begin treatment at 75 mg/m2.  Otherwise, all 
patients will begin treatment with a reduced dose of docetaxel on the first course. Drug-related 
toxicity will be summarized by starting dose, cycle, grade, and type.  
Analysis of Correlative Endpoints 
The associations between over-expression of EGFR/HER2 in tumor tissue or CTCs and PFS, 
objective response rate, and OS will be analyzed. If the PFS in patients with expression of Her2 
in cancer cell specimens exceeds that for patients who are negative for this expression and/or that 
in the docetaxel only arm of the zactima trial in USC, which was led by colleagues at the Dana 
Farber Cancer Center as mentioned before, by more than 4 weeks then we will consider amending 
the protocol to further accrue only patients with HER2 expression either in tumor tissue or CTCs 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
46 
to assess response parameters in that selected population, beyond the initially planned 40 
unselected patients. This will likely extend accrual by 30-35 patients and would only be 
undertaken after discussion with GSK.  
 
The association between circulating tumor cell number (CTC) and PFS will be analyzed.  
The CTC counts will be monitored and compared prior treatment at day1, and after the treatment 
at day 1, Day 7, week 4, week 10, and at progression, in an attempt to evaluate an association 
with response to treatment. Scatterplot will be used to show the patterns of the changes in the 
CTC counts before and after the treatment and repeated measures ANOVA will be used to 
analyze the changes if the CTC counts are normally distributed. The changes in the CTC counts 
between prior treatment at day 1 and after treatment (the lowest count) will be categorized as an 
increase, a decrease, and no change. The association between the change in the CTC counts and 
tumor response, PFS, and OS will be analyzed using Fisher’s exact test and log-rank test 
whenever appropriate. 
 
The effect of lapatinib in human at molecular level by targeting the phosphorylation activity of 
the AKT/ERK on pathway prior and during the treatment with lapatinib will be evaluated by 
descriptive analysis.    
 
We will describe the data of the EGFR and HER2 expression on the tumor blocks, and the HER-
2, AKT and ERK expressions on the circulating tumor cells of this patient population, which 
includes the patients’ data who are not eligible for treatment after screening but allow the testing 
on their tumor block and circulation tumor cells.  
 
Monitoring unacceptable toxicity 
 
The first 6 patients accrued will be dosed with docetaxel 60mg/ m2 for cycle 1, and then escalated 
to 75mg/ m2 at cycle 2 and subsequent cycles, ensuring safety and tolerability of lapatinib and 
docetaxel in bladder cancer. If one or fewer of the first 6 experience any Grade 4 clinical or non-
hematologic abnormalities lasting more than 7 days in the first cycle, then subsequent patients 
will begin treatment at 75 mg/m2.  Otherwise, all patients will begin treatment with a reduced 
dose of docetaxel on the first course. The monitoring rule of unacceptable toxicities will be 
applied to all patients regardless of their starting dose levels. 
 
Note for Amendment dated 5/9/2013: 6 patients were intially treated with docetaxel 60mg/m2 on 
cycle 1 and assessable for toxicity. They did not develop unacceptable toxicity as defined in the 
protocol and from 5/9/2013 all patients will be commenced at the dose level of 75mg/m2 for 
docetaxel.  
 
Although we would expect this regimen to be safe, we have established additional guidelines and 
criteria which will be used to flag an unexpected number of patients who experience unacceptable 
toxicity (TOX). Unacceptable toxicity in this trial will be defined as any death occurring within 
30 days of treatment on this protocol that can be possibly, probably or definitely attributed to the 
regimen.    
 
All toxicities will be recorded and summarized for all patients who receive any lapatinib or 
docetaxel treatment.   
 
The risk set to be used in the safety monitoring decision (to trigger a review and possibly halt the 
trial) will include all patients who have either completed at least one course of treatment or been 
taken off treatment with a TOX event or other adverse events.  

David Quinn, MD,PhD ;  
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47 
 
Every time a patient dies within 30 days of last treatment, this death will be reviewed to ascertain 
whether the death could be attributed to the treatment (possibly, probably or definitely related).  If 
the attribution for the death is at least possibly related, then the total number of patients (X) who 
have experienced a TOX to date, will be compared to the number of patients (N) who are in the 
risk set (defined above).  If the number of patients, N, is greater than NX, the number given in the 
bottom row of the Table below, then accrual will continue.   If N is less than or equal to NX, then 
the monitoring boundary has been crossed and a careful review of the trial data will be mandated. 
 
Criteria for Crossing the Safety Monitoring Boundary and Evaluating Safety  
X: # pts who experienced a TOX event 
2 
3 
4 
≥5 
Nx: safety boundary crossed if # patients in risk set  (N) is 
less than or equal to Nx  (if N ≤ Nx) 
≤ 9 
≤ 22 
≤ 35 
Stop 
 
These rules were selected to ensure a low probability that the safety boundary would be crossed, 
indicating excessive toxicity, if the true chance of unacceptable toxicity were less than 5% and a 
high probability that the boundary would be crossed if the true chance of unacceptable toxicity 
were about 20%.  Criteria for flagging an excessive number of patients with TOX are based on 
the sequential probability ratio test with α=0.10, β=0.05, po=0.03 and pa=0.15.    
 
The table below summarizes these probabilities.  The values in the table below are based on 
10,000 simulations and are accurate to ±0.01 (based on a 95% confidence interval). 
 
Probability of Crossing the Safety Boundary (i.e. too many patients have TOX)  
True Chance of a TOX 
3% 
4% 
5% 
10% 
15% 
20% 
Probability of Crossing the Safety Boundary 
0.05 
0.10 
0.16 
0.57 
0.85 
0.96 
 
14.0 
REGISTRATION GUIDELINES  
_____ 
This is a single arm 2-stage phase II clinical trial. A total of 40 subjects will be enrolled. 
Informed consent, Registration Worksheet will be obtained from each patient. At the time of 
registration, two copies of a signed and dated patient Informed Consent form with Bill of 
Rights must be available (an original for patient’s medical chart; one copy for the patient; and 
the other for the PI’s file).   
 
Study Organization 
                     Institution:    
                   LAC-USC Medical Center  
University of Southern California University Hospital/Norris Comprehensive Cancer 
Center, Hospital and Clinics 
Principal Investigators:  
Sujie Tang, MD, MS 
David Quinn, MD, PhD (Mentor) 
Address: 
1441 Eastlake Avenue, Room 3453 
 
 
Division of Medical Oncology 
 
 
Los Angeles, CA 90033 

David Quinn, MD,PhD ;  
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48 
 
15.  BIOHAZARD CONTAINMENT 
Information of Lapatinib and Docetaxel (Taxotere) Handeling, Disposal, Preparation, 
administration, storage preparation and administration are included in the drug 
information, section 4.  
 
16. 
ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 
Ethical Principles 
 
The study should be conducted according to the principles outlined by the 18th World 
Medical Assembly (Helsinki, 1964, Appendix B) and all applicable amendments; the 
International Conference on Harmonization Guidelines for Good Clinical Practice; and 
FDA regulations regarding the conduct of clinical trials and the protection of human 
subjects. All institutional and Federal regulations concerning the Informed Consent form 
will be fulfilled. The study will be conducted in adherence to ICH Good Clinical Practice. 
 
Specific mechanisms to protect human subjects include: 
• Potential subjects will be informed that participation in this protocol is completely 
elective and the patient will have the option to cancel participation at any time.  
• Participants will be given the name and telephone number of the Principal Investigator 
and the IRB. 
• Informed consent will be obtained after a discussion of risks and benefits and 
alternatives, which include best supportive care. This discussion will be documented in 
the medical record.  
• To insure confidentiality of study data, each subject will be assigned a study ID 
number. Subjects will be identified only by this ID number in computer files used for 
statistical analysis and in laboratory records. All study related paperwork will be stored 
in locked file cabinets. Although the statistician will hold a key that will link the study 
ID number to the patient, this will be stored in a secure place and not made available to 
other project investigators. Specimens associated with the clinical trial will be de-
identified, utilizing the study ID number generated by CAFÉ (the USC Cancer Center 
clinical trials database) so that laboratory personnel performing correlative studies will 
not have access to any protected health information.  Published results from the study 
will be in the form of tabular descriptions of groups only, with no identifiable patient 
information or ID numbers.  
16.2 
Investigational Review Board (IRB) Approval 
 
The Investigator must obtain the approval of the protocol, the informed consent document 
and any other material used to inform the patient about the nature of the trial from the 
local IRB in the form of a written letter. On the approval letter, which must be signed by 
the Chairperson of the IRB or the Chairperson’s designee, the following items should be 
clearly stated: trial title, protocol number and version, study-related documents (protocol, 
informed consent material, advertisement when applicable), IRB review date, and IRB 
decision. The trial should not start until a copy of this written approval has been received 
by the Investigator. 
 
Annually, or more often if stipulated by the IRB, and at the completion or termination of 
the study, the Investigator will report the progress of the trial to the IRB. 
 
16.3 
Data Safety Monitoring Plan 
Active Monitoring Program Details 
 

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a. Adherence to Protocol / per Patient: It is the responsibility of the USC Principal 
Investigator (PI) to ensure that patient recruitment and enrollment, treatment, follow-up for 
toxicities and response, and documentation and reporting at USC are all performed as 
specified in the protocol. When a study is opened at two or more institutions, the PI at each 
institution will assume the responsibilities for the day-to-day monitoring of the trial, as 
described below. 
 
b. Day-to-Day Monitoring – Eligibility: The PI will review the patient eligibility (with 
assistance from the Study Coordinator, who will assemble the required source 
documents, and do an initial review) prior to registering the patient on study. 
 
c. Day-to-Day Monitoring – Informed Consent: Prior to registering the patient on 
study, the Study Coordinator will review the informed consent, to ensure that the patient 
has signed and dated the most current IRB-approved form, and that the form has been 
signed and dated by the person obtaining the consent as well as appropriate witnesses. 
 
d. Day-to-Day Monitoring – Treatment: The PI is responsible for ensuring that 
treatment is given per protocol. If another physician administers treatment, the Study 
Coordinator will review the treatment orders with the PI. Regardless of who the treating 
physician is, there will be only one Study Coordinator for each study at each of the 
hospitals affiliated with the USC/Norris Cancer Center. The PI will review the status of 
each patient on-study, with the Study Coordinators and treating physicians, on an on-
going basis. 
 
e. Day-to-Day Monitoring - Evaluation of Safety: Generally, it is the Study 
Coordinator who schedules the visits to evaluate adverse events to treatment, who 
initially interviews the patient to discuss the symptomatic side effects of the treatment, 
and who initially reviews the lab results. At the USC/Norris Comprehensive Cancer 
Center, we have developed adverse event forms that tailor the collection of side effects 
and toxicity information for each protocol and allow the comparison of past adverse 
events with the current side effects. These are presented to the treating physician who 
will decide on the appropriate course of action - follow-up with additional tests or 
treatment. The PI (if not the treating physician) will review the adverse event assessment 
and changes in schedule on an on-going basis.  
 
f. Day-to-Day Monitoring – Evaluation of Treatment Response: The Study 
Coordinator will schedule the tests or scans that are necessary to evaluate response to 
treatment. Although the treating physician will evaluate the results to establish the 
response, it is the responsibility of the PI to review all the scans and tests of all the 
patients to confirm the initial assessment of the response. 
 
g. Data Management – Medical Records: Some study source documents are stored in 
the patient’s medical record, which is maintained electronically or in hard copy by the 
Department of Medical Records at the appropriate hospital. X-rays and other images are 
stored electronically or in hard copy by the Department of Radiology. Physician’s notes, 
orders, test results and pathology notes, as well as a copy of the signed informed consent, 
are maintained in the patients’ medical records. 
 
h. Data Management  – Research Charts: To facilitate adherence to good clinical 
practice, protocol schedule and data management requirements, research charts are created 
for each patient on a study. Research charts will contain the original, signed, informed 

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50 
consent and HIPAA documents. Protocol calendars, worksheets, and checklists, along with 
relevant notes, orders and results, are also kept in the research chart. It is the responsibility 
of the Study Coordinator and the Data Manager to ensure that the research chart contains 
all the required documents. Research Charts are maintained in the Clinical Investigation 
Support Office until the study is closed to follow-up/or study results have been analyzed for 
publication. These are then stored off-site.  
 
i. Data Management – Case Report Forms: It is the responsibility of the Data Manager 
to complete the required case report forms. For NCCC investigator-initiated (in-house) 
trials, these are electronic CRFs that are maintained in the Cancer Center clinical trials 
database (CAFÉ).    
Quality Assurance Committee (QAC) Monitoring 
 
The USC PI has overall responsibility for the conduct of the clinical trial and the 
completeness and accuracy of the data collected regarding patients enrolled at the NCCC. 
The QAC monitors the progress of all clinical trials conducted at NCCC.  During the 
Phase II trial, the QAC will review the trial semi-annually.  
 
All USC-initiated and managed Phase II trials will be audited by the QAC. The audit 
results, together with the reported violations, and overall accrual rate and toxicities 
observed are used to evaluate the progress of the study.  Failure to report adverse events 
in a timely fashion is considered very serious and will lead to suspension of the trial if not 
corrected.   
 
Protocol Violations 
 
Data managers and Study Coordinators coordinate the reporting of major protocol 
violations to the QAC. This is done by completing a computer form – thereby 
ensuring that the information is stored in the NCCC clinical trials database. Major 
violations are defined as: 
 
(a) Deviation from protocol treatment by 10% or more of a drug dose or a 15% or 
greater deviation in the dose of radiation therapy, delay in treatment by 50% or 
more beyond the prescribed cycle length for drug therapy, 20% or more beyond 
the prescribed cycle length for radiation therapy, failure to hold a drug or 
radiation for reasons of toxicity, or inappropriate administration of a drug or 
radiation therapy. 
 
(b) Departure from the follow-up schedule (i) leading to an inadequate assessment 
of toxicity or (ii) compromising the assessment of the outcome measures. 
 
These reported violations are then reviewed and discussed at the next QAC meeting. 
Repeat violations and patterns are flagged. A memo is sent to the PI, requesting a plan 
to avoid these violations in the future. Sometimes the QAC will suggest a specific 
modification of procedures or protocol amendment. If the PI does not respond or if the 
violations continue, the QAC will report this to the CIC with a recommendation to 
either close the study or suspend accrual until the problems can be resolved. In 
practice, because of the close co-operation between the QAC and the CISO leadership, 
problems can be addressed expeditiously, on a one-to-one basis, usually in 
consultation with the data manager or Study Coordinator– and formal action is not 
required. 

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51 
 
Violations identified early in the conduct of the trial may reveal a logistic difficulty, 
inadequately described protocol procedures, or a misunderstanding on the part of one 
of the trial staff. By monitoring violations on an on-going basis, corrective action can 
be taken before the integrity of the study is compromised.   
 
16.4 Additional Responsibilities of the Investigator 
 
The Investigator(s) agrees to perform the study in accordance with ICH Good Clinical 
Practice and FDA regulations. The Investigator is required to ensure compliance with 
respect to the investigational drug schedule, visit schedule and procedures required by the 
protocol.  
 
The Investigator should be able to recruit the required number of suitable patients and 
should have sufficient time to properly conduct and complete the trial. The Investigator 
should have available an adequate number of qualified staff and adequate facilities for the 
duration of the trial, and should ensure that all persons assisting with protocol therapy 
and trial related duties and functions comply with all appropriate regulations.  
 
The Investigator should be responsible for all trial-related medical decisions. During and 
following a patient’s participation in a trial, the Investigator should ensure that adequate 
medical care is provided to a patient for any adverse events related to the trial. 
 
16.5 
Protocol Amendments 
 
Any changes to this protocol made by the Investigator must be in the form of a written 
amendment and the amendment will be appended to this protocol. Approval of 
amendments by the IRB is required prior to their implementation unless there are 
overriding safety reasons. If the change or deviation increases risk to the study 
population, or adversely affects the validity of the clinical investigation or the subject’s 
rights, full approval must be obtained prior to implementation. For changes that do not 
involve increased risk or affect the validity of the investigation or the subject’s rights, 
approval may be obtained by expedited review. When appropriate, an amendment may 
require a change to a written consent form as well.  
 
17.0 Processing and handling of research blood and tissue samples  
Processing and handling of research blood samples  
Venous blood samples for research purposes should be collected as per the protocol. 
At each collection time point, three 7.5 ml tubes of venous blood (total ~22.5 ml) should be 
collected in CellSave tubes provided by Dr. Amir Goldkorn lab. Total 3 tubes of 7.5ml venous 
blood should be collected and send to Dr. Goldkorn’s lab at the same day of blood collection.  
Samples will be held in Dr. Goldkorn’s lab until the end of the study.   
 
Please contact Dr. Goldkorn lab for CellSave tube and measures.  
Contact information: 
Dr. Amir Goldkorn lab 
Contact person: Roy Lau 
Email: roylau@usc.edu  
Phone: 323 442-7722 
Address: 
1450 Biggy Street, North Research Tower 6516 

David Quinn, MD,PhD ;  
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52 
USC/Norris cancer center 
Los Angeles, CA 90033 
 
 
With the patient's consent, please draw blood for CTC testing before the treatment at cycle 1 day 
1, and during treatment at cycle 1 day 1 (4-6 hours after treatment (patient takes lapatinib in the 
morning, Docetaxel infusion needs to schedule in the morning as well)), Day 7 (before lapatinib 
dose (patient may take the lapatinib right after the blood draw for CTC in the morning)), cycle 2 
day 1 (before lapatanib dose (patient may take the lapatinib right after the blood draw for CTC in 
the morning)), cycle 4 day 1 (before lapatanib dose(patient may take the lapatinib right after the 
blood draw for CTC in the morning)), and at progression, in an attempt to evaluate an association 
with response to treatment. 
 
NOTE: Mr. Roy Lau or Dr. Amir Goldkorn should be notified at least 24 hours in advance via 
email or phone CTC collection and measures. 
SPECIMENS MUST BE DRAWN AND SENT TO THE LAB ON THE SAME DAY.  
1. Collection Instructions: 
Blood samples should be collected using standard venipuncture technique.  
Do not centrifuge the tubes. If brief storage is required, please store at room temperature out of 
direct sunlight. 
2. Label each vial with the patient ID#, patient initials, and date and time of collection. 
Information must be registered for documentation.  
 
Processing and handling of tissue samples 
Tissue from previous TURBT or tumor biopsy will be sent to Dr. Michael Press’s lab to do future 
tissue correlative studies with the possibility of construction of tissue microarrays. Archival tissue 
samples will be used to evaluate EGFR and HER2 and correlate this with clinical outcome. 
Dr. Michael Press’s lab address: 
1441 Eastlake Ave, NOR 5409 
USC/Norris cancer center 
Los Angeles, CA 90033 
Phone: 3238650563 
 
Paraffin-embedded tissue blocks should be shipped at room temperature while frozen tissue 
samples need to be kept on dry ice the entire time.  
Dr. Michael Press or Ivonne Villalobos should be notified in advance via email or phone about 
the delivery of any material. 
 
18.0 TABLES AND APPENDICES 
Table 2. Summary of the second line therapy outcomes in TCC 
Agent  
Dose 
Response 
rate (%) 
No. Median 
TTP / PFS 
(months) 
Median 
Survival 
(months) 
Reference 
 
 
 
 
 
 
 
Ifosfamide 
 
20% 
 
NR 
NR 
(37) 
Gallium nitrate 
 
18% 
 
NR 
NR 
(38) 
Gemcitabine* 
1250 mg/m2 
D1+8 q3 weeks 
11% 
30 
 
8.7 
(39) 

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53 
Paclitaxel 
80mg/m2 weekly 
10% 
31 
2.2 
7.2 
(40) 
Paclitaxel 
80mg/m2 weekly 
 
45 
3 
7 
(41) 
Paclitaxel 
200mg/m2 every 3 
weeks 
7% 
14 
<2 
NR 
(42) 
Docetaxel 
100mg/m2 every 3 
weeks 
13.3% 
(3.8 – 
30.7%) 
30 
NR 
9 
(6) 
Paclitaxel + 
methotrexate 
175mg/m2 every 3 
weeks 
32% 
20 
 
5 
(43) 
Paclitaxel + 
Gemcitabine* 
200mg/m2 every 3 
weeks 
47% 
15 
 
7.5 
(44) 
Docetaxel + 
Ifosfamide 
60mg/m2 every 3 
weeks 
25% 
22 
 
4 
(45) 
Pemetrexed 
500mg/m2 every 
3 weeks 
ORR 
27.7%, 
SD 
21.3% 
47 
2.9 
9.6 
(46) 
Pemetrexed + 
Gemcitabine 
500mg/m2  day1 
+ 1250mg/m2 
Day1 + 8, 3 
weeks 
ORR 
20%, SD 
34% 
47 
3.1 
8.1 
(47) 
Pemextrexed 
500mg/m2 every 
3 weeks 
ORR 8% 
13 
2.2 
NR 
(48) 
Vinflurine + 
BSC 
320 mg/m2 every 
3 weeks 
PR 8.6%, 
SD 
46.5%, 
DCR 
41% 
25
3 
3.0 
6.9 
(49) 
Best 
supportive care 
BSC 
PR 0%, 
SD 
27.1%, 
DCR 
24.8% 
11
7 
1.5 
4.6 
(49) 
* Note: patients had not received gemcitabine as part of first line therapy. 
 
 
 
 
 
Table 3. Summaries of studies on EGFR and HER2 over-expression in patients with bladder 
cancer 
LAB 
Technique 
 
ErbB1 
(epidermal 
growth factor 
ErbB2 
(HER2) 
expression 
. Co- Expression 
of EGFR and 
HER2 
Total number 
of patient 
Reference 

David Quinn, MD,PhD ;  
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54 
receptor) 
IHC* 
14/73 (19.2) 
33/55 (80%) 
NA 
73 and 55 
respectively 
(50) 
IHC 
177 (72.2%) 
109 (44.5%) 
83 (33.9) 
245 
(51) 
IHC  
30 (52%) 
 
25 (44%) 
13 (22%) 
59 
(52) 
IHC overexpression 2+ or 3+ 
*Chakravarti A, study was for patient with muscle invasive bladder cancer only.  
 
APPENDICES 
Appendix A. 
 
ECOG Performance Status 
 
 
ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work, etc. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
Appendix B. 
 
Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975  
35th WMA General Assembly, Venice, Italy, October 1983  
41st WMA General Assembly, Hong Kong, September 1989  
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996  
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
 
A.  INTRODUCTION  
 
1.  The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. The Declaration is intended to be read as a 
whole and each of its constituent paragraphs should not be applied without consideration of 
all other relevant paragraphs.  
2. 
Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 

David Quinn, MD,PhD ;  
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55 
3.  It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfillment of this duty. 
4.  The Declaration of Geneva of the WMA binds the physician with the words, "The health of 
my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act in the patient's best interest when providing medical 
care." 
5.  Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6. 
In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
7.  The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
8.  In medical practice and in medical research, most interventions involve risks and burdens. 
9.  Medical research is subject to ethical standards that promote respect for all human subjects 
and protect their health and rights. Some research populations are particularly vulnerable 
and need special protection. These include those who cannot give or refuse consent for 
themselves and those who may be vulnerable to coercion or undue influence. 
10.  Physicians should consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms 
and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration.  
 
B.  BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
 
11.  It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12.  Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal experimentation. 
The welfare of animals used for research must be respected. 
13.  Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment. 
14.  The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, sponsors, 
institutional affiliations, other potential conflicts of interest, incentives for subjects and 
provisions for treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. The protocol should describe arrangements for post-study 
access by study subjects to interventions identified as beneficial in the study or access to 
other appropriate care or benefits. 
15.  The research protocol must be submitted for consideration, comment, guidance and approval 
to a research ethics committee before the study begins. This committee must be independent 
of the researcher, the sponsor and any other undue influence. It must take into consideration 
the laws and regulations of the country or countries in which the research is to be performed 

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as well as applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No change to the protocol may be made without consideration and approval by the 
committee. 
16.  Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health 
care professional. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professional and never the research subjects, even 
though they have given consent. 
17.  Medical research involving a disadvantaged or vulnerable population or community is only 
justified if the research is responsive to the health needs and priorities of this population or 
community and if there is a reasonable likelihood that this population or community stands 
to benefit from the results of the research. 
18.  Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in 
the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19.  Every clinical trial must be registered in a publicly accessible database before recruitment of 
the first subject. 
20.  Physicians may not participate in a research study involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh 
the potential benefits or when there is conclusive proof of positive and beneficial results. 
21.  Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects. 
22.  Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23.  Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity. 
24.  In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks 
of the study and the discomfort it may entail, and any other relevant aspects of the study. 
The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the 
methods used to deliver the information. After ensuring that the potential subject has 
understood the information, the physician or another appropriately qualified individual must 
then seek the potential subject's freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed. 
25.  For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations where 
consent would be impossible or impractical to obtain for such research or would pose a 
threat to the validity of the research. In such situations the research may be done only after 
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26.  When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent should be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
27.  For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the population represented by the potential subject, the research cannot instead 
be performed with competent persons, and the research entails only minimal risk and 
minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative. The potential subject's dissent should be 
respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. In 
such circumstances the physician should seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research should be obtained as soon as possible from 
the subject or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication of 
the results of research. Authors have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of their 
reports. They should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results should be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
 
C.  ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
 
31.  The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances: 
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
• 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of 
serious or irreversible harm. Extreme care must be taken to avoid abuse of this 
option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 

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access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, designed 
to evaluate its safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, made publicly available. 

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Appendix C. 
 
Elements of Informed Consent  
 
 
The written informed consent document should explain:  
 
1.  That the trial involves research  
2.  The purpose of the trial  
3.  The trial treatments  
4.  The trial procedures to be followed, including all invasive procedures  
5.  The patient’s responsibilities  
6.  Those aspects of the trial that are experimental  
7.  The reasonable foreseeable risks or inconveniences to the patient, and when applicable, to an 
embryo, fetus or nursing infant  
8.  The reasonably expected benefits.  
9.  Alternative procedures or courses of treatment that may be available to the patient, and their 
important potential benefits and risks  
10.  The compensation and/or treatment available to the patient in the event of trial-related injury  
11.  The anticipated payment, if any, to the patient for participating in the trial.  
12.  The anticipated expenses, if any, to the patient for participating in the trial  
13.  That the patient’s participation in the trial is voluntary and that the patient may refuse to 
participate or withdraw from the trial, at any time, without penalty or loss of benefits to 
which the patient is otherwise entitled.  
14.  That monitors, auditors, the IRB and regulatory authorities will be granted direct access the 
patient’s original medical records for verification of clinical trial procedures and/or data, 
without violating the confidentiality of the patient, to the extent permitted by law and 
regulations and that, by signing a written informed consent form, the patient or the patient’s 
legal representative is authorizing such access.  
15.  That records identifying the patient will be kept confidential and, to the extent permitted by 
law and/or regulation, will not be made publicly available. If the results of the trial are 
published, the patient’s identity will remain confidential.  
16.  That the patient or the patient’s legal representative will be informed in a timely manner if 
information becomes available that may be relevant to the patient’s willingness to continue 
participation in the trial.  
17.  The person(s) to contact for further information regarding the trial and the rights of trial 
subjects, and whom to contact in the event of trial-related injury.  
18.  The foreseeable circumstances and/or reasons under which the patient’s participation in the 
trial may be terminated.  
19.  The expected duration of the patient’s participation in the trial.  
20.  The approximate number of patients involved in the trial  
 
 

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APPENDIX D 
Medications Known To Prolong The QT Interval and/or Induce Torsades De 
Pointes (Tdp) 
It has been recognized for a number of years that certain prescription medications can prolong the 
QT/QTc interval and cause a form of acquired Long QT syndrome, known as drug induced 
LQTS. The drugs that prolong the QT interval and/or have a risk of inducing Torsade de Pointes 
(TdP) are listed below. We have divided these into two groups based on their known or perceived 
risk of causing TdP: 
 
Group 1. Drugs That are Generally Accepted by Authorities to Have a Risk of 
Causing Torsades de Pointes 
Concomitant use of these drugs is not allowed during the study or within seven days of study 
entry or entry into the cross-over portion of the trial (at least eight weeks for 
Amiodarone; four weeks for Levomethadyl; and two weeks for Pimozide and Chloroquine). All 
Group 1 Drugs should also be avoided for up to fourteen days following discontinuation of study 
treatment: 
 

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Group 2. Drugs That in Some Reports May be Associated With Torsades de Pointes 
But at This Time Lack Substantial Evidence of Causing Torsades de Pointes two weeks of 
entry into the cross-over portion of the trial with the exception of the following drugs: 
Granisteron, Odansetron, Levofloxacine, and Venlafaxine (not allowed within 48 hours of study 
entry or entry into the cross-over portion of the trial); 
Citalopram, Lexapro, and Paroxetine (not allowed within four days of study entry or entry into 
the cross-over portion of the trial) Some Group 2 drugs may be allowed during the study, at the 
discretion of the Overall Principal Investigator, if considered absolutely necessary. In such cases, 
the patient must be closely monitored, including regular check of QTc and electrolytes. Increased 
ECG monitoring is needed in the setting of Group 2 drugs. The ECG must be checked within 24 
hours of commencing the concomitant medication and then at least once per week while the 
subject remains on the medication. 

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The frequency of ECG monitoring could revert to the standard schedule if no ECG prolongation 
has been noted during 4 weeks of co-administration of a drug from Group 2. 
 
 
 

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APPENDIX E 
Clinically relevant inducers and inhibitors of isoenzyme CYP3A4 
 
Drug Class 
Agent 
Wash-out1 
CYP3A4 Inducers 
Antibiotics 
all rifamycin class agents (e.g., 
rifampicin, rifabutin, rifapentine) 
14 days 
Anticonvulsants 
phenytoin, carbamezepine, barbiturates 
(e.g., phenobarbital) 
Antiretrovirals 
efavirenz, nevirapine 
Glucocorticoids (oral) 
cortisone (>50 mg), hydrocortisone (>40 
mg), prednisone (>10 mg), 
methylprednisolone (>8 mg), 
dexamethasone (>1.5 mg)2 
 
Other 
St. John’s Wort, modafinil 
 
CYP3A4 Inhibitors 
Antibiotics 
clarithromycin, erythromycin, 
troleandomycin 
7 days 
Antifungals 
itraconazole, ketoconazole, fluconazole 
(>150 mg daily), voriconazole 
Antiretrovirals, 
Protease Inhibitors 
delaviridine, nelfinavir, amprenavir, 
ritonavir, indinavir, saquinavir, lopinavir, 
atazanvir 
Calcium channel 
blockers 
verapamil, diltiazem 
Antidepressants 
nefazodone, fluvoxamine 
GI Agents 
cimetidine, aprepitant 
Other 
grapefruit, star fruit, pomegranate, 
papaw and their juices 
 
amiodarone  
6 months 
Miscellaneous 
Antacids 
Mylanta, Maalox, Tums, Rennies 
Excluded 1 

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hour before 
and after 
dosing 
Herbal or dietary 
supplements 
ginkgo biloba, kava, grape seed, valerian, 
ginseng, echinacea, evening primrose oil, 
and St John's Wort 
14 days 
 
 
APPENDIX F 
NEW YORK HEART ASSOCIATION (NYHA) CARDIAC CLASSIFICATION 
The NYHA classification system relates symptoms to everyday activities and the patient’s quality 
of life. 
 
 
 
19.0 REFERENCES: 
1. 
Horner MJ RL, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, 
Huang L, Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards BK 
(eds). SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, 
MD,. http://seer.cancer.gov/csr/1975_2006/, based on November 2008 SEER data 
submission, posted to the SEER web site; 2009. 
2. 
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA 
Cancer J Clin;58(2):71-96. 
3. 
Witte R, Elson P, Bono B, Knop R, Richardson R, Dreicer R, et al. Eastern Cooperative 
Oncology Group phase II trial of ifosfamide in the treatment of previously treated 
advanced urothelial carcinoma. J Clin Oncol. 1997;15(2):589-93. 
4. 
Vaughn D, Broome C, Hussain M, Gutheil J, Markowitz A. Phase II trial of weekly 
paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 
2002;20(4):937-40. 
5. 
Rosenberg J, Carroll P, Small E. Update on chemotherapy for advanced bladder cancer. J 
Urol. 2005;174(1):14-20. 
6. 
McCaffrey J, Hilton S, Mazumdar M, Sadan S, Kelly W, Scher H, et al. Phase II trial of 
docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin 
Oncol. 1997;15(5):1853-7. 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
67 
7. 
de Wit R. Overview of bladder cancer trials in the European Organization for Research 
and Treatment. Cancer. 2003;97(8 Suppl):2120-6. 
8. 
Chow N, Chan S, Tzai T, Ho C, Liu H. Expression profiles of ErbB family receptors and 
prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res. 
2001;7(7):1957-62. 
9. 
Wülfing C, Machiels J, Richel D, Grimm M, Treiber U, De Groot M, et al. A single-arm, 
multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients 
with locally advanced or metastatic transitional cell carcinoma. Cancer. 
2009;115(13):2881-90. 
10. 
Bellmunt J, Hussain M, Dinney C. Novel approaches with targeted therapies in bladder 
cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor 
family. Crit Rev Oncol Hematol. 2003;46 Suppl:S85-104. 
11. 
Baffa R, Letko J, McClung C, LeNoir J, Vecchione A, Gomella L. Molecular genetics of 
bladder cancer: targets for diagnosis and therapy. J Exp Clin Cancer Res. 
2006;25(2):145-60. 
12. 
Black P, Dinney C. Growth factors and receptors as prognostic markers in urothelial 
carcinoma. Curr Urol Rep. 2008;9(1):55-61. 
13. 
Chakravarti A, Winter K, Wu C, Kaufman D, Hammond E, Parliament M, et al. 
Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable 
outcome and reduced complete response rates, respectively, in patients with muscle-
invading bladder cancers treated by concurrent radiation and cisplatin-based 
chemotherapy: a report from the Radiation Therapy Oncology Group. Int J Radiat Oncol 
Biol Phys. 2005;62(2):309-17. 
14. 
Geyer C, Forster J, Lindquist D, Chan S, Romieu C, Pienkowski T, et al. Lapatinib plus 
capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 
2006;355(26):2733-43. 
15. 
McHugh L, Kriajevska M, Mellon J, Griffiths T. Combined treatment of bladder cancer 
cell lines with lapatinib and varying chemotherapy regimens--evidence of schedule-
dependent synergy. Urology. 2007;69(2):390-4. 
16. 
Bonnefoi H ZK, Nobahar M, et al. Lapatax:. A Phase I study of neoadjuvant Lapatinib 
combined with Docetaxel in HER2/neu overexpressing breast cancer (BC). EORTC 
protocol 10054. Poster presented at the San Antonio Breast Cancer Symposium, San 
Antonio, Tx,; December 1014, 2008. P5112. 
17. 
LoRusso P, Jones S, Koch K, Arya N, Fleming R, Loftiss J, et al. Phase I and 
pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer. J Clin 
Oncol. 2008;26(18):3051-6. 
18. 
Budd G, Cristofanilli M, Ellis M, Stopeck A, Borden E, Miller M, et al. Circulating 
tumor cells versus imaging--predicting overall survival in metastatic breast cancer. Clin 
Cancer Res. 2006;12(21):6403-9. 
19. 
Liu M, Shields P, Warren R, Cohen P, Wilkinson M, Ottaviano Y, et al. Circulating 
tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J Clin 
Oncol. 2009;27(31):5153-9. 
20. 
de Bono J, Scher H, Montgomery R, Parker C, Miller M, Tissing H, et al. Circulating 
tumor cells predict survival benefit from treatment in metastatic castration-resistant 
prostate cancer. Clin Cancer Res. 2008;14(19):6302-9. 
21. 
Cohen S, Punt C, Iannotti N, Saidman B, Sabbath K, Gabrail N, et al. Relationship of 
circulating tumor cells to tumor response, progression-free survival, and overall survival 
in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(19):3213-21. 
22. 
Danila D, Heller G, Gignac G, Gonzalez-Espinoza R, Anand A, Tanaka E, et al. 
Circulating tumor cell number and prognosis in progressive castration-resistant prostate 
cancer. Clin Cancer Res. 2007;13(23):7053-8. 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
68 
23. 
Cristofanilli M, Hayes D, Budd G, Ellis M, Stopeck A, Reuben J, et al. Circulating tumor 
cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin 
Oncol. 2005;23(7):1420-30. 
24. 
De Giorgi U, Valero V, Rohren E, Dawood S, Ueno N, Miller M, et al. Circulating tumor 
cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography 
for outcome prediction in metastatic breast cancer. J Clin Oncol. 2009;27(20):3303-11. 
25. 
Koyanagi K, O'Day S, Gonzalez R, Lewis K, Robinson W, Amatruda T, et al. Serial 
monitoring of circulating melanoma cells during neoadjuvant biochemotherapy for stage 
III melanoma: outcome prediction in a multicenter trial. J Clin Oncol. 2005;23(31):8057-
64. 
26. 
Gallagher D, Milowsky M, Ishill N, Trout A, Boyle M, Riches J, et al. Detection of 
circulating tumor cells in patients with urothelial cancer. Ann Oncol. 2009;20(2):305-8. 
27. 
Xu T, Lu B, Tai Y, Goldkorn A. A Cancer Detection Platform which Measures 
Telomerase Activity from Live Circulating Tumor Cells Captured on a Microfilter. 
Cancer Res. 2010. 
28. 
Soria J, Morat L, Durdux C, Housset M, Cortez A, Blaise R, et al. The molecular 
detection of circulating tumor cells in bladder cancer using telomerase activity. J Urol. 
2002;167(1):352-6. 
29. 
Gazzaniga P, Gandini O, Giuliani L, Magnanti M, Gradilone A, Silvestri I, et al. 
Detection of epidermal growth factor receptor mRNA in peripheral blood: a new marker 
of circulating neoplastic cells in bladder cancer patients. Clin Cancer Res. 2001;7(3):577-
83. 
30. 
Desgrandchamps F, Teren M, Dal Cortivo L, Marolleau J, Bertheau P, Villette J, et al. 
The effects of transurethral resection and cystoprostatectomy on dissemination of 
epithelial cells in the circulation of patients with bladder cancer. Br J Cancer. 
1999;81(5):832-4. 
31. 
Konecny G, Pegram M, Venkatesan N, Finn R, Yang G, Rahmeh M, et al. Activity of the 
dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and 
trastuzumab-treated breast cancer cells. Cancer Res. 2006;66(3):1630-9. 
32. 
Wainberg Z, Anghel A, Desai A, Ayala R, Luo T, Safran B, et al. Lapatinib, a dual 
EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric 
cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res. 
2010;16(5):1509-19. 
33. 
Sambade M, Kimple R, Camp J, Peters E, Livasy C, Sartor C, et al. Lapatinib in 
combination with radiation diminishes tumor regrowth in HER2+ and basal-like/EGFR+ 
breast tumor xenografts. Int J Radiat Oncol Biol Phys. 2010;77(2):575-81. 
34. 
O'Brien N, Browne B, Chow L, Wang Y, Ginther C, Arboleda J, et al. Activated 
phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not 
lapatinib. Mol Cancer Ther. 2010;9(6):1489-502. 
35. 
Hegde P, Rusnak D, Bertiaux M, Alligood K, Strum J, Gagnon R, et al. Delineation of 
molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global 
gene expression profiles. Mol Cancer Ther. 2007;6(5):1629-40. 
36. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10. 
37. 
Roth BJ. Ifosfamide in the treatment of bladder cancer. Semin Oncol. 1996;23(3 Suppl 
6):50-5. 
38. 
Petrylak DP. Salvage therapy for platinum-refractory urothelial cancer: designing new 
clinical trials. Cancer Invest. 2002;20(5-6):855-6. 
39. 
Albers P, Siener R, Hartlein M, Fallahi M, Haeutle D, Perabo FG, et al. Gemcitabine 
monotherapy as second-line treatment in cisplatin-refractory transitional cell carcinoma - 

David Quinn, MD,PhD ;  
Version date: 5/9/2013 
 
 
69 
prognostic factors for response and improvement of quality of life. Onkologie. 
2002;25(1):47-52. 
40. 
Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of 
weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin 
Oncol. 2002;20(4):937-40. 
41. 
Joly F, Houede N, Noal S, Chevreau C, Priou F, Chinet-Charrot P, et al. Do patients with 
advanced urothelial carcinoma benefit from weekly paclitaxel chemotherapy? A GETUG 
phase II study. Clin Genitourin Cancer. 2009;7(2):E28-33. 
42. 
Papamichael D, Gallagher CJ, Oliver RT, Johnson PW, Waxman J. Phase II study of 
paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder 
and ureter. Br J Cancer. 1997;75(4):606-7. 
43. 
Bellmunt J, Cos J, Cleries R, Perez M, Ribas A, Eres N, et al. Feasibility trial of 
methotrexate-paclitaxel as a second line therapy in advanced urothelial cancer. Cancer 
Invest. 2002;20(5-6):673-85. 
44. 
Meluch AA, Greco FA, Burris HA, 3rd, O'Rourke T, Ortega G, Steis RG, et al. Paclitaxel 
and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial 
tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 
2001;19(12):3018-24. 
45. 
Krege S, Rembrink V, Borgermann C, Otto T, Rubben H. Docetaxel and ifosfamide as 
second line treatment for patients with advanced or metastatic urothelial cancer after 
failure of platinum chemotherapy: a phase 2 study. J Urol. 2001;165(1):67-71. 
46. 
Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, et al. Phase II 
study of pemetrexed for second-line treatment of transitional cell cancer of the 
urothelium. J Clin Oncol. 2006;24(21):3451-7. 
47. 
von der Maase H, Lehmann J, Gravis G, Joensuu H, Geertsen PF, Gough J, et al. A phase 
II trial of pemetrexed plus gemcitabine in locally advanced and/or metastatic transitional 
cell carcinoma of the urothelium. Ann Oncol. 2006;17(10):1533-8. 
48. 
Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial 
of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. 
Invest New Drugs. 2007;25(3):265-70. 
49. 
Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase 
III trial of vinflunine plus best supportive care compared with best supportive care alone 
after a platinum-containing regimen in patients with advanced transitional cell carcinoma 
of the urothelial tract. J Clin Oncol. 2009;27(27):4454-61. 
50. 
Chakravarti A, Winter K, Wu CL, Kaufman D, Hammond E, Parliament M, et al. 
Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable 
outcome and reduced complete response rates, respectively, in patients with muscle-
invading bladder cancers treated by concurrent radiation and cisplatin-based 
chemotherapy: a report from the Radiation Therapy Oncology Group. Int J Radiat Oncol 
Biol Phys. 2005;62(2):309-17. 
51. 
Chow NH, Liu HS, Yang HB, Chan SH, Su IJ. Expression patterns of erbB receptor 
family in normal urothelium and transitional cell carcinoma. An immunohistochemical 
study. Virchows Arch. 1997;430(6):461-6. 
52. 
Wulfing C, Machiels JP, Richel DJ, Grimm MO, Treiber U, De Groot MR, et al. A 
single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line 
treatment of patients with locally advanced or metastatic transitional cell carcinoma. 
Cancer. 2009;115(13):2881-90.