Conditions: Urinary Bladder Neoplasms Ureteral Neoplasms Urethral Neoplasms
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This is a single arm two-stage phase II study with crizotinib (Xalkori®) in the treatment of subjects with metastatic urothelial cancer of the bladder, upper (ureter or renal pelvis) or lower (urethra) urinary tracts. The purpose of this study is to see if this experimental drug has a potential benefit in subjects with stage 4 urothelial cancer.

This study tests crizotinib used alone in subjects with urothelial cancer, previously treated with chemotherapy, and whose tumors have certain proteins. Proteins are complex natural substances essential to the structure and function of all living cells. These proteins, c-MET or RON, may trigger molecular pathways that are involved in the growth and spread of bladder or upper urinary tract cancer. Crizotinib is a drug taken by mouth that blocks these pathways. Early laboratory research suggests that crizotinib may benefit patients with urothelial and other cancers with these molecular pathways.

Detailed description:
This is a single arm two-stage phase II study designed to evaluate the objective response rate in subjects with metastatic urothelial cancer demonstrating c-MET or RON overexpression who have received prior therapy with a cisplatin or carboplatin containing regimen.

Subjects will be recruited at Levine Cancer Institute (LCI) and other participating sites.

Immunohistochemistry will be utilized to define tumor sample c-MET and RON protein expression patterns for assignment into molecular cohorts as described in section 12.1.

In the first stage of this study, subjects will be enrolled in parallel to three molecularly defined cohorts as follows:

1. c-MET high (\>50%), RON null (0-9%) (n = 14 subjects)
2. c-MET-positive (10-100%), RON-positive (10-100%) (n = 7 subjects)
3. c-MET null (0-9%), RON-positive (10-100%) (n = 7 subjects)

All enrolled subjects will continue with study treatment until criteria for treatment discontinuation has been met.

If Stage 1 response criteria are met in a cohort, the cohort may be considered for expansion, and additional subjects (16 in Cohort 1 or 25 in Cohorts 2 or 3) may then be enrolled into that cohort in Stage 2. An expansion cohort will be defined by the Sponsor- Investigator following review of all available trial data which will be conducted after the first Stage 1 cohort has completed accrual and at least every six months thereafter until all Stage 1 cohorts have completed accrual.

If more than one cohort meets Stage 1 response criteria (2 responses out of 14 subjects for Cohort 1 or 1 response out of 7 subjects for each of Cohorts 2 and 3), then the cohort showing the highest response rate will be given highest consideration for expansion.

Arms:
arm 1: c-MET high (\> 50%), RON null (0-9%) arm 2: c-MET + (10-100%), RON + (10-100%) arm 3: c-MET null (0-9%), RON + (10-100%)

Interventions: intervention 1: Crizotinib
Intervention descriptions: intervention 1: Crizotinib was administered orally at 250mg twice daily

Protocol document:
Prot_SAP_000.pdf: 
Protocol Number:  LCI-GU-URO-CRI-001 
Version 3: April 21, 2018 
i 
 
 
Protocol #:  LCI-GU-URO-CRI-001 
TITLE: A PHASE II STUDY OF CRIZOTINIB IN PATIENTS WITH c-MET OR RON-
POSITIVE METASTATIC UROTHELIAL CANCER 
LAY TITLE: CRIZOTINIB FOR PATIENTS WITH METASTATIC UROTHELIAL 
CANCER. 
Coordinating Center: 
Levine Cancer Institute – Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator: 
Earle Burgess, M.D. 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Telephone: (980) 442-9347 
Email: Earle.Burgess@carolinashealthcare.org  
Pathologist: 
Chad A. Livasy 
Carolinas Medical Center  
Dept. of Pathology  
1000 Blythe Blvd. 
Charlotte, NC 28203 
(704) 355-3468 
Email: Chad.Livasy@carolinashealthcare.org  
Statistician: 
James Symanowski, Ph.D. 
Levine Cancer Institute 
1001 Blythe Blvd. Charlotte, NC 28203 
Telephone: (980) 442-2371 
Email: James.Symanowski@carolinashealthcare.org  
 
 
 


Protocol Number:  LCI-GU-URO-CRI-001 
Version 3:  April 21, 2018 
 
ii 
 
 
Investigational drug: 
 Xalkori (crizotinib) 
 
 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Sponsor-Investigator is not permitted. 
 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
 
 
 
 


Protocol Number:  LCI-GU-URO-CRI-001 
Version 3:  April 21, 2018 
 
iii 
 
 
 Phase 2 / Version 3 / April 21, 2018 
PROTOCOL SUMMARY 
A. Study Title 
A Phase II Study of Crizotinib in Patients with c-MET or RON-Positive 
Metastatic Urothelial Cancer 
B. Indication 
Metastatic urothelial carcinoma after failure of platinum-based 
chemotherapy 
C. Clinical 
Phase 
II 
 
D. Summary of 
Rationale 
 
 
Patients with refractory metastatic urothelial carcinoma have a dismal 
prognosis, and great medical need exists to identify effective therapeutic 
strategies for this population.  After failure of first line platinum-based 
chemotherapy, limited therapeutic options currently exist, and cytotoxic 
monotherapies demonstrate an overall response rate of 10-20% with a time 
to progression of only 3 months.  No molecularly targeted therapy has 
demonstrated meaningful activity in this setting.  c-MET is a receptor 
tyrosine kinase implicated in tumorigenesis and metastasis that is expressed 
in almost 50% of patients with locally advanced urothelial cancer. 
Additionally, RON, a related receptor tyrosine kinase, is expressed in 
approximately 30% of bladder cancers. Crizotinib, a small molecule 
tyrosine kinase inhibitor, is currently FDA approved for patients with ALK-
positive lung cancer, but is also capable of inhibiting c-MET and RON, 
suggesting that crizotinib may have anti-tumoral activity in patients with c-
MET or RON-positive urothelial carcinoma.  
E. Study 
Objectives 
This study seeks to evaluate the potential efficacy of crizotinib in subjects 
with refractory, advanced c-MET or RON-positive urothelial carcinoma.  
The primary objective is to assess the objective response rate.  Secondary 
objectives include assessment of progression free survival, overall survival 
and toxicity.   
F. Sample 
28 subjects will be enrolled in Stage 1 into three separate molecularly 
defined cohorts (14 in Cohort 1, 7 in each of Cohorts 2 and 3).  If a cohort 
is selected for expansion, then additional subjects will be enrolled in Stage 
2 in that cohort (16 in Cohort 1 or 25 in Cohorts 2 or 3). 
 
 


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iv 
 
 
 
G. Inclusion/ 
Exclusion  
 
 
 
Inclusion: 
• Histologically confirmed metastatic urothelial carcinoma of the bladder 
or upper urinary tract 
• Prior treatment with a cisplatin or carboplatin based regimen 
• ECOG Performance Status 0-2 
Exclusion: 
• Uncontrolled and/or current illness including active infection, 
congestive heart failure, etc. 
• Currently receiving any medications or substances which are strong 
inhibitors or inducers of CYP3A 
• Pregnant or breast feeding 
 
H. Dosage/ 
Dosage 
Form, 
Route, And 
Dose 
Regimen 
Subjects will take one 250 mg crizotinib capsules by mouth twice daily with 
or without food continuously until criteria for treatment discontinuation has 
been met. 
I. Statistical 
Analysis 
The overall response rate will be measured in subjects enrolled into three 
molecularly defined cohorts.  If clinical activity is observed in at least one 
cohort, an expansion cohort may be enrolled to test the null hypothesis that 
the objective response rate is less than or equal to 5%.  Based on an alpha = 
0.05 significance level, this sample size will provide at least 90% power to 
reject the null hypothesis, assuming the overall response rate is 30%. 
 
 
 
 
 
 
 
 


Protocol Number:  LCI-GU-URO-CRI-001 
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v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        
Subjects with metastatic urothelial carcinoma 
previously treated with platinum-based regimen 
• 
Baseline staging studies 
• 
Baseline serologies 
• 
Baseline biopsy for molecular 
stratification if prior tissue biopsy 
inadequate for study purposes 
STAGE 1 
(n=14 subjects in Cohort 1; 7 subjects in Cohorts 2 &3) 
Cohort 1: 
c-MET high (>50%) 
RON null (0-9%) 
Cohort 2: 
c-MET + (10-100%) 
RON + (10-100%) 
Cohort 3: 
c-MET null (0-9%) 
RON + (10-100%) 
Crizotinib  
250 mg BID 
Restage 
(imaging) after 
8 weeks 
No 
radiographic 
responses 
Terminate 
participation 
 Radiographic 
responses 
observed 
STAGE 2 
(n = 16 subjects if Cohort 1 selected; 
25 subjects if Cohorts 2 or 3 selected) 
Expansion cohort defined by Stage 1 
cohort response rates 
Crizotinib  
250 mg BID 
Restage every 8 weeks and 
continue crizotinib until criteria for 
study treatment discontinuation is 
met 
SCHEMA 


Protocol Number:  LCI-GU-URO-CRI-001 
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vi 
 
LIST OF ABBREVIATIONS 
 
AE 
 
 
Adverse event 
ALK  
 
Anaplastic lymphoma kinase 
ALT 
 
 
Alanine aminotransferase 
AST 
 
 
Aspartate aminotransferase 
BID 
 
 
Twice a day 
BPM  
 
Beats per minute 
BRR  
 
Best response rate 
BSA  
 
Body surface area 
BUN  
 
Blood urea nitrogen 
CI 
 
 
Confidence interval 
CPT 
 
 
Cell preparation tube 
CR 
 
 
Complete response 
cCR 
 
 
Clinical complete response 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
ECOG  
 
Eastern Cooperative Oncology Group 
eCRF  
 
Electronic Case report form 
EML4  
 
Echinoderm microtubule associated protein like 4 
FDA  
 
Food and Drug Administration 
GFR  
 
Glomerular filtration rate 
IDS 
 
 
Investigational Drug Services 
IHC 
 
 
Immunohistochemistry 
IND 
 
 
Investigational New Drug 
IRB 
 
 
Institutional Review Board 
IV 
 
 
Intravenous 
LCI 
 
 
Levine Cancer Institute 
LDH  
 
Lactate dehydrogenase 
MET  
 
Mesenchymal epithelial transition factor 
MSEC  
 
Milliseconds 
MTD  
 
Maximum tolerated dose 
ORR  
 
Overall response rate 
OS 
 
 
Overall survival 
PD 
 
 
Progressive disease 
PD-1  
 
Programmed cell death protein 1 
PD-L1  
 
Programmed death-ligand 1 
PET 
 
 
Positron emission tomography 
PR 
 
 
Partial response 
PI 
 
 
Principal Investigator 
PFS 
 
 
Progression-free survival 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
RON  
 
Recepteur d’Origine Nantais 
SAE 
 
 
Serious adverse event 
SAR  
 
Suspected adverse reaction 
SD 
 
 
Stable disease 
SI 
 
 
Sponsor-investigator 


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SOP 
 
 
Standard operating procedure 
TTP 
 
 
Time-to-progression 
UAP  
 
Unanticipated adverse problem 
 
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ....................................................................................................... viii 
1. 
OBJECTIVES ..................................................................................................................... 1 
1.1. 
Primary Objective ..................................................................................................... 1 
1.2. 
Secondary Objectives ............................................................................................... 1 
1.3. 
Safety Objectives ...................................................................................................... 1 
1.4. 
Exploratory Objectives ............................................ Error! Bookmark not defined. 
2. 
BACKGROUND AND RATIONALE .............................................................................. 1 
2.1. 
Bladder Cancer ......................................................................................................... 1 
2.2. 
c-MET/RON ............................................................................................................. 1 
2.3. 
Crizotinib .................................................................................................................. 2 
2.4. 
Rationale ................................................................................................................... 3 
3. 
SUBJECT SELECTION .................................................................................................... 3 
3.1. 
Accrual ..................................................................................................................... 3 
3.2. 
Inclusion Criteria ...................................................................................................... 3 
3.3. 
Exclusion Criteria ..................................................................................................... 4 
4. 
INVESTIGATIONAL PLAN ............................................................................................ 6 
4.1. 
Milestone Date Definitions ...................................................................................... 6 
4.2. 
Overall Study Design ............................................................................................... 7 
4.3. 
Registration and Enrollment ..................................................................................... 8 
4.4. 
Pre-treatment Screening ........................................................................................... 8 
4.5. 
Treatment ................................................................................................................ 11 
4.6. 
End-of-Treatment ................................................................................................... 12 
4.7. 
Follow-up ............................................................................................................... 13 
4.8. 
Off-Study ................................................................................................................ 13 
4.9. 
Changes in Subject Participation Status ................................................................. 13 
5. 
STUDY CALENDAR ....................................................................................................... 16 
6. 
TREATMENT PLAN ...................................................................................................... 17 
6.1. 
Crizotinib Dosage and Administration ................................................................... 17 
6.2. 
Treatment Compliance ........................................................................................... 19 


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6.3. 
Drug Accountability ............................................................................................... 19 
6.4. 
Destruction ............................................................................................................. 20 
7. 
TREATMENT-RELATED ADVERSE EVENTS ........................................................ 20 
7.1. 
Adverse Events Related to Crizotinib .................................................................... 20 
7.2. 
 Dose Modifications for Adverse Events ............................................................... 20 
8. 
DATA AND SAFETY MONITORING PLAN .............................................................. 25 
8.1. 
Safety Monitoring ................................................................................................... 25 
8.2. 
Data Quality Assurance .......................................................................................... 26 
8.3. 
Communication Between Investigational Sites ...................................................... 26 
9. 
SAFETY DATA COLLECTION, RECORDING AND REPORTING ...................... 26 
9.1. 
Unanticipated Problem (UAP) Definition .............................................................. 27 
9.2. 
Adverse Event (AE) Definition .............................................................................. 27 
9.3. 
Suspected Adverse Reaction (SAR) Definition ..................................................... 29 
9.4. 
“Unexpected” Definition ........................................................................................ 29 
9.5. 
Serious Adverse Event (SAE) Definition ............................................................... 29 
9.6. 
Safety Reporting to the Sponsor ............................................................................. 31 
9.7. 
Safety Reporting to the IRB ................................................................................... 32 
9.8. 
Safety Reporting to Pfizer ...................................................................................... 32 
10. 
MEASUREMENT OF EFFECT ..................................................................................... 32 
10.1. 
Anti-tumor Effect – Solid Tumor ........................................................................... 33 
11. 
STATISTICAL CONSIDERATIONS ............................................................................ 36 
11.1. 
Sample Size ............................................................................................................ 36 
11.2. 
Endpoint Definitions .............................................................................................. 37 
11.3. 
Analysis Populations .............................................................................................. 38 
11.4. 
Analysis Methods ................................................................................................... 38 
11.5. 
Interim Analyses ..................................................................................................... 40 
12. 
BIOMARKER ANALYSIS ............................................................................................. 40 
12.1. 
Immunohistochemistry ........................................................................................... 40 
12.2. 
Genomic Analysis .................................................................................................. 40 
13. 
STUDY COMPLETION .................................................................................................. 41 
13.1. 
Completion ............................................................................................................. 41 


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13.2. 
Termination ............................................................................................................ 41 
14. 
RETENTION OF RECORDS ......................................................................................... 42 
15. 
ETHICAL AND LEGAL ISSUES .................................................................................. 42 
15.1. 
Ethical and Legal Conduct of the Study ................................................................. 42 
15.2. 
Confidentiality ........................................................................................................ 43 
15.3. 
Publication .............................................................................................................. 43 
REFERENCES ............................................................................................................................ 44 
 
 
 
 
 
 
 
 
 


Protocol Number:  LCI-GU-URO-CRI-001 
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1. OBJECTIVES 
 
1.1. 
Primary Objective 
To assess the objective response rate (ORR) of crizotinib in subjects with c-MET or 
RON-positive advanced urothelial carcinoma previously treated with a platinum-based 
regimen. 
 
1.2. 
Secondary Objectives 
To assess overall survival (OS), progression-free survival (PFS), and the safety and 
toxicity profile with this regimen.  
 
1.3. 
Safety Objectives 
The safety objectives are to evaluate treatment administration, adverse events assessed 
by NCI Common Terminology Criteria for Adverse Events version 4.0, and serious 
adverse events including deaths on study. 
 
 
2. BACKGROUND AND RATIONALE 
 
2.1. 
Bladder Cancer 
Bladder cancer is the fourth most common malignancy in men.1 In 2014, over seventy 
thousand new cases and over fifteen thousand deaths were anticipated in the United 
States in males and females.1 Although patients derived modest benefit following the 
introduction of cisplatin-based chemotherapy in prior decades, no significant clinical 
advances have occurred in recent years.   
 
Patients with advanced refractory urothelial cancer have a poor prognosis with a 
median survival of 14-15 months.2  In patients who progress after first line platinum-
based regimens, limited effective therapeutic options exist.  Commonly used cytotoxic 
monotherapies demonstrate an overall response rate of 10-20% with a time to 
progression of 3 months in the second-line setting.  No molecularly targeted agent has 
yet to demonstrate clinically meaningful activity, which highlights a large unmet 
medical need for this patient population.3   
2.2.    c-MET/RON 


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c-MET is a receptor tyrosine kinase for hepatocyte growth factor that can regulate 
epithelial cell proliferation and motility4 and is implicated in tumorigenesis and 
metastasis.5  Dysregulation of the c-MET pathway is commonly observed in many 
human tumors.6  Recepteur d’Origine Nantais (RON) is a related receptor tyrosine 
kinase that can heterodimerize with and transactivate c-MET,7 which may be 
necessary for c-MET driven oncogene addiction in malignancy.8     
 
Preclinical evidence suggests that activation of the c-MET pathway can enhance 
bladder tumor cell invasion.9  Expression of c-MET is common in urothelial 
carcinoma of the bladder and correlates with adverse clinicopathologic features and 
poor outcome.10-12  In one series of 142 patients with non-metastatic bladder cancer, 
expression of c-MET was observed in 21% of patients with non-invasive disease, 
expression positively associated with stage, and was observed in 45% of patients with 
more advanced muscle-invasive disease.11  Multivariate analysis revealed that high c-
MET expression (more than 50% of tumor cells) predicted for increased likelihood of 
disease progression and death.   
 
In an expanded cohort of 183 patients with bladder cancer from Cheng and colleagues, 
overall and high c-MET expression was observed in 45% and 33% of patients, 
respectively.10  In this cohort, the investigators also measured expression of RON and 
observed overall and high RON expression in 33% and 23% of patients, respectively.  
Co-expression of RON and c-MET occurred in 19% of patients.  In this series, 
multivariate analysis showed that overexpression of RON and coexpression of both 
receptors correlated with inferior survival.  
 
2.3.    Crizotinib 
Preclinical evidence suggests that therapeutic targeting of the c-MET pathway may be 
efficacious in patients with urothelial cancers dependent on c-Met activation.13  
Crizotinib is a specific inhibitor of the c-MET, RON and ALK receptor tyrosine 
kinases that is currently approved for use in patients with ALK-positive non-small cell 
lung cancer.14,15  Pharmacodynamic modeling suggests that the currently 
recommended dose (250 mg twice daily) can achieve clinically significant c-MET 
inhibition in human tumors.16  The potential efficacy of crizotinib for targeting c-MET 
driven tumors is illustrated by the antitumoral activity in human cancer xenografts 
possessing c-MET activation.15,17  Furthermore, in a small case series of patients with 
esophagogastric adenocarcinoma harboring c-MET amplification, two of four patients 
treated with crizotinib demonstrated tumor shrinkage, providing support to the 
rationale behind this therapeutic strategy.18 


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2.4.    Rationale 
Patients with metastatic urothelial carcinoma who have failed prior platinum-based 
therapy have a poor prognosis with limited therapeutic options.  Overexpression of c-
MET and RON has been observed in patients with non-metastatic urothelial carcinoma 
of the bladder and connotes a poor prognosis, though the therapeutic efficacy of 
targeting the c-MET pathway in patients with urothelial carcinoma remains unknown.  
Crizotinib, an inhibitor of c-MET and RON, is well tolerated in patients with advanced 
lung cancer harboring EML4-ALK fusions and may also be an effective therapeutic 
strategy for targeting c-MET dependent tumors.  This study seeks to determine 
whether crizotinib has anti-tumoral activity in patients with c-MET or RON-positive 
urothelial carcinoma, as well as to determine whether c-MET or RON tumor 
expression and tumor derived mutational profiling can predict therapeutic response. 
 
3. SUBJECT SELECTION 
 
3.1.    Accrual 
Following informed consent and registration, subjects will undergo tissue pre-screen 
eligibility screening.  Tumor specimens from potential subjects will then undergo c-
MET and RON expression characterization as described in section 12.1.  Prior to 
presenting treatment consent, the c-Met/RON expression results must be evaluated to 
confirm that the subject meets the criteria for one of the open cohorts. Eligible subjects 
will then be enrolled into available open molecularly defined cohorts as described in 
section 4.2.     
 
If the Stage 1 response criteria are met within a cohort (2 responses in Cohort 1 or 1 
response in either Cohorts 2 or 3), it will be considered for expansion with additional 
subjects enrolled. The cohort showing the highest response rate will be given highest 
consideration, as determined by the Sponsor-Investigator. Trial accrual is anticipated 
to occur  with 28 subjects enrolled during the first stage (14 in Cohort 1, 7 in each of 
Cohorts 2 and 3) with the opportunity for additional subjects to be enrolled if a cohort 
is expanded (16 more in Cohort 1, 25 more in Cohorts 2 and 3). 
Both adult men and women of all races and ethnic groups are eligible for this trial. 
3.2. 
Inclusion Criteria 
 
Subjects must meet all of the following criteria:  


Protocol Number:  LCI-GU-URO-CRI-001 
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1. Histologically confirmed stage IV urothelial carcinoma of the bladder, upper 
urinary tract or urethra. 
2. Prior treatment for metastatic disease with at least one cisplatin or carboplatin-
based multi-agent chemotherapeutic regimen. Prior immunotherapy with anti-PD-
L1 or anti-PD1 agents is allowed. 
o Chemotherapy received peri-operatively for non-metastatic bladder cancer will 
be considered a prior regimen if less than 24 months have elapsed since 
treatment.  
3. Measurable disease per RECIST 1.1.  See Section 10 for the evaluation of 
measurable disease. 
4. Tissue Pre-screen: Archived tissue must have been obtained within 60 months of 
subject signing tissue pre-screen consent. Biopsy accessible disease if adequate 
archival tissue does not exist for molecular characterization. 
Treatment: Available tumor specimen C-MET/RON expression results that meet 
the criteria for one of the three molecularly defined cohorts per Section 4.2  
5. Age ≥ 18 years 
6. ECOG performance status ≤ 2 
7. Adequate liver function: AST and ALT ≤ 2x upper limit of normal, bilirubin ≤ 
1.5x upper limit of normal 
8. Adequate bone marrow function: Platelets ≥ 100,000 cells/mm3, hemoglobin > 8.0 
g/dL and ANC ≥ 1,500 cells/mm3 
9. Adequate renal function with a creatinine clearance (based on Cockgroft-Gault 
formula) ≥ 45 mL/min 
10. Ability to understand and the willingness to sign a written informed consent 
document 
 
11. Able to swallow oral medication 
 
3.3. Exclusion Criteria 
Subjects must not meet any of the following criteria.  
 


Protocol Number:  LCI-GU-URO-CRI-001 
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5 
 
1. Currently receiving any other investigational agents, a prior c-MET inhibitor, or 
crizotinib 
2. Pregnant or breast feeding, because crizotinib can cause fetal harm 
3. Uncontrolled and current illness including, but no limited to:  
o Ongoing or active infection 
o Symptomatic congestive heart failure 
o Unstable angina pectoris 
o Cardiac arrhythmia, or  
o Psychiatric illness/social situations that would limit compliance with 
study requirements 
4. Presence of any of the following within the previous 3 months of treatment 
consent: 
o Myocardial infarction 
o Severe/unstable angina 
o Coronary/peripheral artery bypass graft 
o Congestive heart failure, or 
o Cerebrovascular accident including transient ischemia attack 
5. History of active malignancy other than urothelial carcinoma within the prior 12 
months of the date of treatment consent (except non-melanoma skin cancer or 
localized, treated prostate cancer) 
6. Prolonged QT interval (QTc > 480 msec), symptomatic bradycardia, ongoing 
cardiac dysrhythmias of CTCAE version 4.0 grade 2 ≥ or uncontrolled atrial 
fibrillation of any grade 
 
7.  Pulmonary disorder requiring supplemental oxygen or history of pulmonary 
fibrosis. Sleep apnea considered to be a sleep disorder (and not a pulmonary 
disorder) by the investigator will be allowed. 
8. Subjects receiving any medications or substances that are strong inhibitors or 
inducers of CYP3A are ineligible. Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table/aspx; medical reference texts such 
as the Physicians’ Desk Reference may also provide this information. As part of 
the enrollment/informed consent procedures, the subject will be counseled on the 
risk of interactions with other agents, and what to do if new medications need to 


Protocol Number:  LCI-GU-URO-CRI-001 
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6 
 
be prescribed or if the subject is considering a new over-the-counter medicine or 
herbal product. 
o Medical condition requiring the use of strong CPY3A inhibitors, 
including but not limited to atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, 
saquinavir, suboxone, telithromycin, troleandomycin, and voriconazole. 
o Use of grapefruit or grapefruit juice, which are considered strong 
CYP3A inhibitors. 
o Medical condition requiring the use of strong CYP3A inducers, 
including but not limited to carbamazepine, efavirenz, modafinil, 
nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, 
rifabutin, rifampin, St. John’s Wort, and troglitazone. 
9. Receiving any medications that are CYP3A substrates with a narrow therapeutic 
range (alfentanil, cyclosporine, dihydroergotamine, fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus) 
10.  Subjects may be screened for study participation though may not begin study 
treatment: 
o Within 4 weeks of major surgery  
o Within 2 weeks of prior systemic therapy 
o Within 2 weeks of prior non-palliative radiotherapy 
o Within 48 hours of completion of palliative radiotherapy (≤ 10 
fractions) 
o Until recovery of  adverse events due to prior therapies to ≤ 1 (except 
alopecia) 
11. Presence of untreated brain metastases or ≤ 6 months from prior treatment (from 
the time of enrollment), active neurologic symptoms or the use of prohibited 
medications in subjects with a history of brain metastases 
 
4. INVESTIGATIONAL PLAN 
 
4.1. 
Milestone Date Definitions 
Registration date: the date the subject signs the tissue pre-screen informed consent 
form. 
Eligibility date: the date of the last documented criterion that confirmed subject 
eligibility. 


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7 
 
Enrollment date: the date of initiation of crizotinib treatment. 
Treatment discontinuation date: the date the Investigator decides to discontinue the 
subject from crizotinib treatment. 
 
4.2. 
Overall Study Design 
This is a single arm two-stage phase II study designed to evaluate the objective 
response rate in subjects with metastatic urothelial cancer demonstrating c-MET or 
RON overexpression who have received prior therapy with a cisplatin or carboplatin 
containing regimen.   
 
Subjects will be recruited at Levine Cancer Institute (LCI) and other participating 
sites.  
 
Immunohistochemistry will be utilized to define tumor sample c-MET and RON 
protein expression patterns for assignment into molecular cohorts as described in 
section 12.1. 
In the first stage of this study, subjects will be enrolled in parallel to three molecularly 
defined cohorts as follows: 
1. c-MET high (>50%), RON null (0-9%) (n = 14 subjects) 
2. c-MET-positive (10-100%), RON-positive (10-100%) (n = 7 subjects) 
3. c-MET null (0-9%), RON-positive (10-100%) (n = 7 subjects) 
All enrolled subjects will continue with study treatment until criteria for treatment 
discontinuation has been met (as defined in Section 4.9.2). 
 
If Stage 1 response criteria are met in a cohort, the cohort may be considered for 
expansion, and additional subjects (16 in Cohort 1 or 25 in Cohorts 2 or 3) may then 
be enrolled into that cohort in Stage 2.  An expansion cohort will be defined by the 
Sponsor- Investigator following review of all available trial data  which will be 
conducted after the first Stage 1 cohort has completed accrual and at least every six 
months thereafter until all Stage 1 cohorts have completed accrual.  
    
If more than one cohort meets Stage 1 response criteria (2 responses out of 14 subjects 
for Cohort 1 or 1 response out of 7 subjects for each of Cohorts 2 and 3), then the 
cohort showing the highest response rate will be given highest consideration for 
expansion.   
 
It is possible that the cohort with the highest response rate can be determined prior to 
completion of Stage 1 enrollment in all cohorts.  If there is a significant lag in 


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enrollment in Stage 1 cohorts, an expansion decision may be made without regard to 
the lagging cohorts.  Incompletely accrued Stage 1 cohorts may continue to enroll 
subjects after an expansion cohort has been identified.  Additionally, individual 
cohorts may be closed at the discretion of the Sponsor-Investigator based on 
efficacy/safety/accrual.  
 
Exploratory biomarker analysis including c-MET and RON protein expression will be 
correlated with clinicopathologic outcome.  Additional specimens from selected 
subjects (e.g., those demonstrating clinical benefit) may also be assessed for other 
markers including c-MET gene amplification by fluorescence in situ hybridization or 
the presence of mutations in downstream genes found with high prevalence in 
urothelial carcinoma19-21 to identify potential markers predictive of response or 
resistance to crizotinib.  
 
Data from this study will be collected on electronic case report forms (eCRFs) and 
stored in the clinical trial management system (CTMS).  
 
4.3. 
Registration and Enrollment 
Potentially eligible and interested patients will be presented with the tissue pre-
screening consent and asked for an archived tissue sample, or asked if a new tissue 
sample may be collected. The date the tissue prescreening consent is signed will be the 
registration date. A Study ID number will then be sequentially assigned by the 
Coordinating Center. The Study ID will be a four digit number, where 1001 will be the 
Study ID assigned to the first registered subject. The samples provided will be tested 
for molecular eligibility (i.e. molecular expression meets the criteria in an open 
cohort). The Coordinating Center must grant approval prior to presenting the subject 
with the treatment consent  for molecularly eligible subjects that are still potentially 
eligible and interested in the treatment study.  
 
4.4. 
Pre-treatment Screening 
No protocol-related assessments may be performed prior to obtaining written informed 
consent.  Men and women of child bearing potential on study will be counseled 
regarding risk of teratogenicity and the need to use contraception throughout the 
course of the study and for 90 days after completion of crizotinib administration. 
 
Baseline assessments include: 


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• Demographics and Medical History 
o A complete medical history should be obtained, including 
documentation of any clinically significant pre-existing condition.   
• Physical Examination 
Evaluation by body system, height, weight, and body surface area 
(BSA) should be documented.  Vital signs will be recorded and 
should include temperature, pulse rate, blood pressure, respiratory 
rate and oxygen saturation. ECOG performance status should be 
documented at baseline. 
• Ophthalmologic Examination 
o A baseline exam including visual acuity, fundoscopy and slit lamp 
exam should be performed by an ophthalmologist in subjects with 
history of photopsia or increase in vitreous floaters.  If clinically 
indicated, additional eye examinations will be performed when 
visual disturbances have been observed and when there is an 
increase in grade for visual disturbances. 
• Pregnancy Test 
o A serum or urine pregnancy test will be performed at screening and 
as clinically indicated for women of childbearing potential. 
• Concomitant Medications 
o Any medications, other than crizotinib, taken up to 14 calendar 
days prior to signing of the treatment informed consent will be 
considered a concomitant medication. Dose, route, frequency, 
administration and start/stop dates will be documented. 
Concomitant medications include but are not limited to over the 
counter medications, supplements, and vitamins. 
• Symptoms and Toxicities 
o Baseline adverse events will be documented at screening. 
• Clinical Laboratory Tests 
o The blood-based clinical laboratory tests will be performed at 
screening and include a complete blood count with differential and 
platelets, a complete metabolic panel (including sodium, 
potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase), magnesium, phosphorus, and LDH. 


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• Electrocardiogram 
o A baseline 12 lead electrocardiogram (EKG) will be required at 
screening for assessment of QT interval.   
• Radiology and Tumor Measurements 
o A computed tomography (CT) scan with oral and intravenous 
contrast of the chest, abdomen and pelvis and radionuclide bone 
scan or positron emission tomography (PET)/CT scan defining the 
extent of existing disease must be performed and documented 
within 30 days prior to the first dose of study treatment.  If a 
PET/CT scan is utilized to document extent of metastatic disease at 
baseline, measurable target lesions must be identified by the CT 
portion of the exam and cannot solely be determined by an 
abnormal fluorodeoxyglucose signal alone if lesion size cannot be 
easily measured by the corresponding CT images.   
• Tissue Biomarkers 
o See the Manual of Procedures for tissue requirements and shipping 
instructions (Participating Sites) 
o Subjects must undergo core needle biopsy of a metastatic lesion to 
define c-MET/RON expression status if an adequate archival 
tumor specimen is not available.  Adequate archival specimens 
include diagnostic slides from the urothelial primary or metastatic 
lesion and corresponding paraffin-embedded tumor block and must 
have been obtained within 60 months prior to the date of subject 
signing tissue pre-screen consent.  Adequacy of archival specimen 
will be determined by the study pathologist. 
o If an archival specimen derived from a primary tumor is utilized 
for screening purposes and does not demonstrate c-MET or RON 
protein expression, subject may undergo a fresh biopsy of a 
metastatic lesion to assess for discordant expression patterns and 
will be eligible for study participation if c-MET or RON protein 
expression is observed on the subsequent fresh biopsy specimen. 
o For newly collected tissue specimens, core biopsy samples will be 
collected per standard operating procedures and immediately 
placed in 10% neutral-buffered formalin for a total fixation time 
between 6 and 48 hours.   
o  Tissue is to be shipped to:  


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Atrium Health Biospecimen Repository 
10545 Blair Rd., Suite 1001 
 
Mint Hill, NC 28227 
 
(704) 863-4001 
 
o c-MET and RON protein expression will be assessed by 
immunohistochemistry as described in section 12.1, and subjects 
with expression patterns required for enrollment in open cohorts as 
defined in section 4.2 will be eligible to receive study treatment. 
 
4.5. 
Treatment 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat 
the subject's malignancy. 
Subjects will receive treatment as described in Sections 5 and 6.  Treatment 
assessments include: 
• Physical Examination 
Evaluation by body system, weight, and body surface area (BSA) 
should be documented.  Vital signs will be recorded and should 
include temperature, pulse rate, blood pressure, respiratory rate and 
oxygen saturation.  
• Symptoms and Toxicities 
o All adverse events and serious adverse events will be documented 
regardless of attribution on an ongoing basis from study treatment 
initiation through 30 days after last dose of study treatment. 
• Concomitant Medications 
o Any medications, other than crizotinib, taken up to 14 calendar 
days before completing the treatment informed consent through 30 
days after last dose of study treatment will be considered a 
concomitant medication and dose, route, frequency, administration 
and start/stop dates will be documented. This includes but is not 
limited to, over the counter drugs, vitamins, and supplements. 
•  Electrocardiogram 


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o A 12 lead EKG will be obtained 28 days (+/- 7 days) after the start 
of therapy and then as indicated by the subject’s clinical history 
and treating physician’s discretion.  Subjects at increased risk of 
QTc prolongation include those with bradyarrhythmia or 
congestive heart failure. 
• Clinical Laboratory Tests 
o The blood-based clinical laboratory tests will include a complete 
blood count with differential and platelets, a complete metabolic 
panel (including sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, 
AST, ALT, alkaline phosphatase), magnesium, phosphorus, and 
LDH obtained prior to the start of each cycle.  Additionally, liver 
function tests (including total bilirubin, AST, ALT, alkaline 
phosphatase) will be obtained on day 15 (+/-7 days) of the first two 
cycles only. 
• Radiology and Tumor Measurements 
o A CT scan with oral and intravenous contrast of the chest, 
abdomen and pelvis or PET/CT defining the extent of disease will 
be performed every 8 weeks (+/- 7 days) .  The first follow-up 
imaging timepoint should be 8 weeks (+/- 7 days) from C1D1. 
Subsequent follow-up imaging should be performed every 8 weeks 
(+/- 7 days) based on the timepoint of the previous scan, not C1D1. 
For subjects being followed with CT scan of chest/abdomen pelvis,  
a radionuclide bone scan will also be obtained at the same 
frequency as the CT scan if skeletal metastases are present at 
baseline or if the subject develops new skeletal pain or abnormal 
alkaline phosphatase (> upper limit of normal) in the absence of 
hepatic metastasis.  Identical methodology should be used for 
disease assessment at baseline and throughout the study. 
 
4.6. 
End-of-Treatment 
Subjects will continue study treatment until criteria for treatment discontinuation are 
met (as defined in Section 4.9.2). Every subject will undergo an end-of-treatment 
evaluation at the time it is determined that he or she is no longer eligible to receive 
study treatment.  End of treatment evaluations will include a physical examination 
with vital signs and weight measurements, toxicity evaluation, concomitant 
medications evaluation, and laboratory evaluation per Section 5.0. The end of 


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treatment evaluation must be completed within 30 days after the last dose of study 
treatment. 
 
4.7. 
Follow-up 
Subjects will be tracked for at least 30 days following cessation of treatment to 
monitor for adverse events, serious adverse reactions, and any other unanticipated 
problems.  If the end of treatment visit occurs prior to 30 days from last dose, subjects 
will be contacted by telephone on day 30 or next business day by telephone for 
monitoring.  If subject cannot be contacted following three attempted telephone calls 
on subsequent days, subject will be contacted in writing.  Following this period, 
subjects will be contacted every 6 months by telephone, in writing, or during clinic 
visits after treatment discontinuation for collection of follow-up data until death, lost 
to follow-up, or until the criteria for final analyses have been met (Section 11.4.1). 
Lost to follow-up is defined as three consecutive unsuccessful documented attempts at 
contacting the subject.  Follow-up clinical information may also be obtained through 
chart reviews or other data sources (e.g. death registries).   
All subjects, regardless of when they discontinue treatment, will be followed per 
standard of care procedures until all treatment-related toxicities have resolved, 
returned to baseline, stabilized, or are deemed irreversible. 
 
4.8. 
Off-Study 
Subjects will be considered off-study when death or lost to follow-up occurs.  Subjects 
who withdraw consent voluntarily and subjects withdrawn by the Investigator are 
considered off-study per the documented date of withdrawal.  Additionally, subjects 
will be considered off-study when it is determined that the follow-up period for the 
study is ended (per criteria in Section 11.4.1).  Off-study subjects will not receive 
study treatment or participate in any study procedures, including data collection.  
 
4.9. Changes in Subject Participation Status 
 
4.9.1. Subject Replacements 
Enrolled subjects who have discontinued treatment or who have withdrawn after 
receiving their first dose of study drug will not be replaced. 
  
A subject who, for any reason (e.g. failure to satisfy the selection criteria or 
withdraws consent), terminates participation in the study before receiving first 


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dose of study drug is regarded as a “screen failure”.  Screen failures may be 
replaced. 
 
All screen failures will be tracked in the CTMS. 
 
4.9.2. Treatment Discontinuation 
Subjects are discontinued from treatment if there is evidence of progressive 
disease, unacceptable toxicity, or they withdraw consent for treatment only.  
Additionally, a subject may be discontinued from treatment if, in the 
Investigator's opinion, continuation of the treatment would be harmful to the 
subject.  
These subjects are still considered to be on-study and may continue to 
participate in study procedures (e.g. labs, scans, follow-up). 
Other reasons for treatment discontinuation include, but are not limited to: 
• Pregnancy.  Pregnancy will be reported as an SAE per Section 9.6.  
(Note: Subjects who have discontinued treatment with study drug because 
of pregnancy should not undergo CT scans [with contrast] or bone scans 
while pregnant.) 
• Deterioration of ECOG performance status to 4 
• Use of illicit drugs or other substances that may, in the opinion of the 
Investigator, have a reasonable chance of contributing to toxicity or 
otherwise skewing trial result 
 
• Severe allergic reaction to crizotinib (Grade 3 or 4 hypersensitivity 
reaction) 
• The development of a second cancer  
• Any other (non-disease related) reason, at the Investigator’s discretion 
 
 


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4.9.3. Subject Withdrawal 
Subjects are defined as withdrawn from the study if they revoke consent for both 
treatment and study procedures or the Investigator withdraws them from the 
study.  Subjects must be withdrawn from the trial for the following reasons:  
• Subject withdraws consent from study treatment and study procedures.  A 
subject must be removed from the trial at his/her own request. At any time 
during the trial and without giving reasons, a subject may decline to 
participate further.  The subject will not suffer any disadvantage as a result. 
• Subject is lost to follow-up after three consecutive unsuccessful documented 
attempts at contacting the subject. 
 
Subjects may be withdrawn from the study by the Investigator for the following 
reasons: 
• The subject is non-compliant with study drug, study procedures, or both (as 
determined by the Investigator); including the use of anti-cancer therapy not 
prescribed by the study protocol. 
• Development of an intercurrent illness or situation which would, in the 
judgment of the Investigator, significantly affect assessments of clinical status 
and trial endpoints. 
 
Any subject who withdraws themselves or who is withdrawn from the study by the 
Investigator will remain under medical supervision until discharge or transfer is 
medically acceptable. 
 
In all cases, the reason for withdrawal must be documented in the subject's medical 
records and/or research chart and recorded in the CTMS.  Withdrawn subjects are 
considered to be off-study. 
 
Details for the premature termination of the study as a whole are provided in 
Section 13.2. 
 
 


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5. STUDY CALENDAR 
Required 
Procedures 
Tissue 
Pre-
Screen 
Screening 
Study Treatmenta 
Post-Treatment 
 
 
 
Cycle 1 
Cycle 2 
Cycles ≥ 3 
End of Treatment 
Follow-up 
 
 
Within 30 
days prior 
to 
treatment 
initiation 
unless 
otherwise 
specified 
Day 
1 (+/- 
7 
days) 
Day 
15 
(+/- 7 
days) 
Day 1 
(+/- 7 
days) 
Day 
15 
(+/- 7 
days) 
Day 1 (+/- 
7 days) 
unless 
otherwise 
specified 
Within 30 days after 
the last dose of 
study treatment 
unless otherwise 
specified 
Every 6 
months until 
death or lost 
to follow-up 
up to at least 
2 years 
Informed 
consent 
X 
X 
 
 
 
 
 
 
 
Demographics 
 
 
X 
 
 
 
 
 
 
 
Medical and 
Treatment 
History 
 
X 
 
 
 
 
 
 
 
Physical Examm 
 
X 
X 
 
X 
 
X 
X 
 
Pregnancy Test   
(serum or urine) 
 
Xc 
 
 
If/when 
clinically 
indicated 
 
If/when 
clinically 
indicated 
If/when clinically 
indicated 
 
Ophthalmologic 
Exam 
 
Xd 
If new or an increase in grade of visual disturbances  
 
 
 
Symptoms & 
Toxicities 
 
Xe 
Documented on a continuous basis until 30 days after last dose of study treatment 
 
 
Concomitant 
Medications 
 
Xf 
Documented on a continuous basis until 30 days after last dose of study treatment 
 
 
Laboratory Tests 
 
Xl 
Xb,k 
Xg 
Xk 
Xg 
Xk 
Xk 
 
12 lead EKG 
 
X 
 
 
Xl 
 
Xh 
 
 
Radiology & 
Tumor 
Measurementsi 
 
X 
Every 8 weeks (+/- 7 days) until documented progression or initiation of subsequent anti-cancer therapy 
Tissue 
Collection for 
Biomarker 
Analysis 
 
Xj 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
X 
a. 
study cycle length is 28 days. 
b. required if study treatment is not started within 7 days of screening visit. 
c. 
in women of child-bearing potential 
d. baseline exam required only in subjects who report a history of photopsia or increase in visual floaters in 90 
days prior to signing the treatment consent. 
e. 
 Baseline adverse events will be documented at screening 
f. 
Concomitant medications taken up to 14 calendar days prior to the treatment informed consent should be 
documented at screening  
g. total bilirubin, AST, ALT, alkaline phosphatase only 
h. additional EKGs should be obtained at the discretion of Investigator.   
i. 
CT of the chest, abdomen and pelvis and radionuclide bone scan or PET/CT scan at screening. See Section 
4.4 for criteria for PET/CT. Identical methodology should be used for subsequent imaging. The first 
follow-up imaging timepoint should be 8 weeks (+/- 7 days) from C1D1. Subsequent follow-up imaging 
should be performed every 8 weeks (+/- 7 days) based on the timepoint of the previous scan. For subjects 


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being followed with CT scan of chest/abdomen pelvis, a bone scan is also required at the same frequency as 
the CT scan if skeletal metastases are identified at baseline or at the time of developing new skeletal pain or 
abnormal alkaline phosphatase in the absence of liver metastasis. For subjects who discontinue study 
treatment and have not had progression or initiated subsequent anti-cancer therapy, the frequency of 
imaging will be determined by the treating investigator. 
j. 
After tissue pre-screen informed consent; fresh tissue to be obtained if adequate archival tissue is 
unavailable as described in Section 4.4 
k. including CBC/differential, a complete metabolic panel (including sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase), magnesium, LDH, and phosphorous 
l. 
A 12 lead EKG will be obtained 28 days (+/- 7 days) after the start of study treatment 
m. To include height and ECOG performance status at screening only. All time-points to include weight and 
vital signs including oxygen saturation. 
n. Baseline adverse events will be documented at screening 
 
6. TREATMENT PLAN 
 
6.1. 
Crizotinib Dosage and Administration  
Treatment will be administered orally on an outpatient basis.  Reported adverse events 
and potential risks are described in Section 7.  Dose modifications are described in 
Section 7.  No investigational or commercial agents or therapies other than crizotinib 
may be administered with the intent to treat the subject's malignancy.  The study drug 
will be exclusively used for the investigation specified in this protocol and it will only 
be accessible to authorized staff. 
 
Crizotinib will be started on the day of the enrollment visit (Cycle 1 Day 1).  
Crizotinib is administered orally at 250mg twice daily.  Subjects will swallow one 
250mg crizotinib capsule whole with or without food each morning and evening.  
Capsules should not be broken or crushed.  If a dose is missed, subject will make up 
that dose unless the next dose is due within 6 hours.  If vomiting occurs after taking a 
dose of study drug, an extra dose should not be taken. The subject should take the next 
dose at the regular time.  Each study cycle length is 28 days. 
6.1.1. Crizotinib Drug Supply 
Crizotinib capsules for oral administration are formulated as a hard gelatin 
capsules in two dosages.  250mg capsules contain a pink opaque cap and body 
with “Pfizer” on the cap and “CRZ250” on the body.  200mg capsules contain a 
white opaque body and pink opaque cap with “Pfizer” on the cap and “CRZ 200” 
on the body. Crizotinib will be supplied by Pfizer.  To request crizotinib from 
Pfizer, LCI Investigational Drug Services (IDS) Pharmacy will complete the 
Pfizer-provided Drug Supply Request Form. Participating Sites will request 
crizotinib supplies from the LCI IDS utilizing the study specific Drug Order 


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Form. Drug inventory levels should be able to provide subjects with crizotinib for 
up to four weeks while waiting for additional ordered supplies. 
Crizotinib will be supplied in study drug bottles containing 60 capsules 
each(250mg or 200mg dosage). The study drug bottles will have a label affixed 
containing study identification, product identification and quantity of capsules.   
Once the drug has been received, it must be kept in a secure, dry location.  Study 
drug must be stored in its original study drug bottle at room temperature 20° to 
25°C (68° to 77°F).  Temperature excursions between 15° to 30°C (59° to 86°F) 
are permitted. 
Study drug bottles dispensed to subjects will be labeled as an investigational 
treatment and subjects will be instructed to comply with the following 
directions: 
• Store capsules in the original study drug bottle. 
• Take capsule at the same time twice daily, unless otherwise instructed, 
with or without food. 
• Swallow capsule whole. 
• If a dose is missed, it should be taken as soon as possible. Unless it is 
close to the next dose (within 6 hours), in which case the normal dose 
should be taken at the usual time. 
• If vomiting occurs after taking a dose, an additional dose should not be 
taken.  The next dose should be taken when due. 
• Avoid grapefruit and the use of grapefruit juice while taking study 
treatment. 
• Subjects of childbearing potential should use adequate contraceptive 
methods (per Section 7.1.1) while taking study treatment and for at 
least 90 days after completing therapy. 
 
6.1.2. Concomitant Therapy Medications 
6.1.2.1. 
Medications 
Anticancer therapy with agents other than crizotinib is not permitted.  Medication that 
is considered necessary for the subject’s welfare, and which is not expected to 
interfere with the study treatment, may be given at the discretion of the Investigator.  
Crizotinib inhibits CYP3A in vivo.  Specific caution should be taken when considering 
administration of a concomitant medication that is metabolized by the cytochrome 
enzyme CYP3A.  Such concomitant medication should be avoided if possible.  


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Concomitant use of crizotinib with strong CYP3A inhibitors, inducers or CYP3A 
substrates with a narrow therapeutic range as listed in section 3.3 while on study 
treatment is prohibited. 
Grapefruit or grapefruit juice should be avoided while on study per exclusion criteria. 
Bisphosphonate therapy for metastatic skeletal involvement is permitted. 
6.1.2.2. 
Radiotherapy 
The development of a new symptomatic disease site requiring palliative radiotherapy 
constitutes subjective disease progression as defined in section 10.1.4 and requires 
subject discontinuation from study treatment.  Palliative radiotherapy may begin at 
least one day after crizotinib treatment is stopped. 
6.1.2.3. 
Surgery 
The impact of crizotinib on wound healing is not known.  If surgical intervention is 
necessary during study participation, crizotinib should be stopped 48 hours before 
surgery and resumed no sooner than 48 hours after surgery. 
 
6.2. 
Treatment Compliance 
Study drug will be dispensed to subjects with instructions to bring all study drug 
containers to each study visit (do not discard). At the end of each cycle, the study drug 
pill bottles will be returned to the research staff and counted. The number of capsules 
taken by the subject per cycle will be derived from these capsule counts rather than 
reported by the subjects on a pill diary. 
 
Subject compliance with the treatment and protocol includes willingness to comply 
with all aspects of the protocol.  Subjects will be asked to return used study drug 
bottles.  Compliance with study treatment will be assessed at the end of each cycle.   
 
At the discretion of the Sponsor-Investigator or the subject’s Physician Investigator, a 
subject may be discontinued from the protocol for non-compliance with study visits or 
study drug.  
 
 
6.3. 
Drug Accountability 
All study drugs will be stored at the investigational site in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements and 
will be inaccessible to unauthorized personnel.  


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An adequate record of receipt, distribution, and destruction of all study drugs must be 
kept in the form of a Drug Accountability Form. The Investigator, or responsible party 
designated by the Investigator, will maintain a careful record of the inventory using 
the Drug Accountability Form.  
 
6.4. 
Destruction 
At the end of the study, unused supplies of crizotinib will be destroyed and 
documented according to institutional pharmacy policies.  Destruction records will be 
reviewed and confirmed by the LCI IDS Pharmacy staff who will then complete the 
Study Closure Form provided by Pfizer certifying that all remaining drug was 
destroyed.  
 
7.   TREATMENT-RELATED ADVERSE EVENTS  
 
7.1. 
Adverse Events Related to Crizotinib 
Based on prior clinical studies with crizotinib, the Investigator should anticipate that 
any of the following AEs could occur with the use of this medication.  The occurrence 
of AEs and SAEs should prompt immediate notification of the appropriate agencies as 
outlined in Section 9.  
 
7.1.1. 
Reproductive Risks 
 
Crizotinib can cause harm to the developing human fetus.  For this reason, women of 
childbearing potential and men must agree to use adequate contraception (e.g., prior 
surgical sterilization, hormonal or barrier method of birth control; abstinence) prior to 
study entry, the duration of study participation and for at least 90 days after 
completion of study treatment.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician and the investigator immediately 
 
7.2.  Dose Modifications for Adverse Events 
 
The starting dose of crizotinib is 250mg twice daily (dose level 0).  Doses will be 
delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protoco7l therapy according to the guidelines shown in the 
tables that follow.  Dose modifications will follow pre-defined dose levels.  Dose 
adjustments for hematologic toxicity are based on the blood counts obtained in 


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preparation for the day of treatment. In the event of a treatment delay at the scheduled 
Day 1 of a cycle, Day 1 of the cycle will be delayed until crizotinib is re-started. This 
may cause the cycle to extend to longer than 28 days.  
 
Dose Level 
Crizotinib Dose 
0 
250 mg, twice daily 
-1 
200 mg, twice daily 
-2 
250 mg, once daily 
 
If a subject experiences more than one toxicity, dose reduction should be according to 
the toxicity with the highest grade.  In the case of two or more toxicities of the same 
grade, the Investigator may dose reduce according to that deemed most causally 
related to study treatments.  If treatment is held for more than 4 weeks due to toxicity 
or if dose reductions beyond dose level -2 are necessary, then treatment will be 
permanently discontinued. 
 
 


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Table 1: Dose Adjustments for Treatment-Related Toxicities 
Dose Adjustments for Treatment-Related Toxicitiesa 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-
hematologic 
General (except 
as noted 
below). 
 
Continue at the 
same dose 
level. 
 
Continue at the 
same dose 
level. 
 
Withhold dose 
until toxicity is 
grade ≤1, or 
has returned to 
baseline, then 
resume 
treatment at the 
same dose level 
or reduce the 
dose by 1 level 
at the 
discretion of 
the 
investigatorb. 
 
Withhold dose 
until toxicity is 
grade ≤1, or 
has returned to 
baseline, then 
reduce the dose 
by 1 level and 
resume 
treatment, or 
discontinue at 
the discretion 
of the 
investigatorb. 
 
 
a Utilizing NCI Common Terminology Criteria for Adverse Events version 4.0 
b Patients who develop Grade 4 hyperuricemia or Grade 3 hypophosphatemia without clinical symptoms may 
continue study treatment without interruption at the discretion of the investigator. Nausea, vomiting or diarrhea must 
persist at Grade 3 or 4 despite maximal medical therapy, to require dose modification.  Administration of study 
treatment with food may reduce likelihood of nausea. 
 
Table 2: Dose Adjustments for Hematologic Toxicitiesa 
 
 
 
 
 
 
 
a Excluding lymphopenia unless associated with clinical event such as related infection. 
b NCI Common Terminology Criteria for Adverse Events version 4.0 
 
 
 
CTCAEb Grade 
Crizotinib Dosing 
≤ Grade 2 
No change in dose 
Grade 3 
Hold until ≤ Grade 2.  Resume 
at same dose level. 
Grade 4 
Hold until ≤ Grade 2.  Resume 
at next lower dose level. 


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Table 3: Dose adjustments for abnormal liver function related to study druga 
CTCAE Grade 
Crizotinib Dosing 
Grade 3 or 4 alanine 
aminotransferase (ALT) or 
aspartate aminotransferase (AST) 
elevation with Grade ≤ 1 total 
bilirubin 
Hold until ≤ Grade 1 or baseline, 
then resume at next lower dose level. 
Grade 2, 3 or 4 alanine 
aminotransferase (ALT) or 
aspartate aminotransferase (AST) 
elevation with concurrent Grade 2, 
3 or 4 total bilirubin elevation in the 
absence of cholestasis or hemolysis 
Permanently discontinue. 
 
 
aAbnormal elevations in AST or ALT or both, concurrent with abnormal elevations 
in total bilirubin (as defined in Section 9.5), with no other known cause of liver 
injury must be reported as a SAE to Pfizer per Section 9.8. 
 
Table 4: Dose adjustments for pneumonitis 
CTCAE Grade 
Crizotinib Dosing 
Any grade pneumonitis 
Permanently discontinue. 
 
Table 5: Dose adjustments for QTc prolongation 
Grade 3 QTc prolongation 
Hold until recovery to baseline or 
QTc < 481 msec, then resume at next 
lower dose level.  
Grade 4 QTc prolongation 
Permanently discontinue. 
 
 


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Table 6: Dose adjustments for bradycardia 
Grade 2, 3 bradycardia 
Hold until recovery to asymptomatic 
bradycardia or heart rate ≥ 60 bpm, 
evaluate concomitant medications.    
If contributing concomitant 
medication is identified and 
discontinued, or its dose is adjusted, 
resume crizotinib at previous dose 
after recovery (asymptomatic 
bradycardia or heart rate ≥ 60 bpm). 
If no contributing concomitant 
medication is identified, or if 
contributing concomitant medication 
is not dose adjusted or discontinued, 
resume at next lower dose level after 
recovery (asymptomatic bradycardia 
or heart rate ≥ 60 bpm). 
Grade 4 bradycardia 
If contributing concomitant 
medication is identified and dose 
adjusted or discontinued, resume 
crizotinib at 250 mg once daily after 
recovery (asymptomatic bradycardia 
or heart rate ≥ 60 bpm), with 
monitoring of pulse rate at least once 
per week for a minimum of three 
weeks  
Permanently discontinue crizotinib if 
no contributing concomitant 
medication is identified. 
 
 
 


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Table 7: Dose adjustments for visual disturbance 
Toxicitya 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Visual 
Disturbance 
 
Continue at the 
same dose 
level. Repeat 
ophthalmologic 
examination.b 
Continue at the 
same dose 
level. Repeat 
ophthalmologic 
examination.b 
Hold until 
recovery. 
Repeat 
ophthalmologic 
examination.b 
Resume 
treatment by 
reducing by 
one dose level. 
 
Permanently 
discontinue 
treatment. 
Repeat 
ophthalmologic 
examination.b 
a NCI Common Terminology Criteria for Adverse Events version 4.0 
b Ophthalmologic examination includes visual acuity, fundoscopy, and slit lamp and should be performed 
by an ophthalmologist. 
 
8. DATA AND SAFETY MONITORING PLAN 
 
8.1. 
Safety Monitoring 
This protocol will be monitored according to the processes in effect for all Levine 
Cancer Institute investigator- initiated studies and the protocol-specific monitoring 
plan, and will abide by standard operating procedures set forth by both the Atrium 
Health Office of Clinical and Translational Research and the Levine Cancer Institute.  
It is the responsibility of the Sponsor-Investigator to monitor the safety data for this 
study.  The Sponsor-Investigator, Statistician, and other Coordinating Center team 
members as needed will meet regularly to monitor subject consents, enrollment and 
retention, safety data for all subjects [including adverse events (AEs) for all grades and 
attributions, serious adverse events (SAEs)], study drug administration, and 
validity/integrity of the data. Documentation of these meetings will be kept with study 
records. SAEs will be reported to the IRB per their requirements.  Major protocol 
deviations that result in a threat to subject safety or the integrity of the study will be 
reported to the IRB per their requirements. The Sponsor-Investigator will submit data 


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26 
 
to the LCI Data and Safety Monitoring Committee according to the overarching LCI 
Data and Safety Monitoring Plan. 
 
8.2. 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the study 
protocol, institutional standard operating procedures (SOPs) Atrium Health and other 
applicable regulations and guidelines (e.g. GCP).  
 
Data will be collected on electronic Case Report Forms (eCRFs). 
 
Subjects will be monitored by Levine Cancer Institute Research Monitors routinely for 
data quality. This monitoring will be done by comparing source documentation to the 
eCRFs.  
 
The study database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures. Data 
queries requiring clarification will be generated and addressed by the appropriate 
research personnel. Only authorized personnel will make corrections to the study 
database and all corrections will be documented in an electronic audit trail. 
 
Any variation between source documentation and the data set will be discussed with 
the appropriate research personnel. 
 
8.3. 
Communication Between Investigational Sites 
Investigational sites will be required to report SAEs, problems with study drug 
administration, or any other problem that could affect the validity/integrity of the study 
data to the Sponsor-Investigator.  All investigational sites will record AEs using the 
eCRFs and SAEs using the SAE reporting function in the CTMS to the Sponsor.  
SAEs will be reported within 24 hours of the Investigator learning of the event.  Any 
problem impacting subject safety or data integrity should be communicated to the 
Sponsor-Investigator by email or phone as soon as possible but within 2 business days 
of the Investigator learning of the event. 
 
 
 
 
 
9. SAFETY DATA COLLECTION, RECORDING AND REPORTING 


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All subjects who receive at least one dose of study treatment will be evaluable for the 
safety analysis. All observations pertinent to the safety of the study treatment will be 
recorded and included in the final report. 
 
Safety variables include the following: treatment administration, AEs, and SAEs 
(whether related to crizotinib or not),  safety and tolerability, relationship to treatment 
and intensity will be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. All adverse events (Grades 1 – 5) will be 
determined by the Investigator and documented in subject study charts. 
 
9.1. 
Unanticipated Problem (UAP) Definition 
An UAP is any incidence, experience or outcome that is unexpected, given the 
information provided in research-related documentation (e.g. Investigator’s brochure, 
protocol, informed consent) and the study population characteristics that is related or 
possibly related to participation in the research study and places the participant at an 
increased risk.   
 
9.2. 
Adverse Event (AE) Definition 
An adverse event or adverse experience is any untoward medical occurrence in a study 
subject who is administered a study drug that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of the 
study drug, whether or not considered related to the study drug.  Pre-existing 
conditions that increase in frequency or severity or change in nature during or as a 
consequence of use of a drug in human clinical trials are also considered adverse 
events.  Adverse events may also include complications that occur as a result of 
protocol mandated procedures (e.g., invasive procedures such as biopsies). 
 
Any continuing medical condition or clinically significant laboratory abnormality with 
an onset date before the first date of study drug administration should be considered 
pre-existing and should be documented in the subject’s medical records and/or in the 
research chart. 
 
An AE does not include: 
• 
relapse or progression of the underlying malignant disease; however, the 
associated signs, symptoms, or diagnoses should be recorded as adverse events 
(e.g., “jaundice” due to new or increasing liver metastases, or “tumor pain” or 
“bone pain” due to progressive disease); 


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28 
 
• 
medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
 
transfusion).  The condition that leads to the procedure is the adverse event; 
• 
situations where an untoward medical occurrence has not occurred (e.g., 
 
hospitalization for elective surgery, social and/or convenience admissions); 
• 
overdose of either study drug or concomitant medication without any signs or 
symptoms unless the subject is hospitalized for observation; and  
• 
pregnancy (pregnancy during treatment should be reported as an SAE).  
 
Laboratory abnormalities are usually not recorded as adverse events; however, signs 
and/or symptoms that are associated with laboratory findings requiring study 
withdrawal, dose modification, or medical intervention (e.g., anemia requiring 
transfusions or hyperglycemia requiring treatment) or other abnormal assessments 
(e.g., ECG, radiographs, vital signs) must be recorded as adverse events if they meet 
the definition of an adverse event.  In addition, laboratory abnormalities marked as 
clinically significant by the Investigator should also be recorded as adverse events on 
the eCRF.  The Investigator will record the most severe grade of the clinically 
significant laboratory abnormality and will evaluate its relationship to the study drug 
and clinical condition if/when a clinically significant laboratory abnormality occurs.   
 
All adverse events (including event name, grade, start/stop date and attribution) will be 
documented in the medical record and/or research chart. 
 
The Investigator is responsible for verifying and providing source documentation for 
all adverse events and assigning the attribution for each event for all subjects enrolled 
on the trial. 
 
9.2.1. Adverse Event Attribution 
Descriptions and grading scales listed in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all AE 
reporting.  Each AE will be assigned an attribution to one of the following categories: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE is possibly 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. 


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For the purposes of statistical analyses, the relationship to study drug will be further 
dichotomized into the following categories: 
 
“Not Related”:  This includes events that are considered unlikely or unrelated to study 
drug.  In the Investigator’s opinion, the AE has an etiology other than the study drug 
(e.g., pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication).   
 
“Related”:  This includes events that are considered possibly, probably, or definitely 
related to study drug.  A temporal relationship exists between the event onset and 
administration of the study drug.  It cannot be readily explained by the subject’s 
clinical state, intercurrent illness, or concomitant therapies.  In the case of cessation or 
reduction of the dose, the event abates or resolves and reappears upon rechallenge.  
Ineffective study drug treatment should not be considered as causally related in the 
context of AE reporting.   
 
9.3. 
Suspected Adverse Reaction (SAR) Definition 
A SAR is an adverse event in which there is reasonable possibility that the study drug 
caused the adverse event as defined by 21 CFR 312.32.  The Investigator is 
responsible for judging whether it is a reasonable possibility that the study drug caused 
the adverse event. 
 
9.4. 
“Unexpected” Definition 
An AE or SAR is to be considered unexpected if the event is not listed in the current 
version of the Investigator Brochure (IB), package insert or is not listed in the severity 
or specificity observed.  Investigators should refer to the Safety Information section of 
the current IB and/or package insert for crizotinib, including the DCSI (development 
core safety information), for the expected side effects of crizotinib.  As with any agent, 
there is always the potential for unexpected AEs, including hypersensitivity reactions.   
 
9.5. 
Serious Adverse Event (SAE) Definition 
Adverse events may also be considered serious adverse events. An SAE is any 
adverse event, without regard to causality, that is life-threatening (i.e., causes an 
immediate risk of death) or that results in any of the following outcomes:  
• Death; 


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• In-patient hospitalization or prolongation of existing hospitalization; 
• Persistent or significant disability or incapacity (i.e., substantial disruption of 
the ability to conduct normal life functions);  
• Secondary malignancies (defined as new cancers, not transformations or 
progression of original disease),  
• Grade ≥ 2 Potential Sight Threatening (PST) (with the exception of Visual 
field defect, for which grade ≥ 3 is the standard)/Severe Visual Loss (SVL). 
Please refer to the list of terms that are considered indicative of a PST or SVL 
event later in this section*  
• Exposure to crizotinib during pregnancy or lactation; 
• Congenital anomaly or birth defect in the offspring of a subject who received 
study drug;  
• Occupational exposure to crizotinib; 
• Lack of effect of crizotinib if associated with an SAE 
• Any other medical event that, in the medical judgment of the Sponsor-
Investigator, may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the outcomes listed above is also considered an 
SAE. The following criteria are considered medically important events for this 
protocol and should be reported as SAEs: 
o  Hy’s Law Cases: 
▪ Subjects with AST/ALT and TBili baseline values within the 
normal range who subsequently present with AST OR ALT 
values >3 x ULN AND a TBili value >2 × ULN with no 
evidence of hemolysis and an alkaline phosphatase value < 2 x 
ULN or not available 
▪ For subjects with AST or ALT OR TBili baseline values above 
the ULN, the following threshold values are used in the 
definition mentioned above, as needed, depending on which 
value(s) are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the 
normal range: AST or ALT values > 2 times the 
baseline values AND >3 × ULN; or >8 × ULN 
(whichever is smaller). 
• Preexisting values of TBili above the normal range: 
TBili level increased from baseline value by an amount 
of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller). 
 
*Terms included as PST or SVL events: 


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Amaurosis, Amaurosis fugax, Blindness, Blindness cortical, Blindness day, Blindness 
night, Blindness transient, Blindness unilateral, Hemianopia, Hemianopia 
heteronymous, Hemianopia homonymous, Optic atrophy, Optic ischaemic 
neuropathy, Optic nerve disorder, Optic neuropathy, Quadranopia, Retinopathy, 
Sudden visual (or vision) loss, Toxic optic neuropathy, Tunnel vision, Visual cortex 
atrophy, Visual field defect, Visual pathway disorder, Retinal oedema, Retinal 
detachment, Maculopathy, Iritis, Uveitis, Visual field test abnormal.  
 
The occurrence of Grade ≥2 of any of these events should be treated as a SAE, except for Visual 
field defect, for which only Grade ≥3 should be treated as a SAE. Grade 2 events are considered 
to be PST and Grade ≥3 events are considered to be SVL. 
 
Planned hospitalizations: 
Elective surgeries that have been planned prior to subject enrollment in the study or 
for conditions existing prior to study enrollment do not need to be captured as SAEs, 
unless complications occur or the conditions are worse than the subject’s baseline. If 
there are complications, they should be clearly documented.  
 
A planned medical or surgical procedure is not, in itself, an SAE.    
 
9.6. 
Safety Reporting to the Sponsor 
SAEs will reported to the Sponsor-Investigator within 24 hours of investigator 
awareness (immediately if fatal or life-threatening) via the CTMS. 
 
SAEs will be reported from the time of enrollment through 30 days after the date of 
the last study drug administration.   
 
SAEs will be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, until progression has been stabilized, or until there has been 
acceptable resolution of the event. This may at times cause the follow-up period for 
SAEs to be greater than 30 days.  The above referenced 30-day time period applies 
even if the subject is taken off study treatment and initiated on new treatment during 
this time period. Similarly, the Sponsor-Investigator is responsible for following the 
subject during the required follow-up period even if the subject lives elsewhere or has 
been released from his or her care and is being treated by another provider. 
 
SAEs determined to be related to study treatment or procedures are reportable from 
informed consent throughout the duration of the subject’s participation in the study.  


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32 
 
All SAEs (including event name, grade, start/stop date and attribution) will be 
documented in the medical record and/or research chart and recorded on the eCRF for 
this protocol.  SAE attributions follow the same scale as described in Section 9.2.1. 
 
The Investigator is responsible for verifying and providing source documentation for 
all SAEs and assigning the attribution for each event for all subjects enrolled on the 
trial. 
 
9.7. 
Safety Reporting to the IRB 
All events occurring during the conduct of a protocol and meeting the definition of an 
UAP or SAE will be reported to the IRB per their reporting requirements.  
 
Protocol deviations will be reported to the IRB per their reporting requirements. 
 
9.8. 
Safety Reporting to Pfizer  
SAEs will be reported to Pfizer within 24 hours of the Sponsor-Investigator learning of 
the event (immediately if fatal or life-threatening).  SAEs are reportable to Pfizer from 
first dose of study drug through 28 days after last dose of study drug. SAEs 
determined to be related to study drug and reportable to Pfizer from first dose of study 
drug throughout the duration of the subject’s participation in the study.  
 
Exceptions for SAE reporting to Pfizer: 
• Any SAE identified in the protocol as anticipated to occur in the study 
population at some frequency independent of drug exposure, unless the 
Sponsor-Investigator assesses such an event as related to study drug 
• Any SAE judged by the Sponsor-Investigator to represent progression of the 
malignancy under study, unless it results in death within the SAE reporting 
period 
 
SAE reports should be completed using the Pfizer-provided Investigator-Initiated 
Research Serious Adverse Event Form.  
 
All reports shall be sent via facsimile to:  
Pfizer U.S. Clinical Trial Department 
Fax: 1-866-997-8322 
 
 
  
 
 
10. MEASUREMENT OF EFFECT 


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10.1. Anti-tumor Effect – Solid Tumor 
Response and progression will be evaluated in this study using the revised response 
evaluation criteria in solid tumors (RECIST) guideline version 1.1. 
 
10.1.1. Definition 
Evaluable for overall response.  Only those subjects who have measurable disease 
present at baseline and have received at least one dose of study therapy will be 
considered evaluable for overall response.  These subjects will have their response 
classified according to the definitions stated in Section 10.1.4.   
 
10.1.2. Disease Parameters 
Target lesions: When more than one measurable lesion is present at baseline 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 
and will be recorded and measured at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter), be representative of 
all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. 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. Lymph nodes merit special mention since they are normal anatomical 
structures which may be visible by imaging even if not involved by tumor. 
Pathological nodes which are defined as measurable and may be identified as 
target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only 
the short axis of these nodes will contribute to the baseline sum. The short axis of 
the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial 
plane). The smaller of these measures is the short axis. All other pathological 
nodes (those with short axis ≥ 10 mm but <15 mm) should be considered non-
target lesions. Nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters. If lymph nodes are 
to be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum diameters will be used as reference to further 


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34 
 
characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions: All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. 
 
10.1.3. Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and within 30 days prior to first dose of study therapy. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline throughout the study.  
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the anti-tumor effect of a treatment.  The 
tumor measurements will be documented on the eCRF.  
 
10.1.4. Response Criteria 
Response will be evaluated using RECIST 1.1 Criteria. 
 Complete Response: 
• Target lesion: Disappearance of all target lesions. Any pathological lymph  
 
 
nodes (whether target or non-target) must have reduction in short axis to  
 
 
<10 mm. 
• Non-target lesion: Disappearance of all non-target lesions. All lymph nodes   
 
must be non-pathological in size (<10 mm short axis). 
 
Partial Response: 
• Target lesion: At least a 30% decrease in the sum of diameters of target, 
 
taking as reference the baseline sum diameters. 
• Non-target lesion: Not applicable 
 
Stable Disease: 
• Target lesion: Neither sufficient shrinkage to qualify for a partial response,  
 
 
nor sufficient increase to qualify for progressive disease, taking as reference   
 
the smallest sum diameters while on study. 


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35 
 
• Non-target lesion: Not applicable. 
 
Progressive Disease: 
• Target lesion: At least a 20% increase in the sum of diameters of target  
 
 
lesions, taking as reference the smallest sum on study (this includes the  
 
 
baseline sum if that is the smallest on study). In addition to the relative  
 
 
increase of 20%, the sum must also demonstrate an absolute increase of at 
 
least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
• Non-target lesion: Unequivocal progression (as described in RECIST version   
 
1.1) of existing non-target lesions. (Note: the appearance of one or more new   
 
lesions is also considered progression). 
 
Non-Complete Response / Non-Progressive Disease: 
• Target lesion: Not applicable 
• Non-target lesion: Persistence of one or more non-target lesion(s) 
  
Table 8: Summary of RECIST: 
 
 
 
Target 
Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category also requires 
CR 
CR 
No 
CR 
Documented at least once 
 4 weeks from baseline 
CR 
Non-CR/Non-PD 
No 
PR 
Documented at least once 
 4 weeks from baseline 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Documented at least once 
 4 weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
N/A 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, and  
NE = inevaluable. 


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When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. This means 
that subjects with CR may not have a total sum of the diameters of ‘zero’. 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as ‘symptomatic deterioration’. Every effort should be made to document 
objective progression even after discontinuation of treatment. Symptomatic 
deterioration is not a descriptor of an objective response: it is a reason for stopping 
study therapy.  It is included as part of the criteria for determination of Progression 
Free Survival.  The objective response status of such subjects is to be determined by 
evaluation of target and non-target disease. 
The development of pain or alternate symptoms requiring palliative radiotherapy 
constitutes subjective clinical disease progression, and study treatment should be 
stopped.   
For equivocal findings of progression (e.g. very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is confirmed, 
the date of progression should be the earlier date when progression was suspected. 
 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1. Sample Size  
Subjects will be enrolled in parallel to the three molecularly defined cohorts as 
described in Section 4.2.  Due to the observed prevalence of the molecular expression 
patterns, the Cohort 1 Stage 1 sample size is designed to be larger than that of Cohorts 
2 and 3.  
For Cohort 1, a 2-stage design was selected, where the Stage 1 sample size will be 14 
subjects.  Objective response (OR) will be evaluated on the Stage 1 subjects and, if 
two or more responders (CR or PR) are observed in Stage 1, the cohort will be 
expanded. If Cohort 1 is expanded, an additional 16 subjects will be enrolled in the 
second stage, for a total of 30 Cohort 1 subjects. This design will be used to test the 
hypothesis that the ORR for a cohort of subjects is less than or equal to 5%.  If 
objective responses occur in at least 5 of 30 subjects, the null hypothesis will be 


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rejected and the use of crizotinib for treatment of patients with previously treated 
metastatic urothelial carcinoma may be considered for further evaluation.  Based on an 
alpha = 0.05 significance level, this sample size will provide at least 90% power to 
reject the null hypothesis, assuming the overall response rate (ORR) is 30%. 
A 2-stage design was selected so that the Stage 1 sample size was minimized for 
Cohorts 2 and 3 (due to the low prevalence of the c-MET and RON protein expression 
patterns in those cohorts) while the alpha and power constraints as described below 
were met.  This will be accomplished with a Stage 1 sample size of 7 subjects in each 
of the 2 cohorts.  Objective response (OR) will be evaluated on the Stage 1 subjects.  If 
one or more responders (CR or PR) are observed in Stage 1, the cohort may be 
considered for expansion.  If either molecular cohort 2 or 3 is expanded, an additional 
25 subjects will be enrolled in the second stage (total of 32 subjects in that cohort).  
This design will be used to test the hypothesis that the ORR for a cohort of subjects is 
less than or equal to 5%.  If objective responses occur in at least 4 of 32 subjects, the 
null hypothesis will be rejected and the use of crizotinib for treatment of patients with 
previously treated metastatic urothelial carcinoma may be considered for further 
evaluation.  Based on an alpha = 0.05 significance level, this sample size will provide 
at least 90% power to reject the null hypothesis, assuming the ORR is 30%. 
More detail regarding selection of the molecularly defined cohort for Stage 2 
expansion is provided in Section 4.2.   
11.2. Endpoint Definitions 
 
11.2.1. Objective Response 
 
Objective response will be determined for each subject as a binary variable 
indicating whether or not the subject achieved a best overall response of CR or PR 
as determined by RECIST 1.1.  For the purposes of response determination, a 
confirmatory scan for CR and PR is required. 
 
 
11.2.2. Progression-Free Survival 
PFS is defined as the duration of time from enrollment to the study to first 
occurrence of either progressive disease or death. Disease progression can be 
objectively determined as per Section 10.1.4 (RECIST 1.1 criteria) or progression 
can be clinically determined by the investigator. Evidence for clinical progression 
must be documented in the medical records. For objective disease progression, the 
date of PD is the date of the radiologic assessment that identified RECIST-defined 
progressive disease. For clinical disease progression, the date of PD is the date 


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that the clinician makes the determination of disease progression. If the subject 
died without documented disease progression, the date of progression will be the 
date of death. For surviving subjects who do not have documented disease 
progression, PFS will be censored at the date of last radiologic assessment. For 
subjects who receive subsequent anti-cancer therapy prior to documented disease 
progression, PFS will be censored at the date of last radiologic assessment prior to 
the commencement of subsequent therapy. Subjects who have an initial PFS event 
immediately following 2 or more consecutive missed assessments will be 
censored at the date of the last assessment prior to those missed assessments. For 
participants with only one missed assessment, the documented progressive disease 
status and assessment date will be used. 
 
11.2.3. Overall Survival 
Overall survival is defined as the duration from enrollment date to the date of 
death from any cause.  Subjects who are alive or lost to follow-up at the time of 
the analysis will be censored at the last known date they were alive. 
 
11.2.4. Safety Endpoints 
Safety endpoints will include treatment administration (dose intensity, planned 
dose intensity, and relative dose intensity), AEs, SAEs, and deaths while on study 
therapy.  
 
11.3. Analysis Populations 
Efficacy and safety analyses will be conducted on the population of subjects who 
begin crizotinib treatment.  The date of initiation of crizotinib treatment will be the 
enrollment date.  Analysis of objective response rate will be conducted on those 
subjects in the efficacy population with measurable disease present at baseline. 
 
11.4. Analysis Methods 
 
11.4.1. Timing of Analysis 
 
For each cohort, the Stage 1 analysis will occur after the best overall response has 
been determined for all Stage 1 subjects.  The primary analysis of an expanded cohort 
will be conducted after the best overall response has been determined for all subjects 
in that cohort.  Secondary analyses of all cohorts will be conducted after the overall 
PFS censoring rate reaches 20% or when all surviving subjects have at least 1 year of 
follow-up, whichever occurs first.  A final analysis will be conducted after the overall 


Protocol Number:  LCI-GU-URO-CRI-001 
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39 
 
survival censoring rate reaches 20% or after all surviving subjects have at least 2 years 
of follow up.  
 
11.4.2. Subject Disposition 
An accounting of all consenting subjects will be provided at the end of the study. This 
will include a breakdown of subjects who consented, were treated, discontinued 
treatment, died, and were lost to follow-up or withdrew consent. 
 
11.4.3. Baseline Subject and Disease Characteristics 
A summary of subject demographics and disease-related characteristics will be 
completed and subject medical history will be assessed. 
 
11.4.4. Efficacy Analyses 
 
11.4.4.1. Primary Analysis 
The frequency and proportion of responders will be calculated for the 
cohort that was expanded to Stage 2.  A corresponding 95% confidence 
interval will be estimated using the Clopper-Pearson method.  A one-sided 
test for binomial proportions using the rejection regions described in 
Section 11.1 will be carried out, testing the null hypothesis that the ORR is 
less than 5%.  Based on the 2-stage design and corresponding sample size 
calculations described in Section 11.1, if there are at least 5 responders in 
Cohort 1 or 4 responders in Cohort 2 or 3, the null hypothesis can be 
rejected. 
Based on pooling all three molecular cohorts of subjects, logistic 
regression techniques will be used to correlate response rate to c-MET and 
RON levels.  This will include multiple regression models incorporating 
key baseline subject and disease characteristics.  
 
11.4.4.2. Secondary Analyses 
Overall and progression free survival will be analyzed using Kaplan Meier 
techniques.  Medians, 25th, and 75th percentiles will be estimated.  
Selected landmarks for OS (1, 3, 6, and 9 month survival rates) and PFS 
(1, 3, and 6 month PFS rates) will form the Kaplan Meier curve.   Based 
on pooling all three molecular cohorts of subjects, Cox proportional 
hazards models will be used to correlate OS and PFS to c-MET and RON 


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40 
 
levels.  This will include multiple regression models incorporating key 
baseline patient and disease characteristics. 
 
11.4.5. Safety Analyses 
The number of cycles administered, dose intensity, and relative dose 
intensity will be summarized quantitatively. 
Incident rates for treatment emergent adverse events, SAEs, and deaths 
while on study therapy will be summarized. Treatment emergent adverse 
events are defined as follows: 
• An adverse event that occurs after treatment start that was not 
present at the time of treatment start; OR 
• An adverse event that increases in severity after treatment start if 
the event was present at the time of treatment start. 
 
11.4.6. Exploratory Analyses 
 
Cox proportional hazards models and logistic regression will be used to 
assess the correlation between additional baseline biomarkers with clinical 
outcomes. 
 
11.5. Interim Analyses 
 
For each molecular cohort an evaluation of ORR will be made after Stage 1 as 
described in Section 4.2.    
 
12. BIOMARKER ANALYSIS 
 
12.1. 
Immunohistochemistry 
Tumor specimens as defined in section 4.4 from all subjects will be assessed for 
c-MET and RON protein expression by immunohistochemistry in a semi-
quantitative fashion for the purpose of determining subject eligibility for 
enrollment into open study cohorts.  Protein expression will be graded based on 
the percentage of positive staining tumor cells.  Specimens with 0-9% of tumor 
cells staining positive will be considered negative for protein expression for the 
purposes of this study.  c-MET and RON protein expression will also be 
correlated with primary and secondary endpoints. 
 
12.2. 
Genomic Analysis 


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41 
 
Additional specimens from selected subjects may also be assessed for other 
markers including c-MET gene amplification by fluorescence in situ hybridization 
or undergo tumor genomic sequencing for the purpose of therapeutic biomarker 
discovery.    
 
13. STUDY COMPLETION 
 
13.1. 
Completion 
The study will be considered complete when one or more of the following 
conditions is met: 
• 
All subjects are dead and/or withdrawn from the study. 
• 
All subjects have discontinued from the study. 
• 
The IRB, LCI DSMC, Sponsor-Investigator or Pfizer discontinues the    
study because of safety considerations. 
• 
The Sponsor-Investigator defines an administrative or clinical cut-off date. 
 
13.2. 
Termination 
The study will be terminated when one or more of the following conditions occur: 
If risk-benefit ratio becomes unacceptable owing to, for example: 
• 
Safety findings from this study (e.g. SAEs) 
• 
Results of any interim analysis 
• 
Results of parallel clinical studies 
• 
Results of parallel animal studies (e.g. toxicity, teratogenicity,  
   carcinogenicity or reproduction toxicity). 
• 
If the study conduct (e.g. recruitment rate; screen failure rate; withdrawal 
rate; data quality; protocol compliance) does not suggest a proper 
completion of the trial within a reasonable time frame. 
The Sponsor-Investigator has the right to close the trial at any site and at any time. 
For any of the above closures, the following applies: 
• 
Closures should occur only after consultation between involved parties. 
• 
All affected institutions must be informed as applicable according to local 
law.   
• 
In case of a partial study closure, ongoing subjects, including those in 
follow-up, must be taken care of in an ethical manner. 
 
 
Details for individual subject's withdrawal can be found in Section 4.9.3.  
 


Protocol Number:  LCI-GU-URO-CRI-001 
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42 
 
14. RETENTION OF RECORDS 
 
Essential documentation (e.g. adverse events, records of study drug receipt and dispensation), 
including all IRB correspondence, will be retained for at least 2 years after the investigation 
is completed.  Documentation will be readily available upon request. 
 
15. ETHICAL AND LEGAL ISSUES 
15.1. 
Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and  
documentation of this study, are designed to ensure that the Investigator abides by 
Good Clinical Practice (GCP) guidelines and under the guiding principles detailed 
in the Declaration of Helsinki.  The study will also be carried out in keeping with 
applicable local law(s) and regulation(s). 
 
Documented approval from appropriate agencies (e.g. IRB) will be obtained for 
all participating centers before start of the study, according to GCP, local laws, 
regulations and organizations.  When necessary, an extension, amendment or 
renewal of IRB approval must be obtained and forwarded to Pfizer. 
 
Strict adherence to all specifications laid down in this protocol is required for all 
aspects of study conduct. The Investigators may not modify or alter the 
procedures described in this protocol.   
 
Modifications to the study protocol will not be implemented by the Sponsor-
Investigator without discussion and agreement by Pfizer.  However, the 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to the trial subjects without prior approval from 
applicable agencies.  As soon as possible, the implemented deviation or change, 
the reasons for it and if appropriate the proposed protocol amendment should be 
submitted to the appropriate agencies.  Any deviations from the protocol must be 
explained and documented by the Investigator. 
 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the 
sites in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Sponsor-Investigator is responsible for overseeing 
the treatment of all study subjects.  The Sponsor-Investigator must assure that all 
study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all applicable regulations and guidelines 
regarding clinical trials both during and after study completion. 


Protocol Number:  LCI-GU-URO-CRI-001 
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43 
 
 
The Sponsor-Investigator will be responsible for assuring that all the required data 
will be collected and properly documented. 
 
15.2. 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. 
 
15.3. 
Publication 
The Sponsor-Investigator must send a draft manuscript of the publication or 
abstract to Pfizer prior to submission of the final version for publication or 
congress presentation. All relevant aspects regarding data reporting and 
publication will be part of the contract between Pfizer and the Sponsor-
Investigator. 
 
The Sponsor-Investigator will ensure that the information regarding the study be 
publicly available on the internet at www.clinicaltrials.gov.  
 
 


Protocol Number:  LCI-GU-URO-CRI-001 
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44 
 
REFERENCES 
 
1. 
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for 
clinicians. Jan-Feb 2014;64(1):9-29. 
2. 
von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus 
methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder 
cancer: results of a large, randomized, multinational, multicenter, phase III study. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology. Sep 
2000;18(17):3068-3077. 
3. 
Apolo AB, Kwiatkowski DJ. Targeting molecular aberrations in urothelial carcinoma. 
American Society of Clinical Oncology educational book / ASCO. American Society of 
Clinical Oncology. Meeting. 2013;2013:195-199. 
4. 
Zhang YW, Vande Woude GF. HGF/SF-met signaling in the control of branching 
morphogenesis and invasion. Journal of cellular biochemistry. Feb 1 2003;88(2):408-
417. 
5. 
Jeffers M, Rong S, Vande Woude GF. Hepatocyte growth factor/scatter factor-Met 
signaling in tumorigenicity and invasion/metastasis. Journal of molecular medicine. Sep 
1996;74(9):505-513. 
6. 
Peters S, Adjei AA. MET: a promising anticancer therapeutic target. Nature reviews. 
Clinical oncology. Jun 2012;9(6):314-326. 
7. 
Follenzi A, Bakovic S, Gual P, Stella MC, Longati P, Comoglio PM. Cross-talk between 
the proto-oncogenes Met and Ron. Oncogene. Jun 22 2000;19(27):3041-3049. 
8. 
Benvenuti S, Lazzari L, Arnesano A, Li Chiavi G, Gentile A, Comoglio PM. Ron kinase 
transphosphorylation sustains MET oncogene addiction. Cancer research. Mar 1 
2011;71(5):1945-1955. 
9. 
Wang P, Nishitani MA, Tanimoto S, et al. Bladder cancer cell invasion is enhanced by 
cross-talk with fibroblasts through hepatocyte growth factor. Urology. Apr 
2007;69(4):780-784. 
10. 
Cheng HL, Liu HS, Lin YJ, et al. Co-expression of RON and MET is a prognostic 
indicator for patients with transitional-cell carcinoma of the bladder. British journal of 
cancer. May 23 2005;92(10):1906-1914. 
11. 
Cheng HL, Trink B, Tzai TS, et al. Overexpression of c-met as a prognostic indicator for 
transitional cell carcinoma of the urinary bladder: a comparison with p53 nuclear 
accumulation. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. Mar 15 2002;20(6):1544-1550. 
12. 
Sanchez-Carbayo M, Socci ND, Lozano JJ, Haab BB, Cordon-Cardo C. Profiling bladder 
cancer using targeted antibody arrays. The American journal of pathology. Jan 
2006;168(1):93-103. 
13. 
Bottaro DP, Lee YH, Agarwal PK, Apolo AB. Met signaling in urothelial carcinoma of 
the bladder. ASCO Meeting Abstracts. June 11, 2014 2014;32(15_suppl):4551. 
14. 
Rodig SJ, Shapiro GI. Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK 
receptor tyrosine kinases. Current opinion in investigational drugs. Dec 
2010;11(12):1477-1490. 


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15. 
Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-Met, PF-
2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and 
antiangiogenic mechanisms. Cancer research. May 1 2007;67(9):4408-4417. 
16. 
Yamazaki S. Translational pharmacokinetic-pharmacodynamic modeling from 
nonclinical to clinical development: a case study of anticancer drug, crizotinib. The AAPS 
journal. Apr 2013;15(2):354-366. 
17. 
Okamoto W, Okamoto I, Arao T, et al. Antitumor action of the MET tyrosine kinase 
inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. 
Molecular cancer therapeutics. Jul 2012;11(7):1557-1564. 
18. 
Lennerz JK, Kwak EL, Ackerman A, et al. MET amplification identifies a small and 
aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness 
to crizotinib. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. Dec 20 2011;29(36):4803-4810. 
19. 
Culine S, Flechon A, Guillot A, et al. Gemcitabine or gemcitabine plus oxaliplatin in the 
first-line treatment of patients with advanced transitional cell carcinoma of the 
urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the 
French Genitourinary Tumor Group (GETUG V01). European urology. Dec 
2011;60(6):1251-1257. 
20. 
Juanpere N, Agell L, Lorenzo M, et al. Mutations in FGFR3 and PIK3CA, singly or 
combined with RAS and AKT1, are associated with AKT but not with MAPK pathway 
activation in urothelial bladder cancer. Human pathology. Oct 2012;43(10):1573-1582. 
21. 
Cancer Genome Atlas Research N. Comprehensive molecular characterization of 
urothelial bladder carcinoma. Nature. Mar 20 2014;507(7492):315-322. 
 
 
 
 
 
 
 

ICF_001.pdf: 
Official Title: LCI-GU-URO-CRI-001: A Phase II Study of Crizotinib in Patients With c-MET or RON-
Positive Metastatic Urothelial Cancer
NCT02612194
IRB-Approved Date: 7/6/2018


Levine Cancer Institute / Protocol Number LCI-GU-URO-CRI-001 
Page 1 of 11 
 
 
Earle Burgess, MD 
Advarra IRB Approved Version 6 Jul 2018 
 
 
 
 
CAROLINAS HEALTHCARE SYSTEM 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
 
Sponsor / Study Title: 
  
Levine Cancer Institute / “A PHASE II STUDY OF 
CRIZOTINIB IN PATIENTS WITH c-MET OR RON-
POSITIVE METASTATIC UROTHELIAL CANCER” 
 
Protocol Number: 
 
LCI-GU-URO-CRI-001 
Principal Investigator: 
(Study Doctor) 
 
Earle Burgess, MD 
 
Telephone: 
 
(24 Hours) 
(24 Hours) 
 
Address: 
Levine Cancer Institute 
 
 
 
 
INTRODUCTION 
 
The study doctor and his associates (the investigators) are asking you to participate in a research 
study at Levine Cancer Institute (LCI) and Carolinas HealthCare System (CHS) of a study with 
crizotinib (Xalkori®) in the treatment of subjects with metastatic urothelial cancer of the bladder, 
upper (ureter or renal pelvis) or lower (urethra) urinary tracts.  The purpose of this study is to see if 
this experimental drug has a potential benefit in subjects with stage 4 urothelial cancer.  You are 
being asked to take part in this study because you have metastatic urothelial cancer, have received 
treatment with cisplatin or carboplatin in the past, and your tumor contains certain proteins.   
 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to make your 
decision about taking part. You have also been told that you have the option not to participate. You 
may discuss your decision with your friends and family. You can also discuss it with your health care 
team. If you have any questions, you can ask your study doctor for more explanation.  
 
This study is being carried out under the sponsorship of Levine Cancer Institute (LCI). Pfizer Inc. is 
the company that makes crizotinib that will be used in this study and is providing the drug for this 
study.  
 
WHY IS THIS STUDY BEING DONE? 


Levine Cancer Institute / Protocol Number LCI-GU-URO-CRI-001 
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Earle Burgess, MD 
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Urothelial cancer that has spread to another part of the body and is resistant to treatment is 
considered very difficult to treat.  The most common approved treatment includes chemotherapy 
containing either cisplatin or carboplatin with other medications.  No currently approved standard 
of care exists for subjects whose cancers worsen after this initial treatment.  Additional 
chemotherapy medications often prevent cancer growth for no more than three months. 
 
This study tests crizotinib used alone in subjects with urothelial cancer, previously treated with 
chemotherapy, and whose tumors have certain proteins. Proteins are complex natural substances 
essential to the structure and function of all living cells.  These proteins, c-MET or RON, may 
trigger molecular pathways that are involved in the growth and spread of bladder or upper urinary 
tract cancer.  Crizotinib is a drug taken by mouth that blocks these pathways.  Early laboratory 
research suggests that crizotinib may benefit patients with urothelial and other cancers with these 
molecular pathways.  Although crizotinib is currently approved by the Food and Drug 
Administration (FDA) for the treatment of lung cancer that has spread, its use in subjects with 
urothelial cancer is experimental and the potential benefits are not yet known. 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
You will be one of approximately 53 subjects participating in this study at multiple centers in the 
United States.  
 
 
HOW THE STUDY WORKS 
 
Before you begin the study (Baseline) 
 
In order to participate in this study, you will need to review, sign and date this consent form. We 
have previously collected information from your medical record to determine your eligibility to 
enroll on the study. We have also collected information about your demographics (i.e. age, race, 
etc.), medical history, your current disease, any treatments received before, and any medications you 
are taking.  Please let us know if any of this information has changed since your last consent.  
 
If not already done within 30 days before starting study treatment on the study, you will have scans 
of the chest, abdomen, pelvis and bones. The scans performed will be either a computerized 
tomography (CT) of your chest, abdomen, and pelvis (x-ray machine that uses a computer to take 
pictures or computerized tomography) and a bone scan (produces pictures of internal body parts 
using small amounts of radioactive material called a radionuclide scan), or a PET/CT scan (using an 
imaging scanner called a Positron Emission Tomography (PET) in combination with a CT scan). 
The method of scan performed will be determined by your study doctor. We will also collect blood 
for laboratory tests. The labs will help evaluate your kidneys, liver, other organ function, and blood 
cell counts.  
 
Please tell your study doctor if you have noticed new visual floaters or flashes of light in your eyes in 
the last three months. An eye exam performed by an ophthalmologist may be necessary prior to 
study entry.  
 


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Earle Burgess, MD 
Advarra IRB Approved Version 6 Jul 2018 
 
 
A urine pregnancy test will also be done for women who can have children. The results of the 
pregnancy test must be negative in order to be in the study.  
 
You will also have an electrocardiogram (EKG) to evaluate the electrical activity of your heart.  
 
The sample of your tumor has already been tested and we have determined that it does contain the 
proteins needed to qualify for study participation.  
 
If you qualify for the study and agree to participate, you will be enrolled and we will make 
arrangements to supply you with the study drug. The first dose of study drug should be taken on the 
day of your enrollment visit on Cycle 1 Day 1.  
 
During the study (Intervention) 
 
During the study treatment period, each 4-week period of time is considered a “cycle.”  The cycles 
are repeated every 28 days, unless a study treatment delay is needed due to side effects. Study 
treatment will be given to you to take home. One 250mg crizotinib capsule should be taken twice 
daily with or without food. Your dose may be adjusted by your study doctor if you experience 
significant side effects. If side effects or complications from study treatment occur, your study 
doctor may tell you to temporarily stop taking the study drug or to adjust the dose.   
 
In addition to taking crizotinib twice daily, you must also do the following:  
• Swallow the capsule whole. Capsules should not be broken or crushed.  
• Keep the tablets in their original bottle.  
• If you miss a dose, you should take it as soon as possible unless the next dose is due within 6 
hours. 
• If vomiting occurs after taking a dose, an extra dose should not be taken. 
• Do not eat grapefruit or drink grapefruit juice.  
• Do not take any new (including herbal) medication without first speaking with your study 
doctor or research staff.  
• Use caution when driving a car, using machinery, or doing anything that needs you to be 
alert if you experience changes in your vision, dizziness and tiredness. 
  
Every two weeks for the first eight weeks, you will meet with your study doctor and/or clinical study 
staff. After that, you will meet with your study doctor and/or clinical study staff every four weeks 
for as long as you are being treated on the study. During these visits, we will take some blood  to 
periodically check your blood counts and kidney and liver  function. We will also check your vital 
signs and weight and ask about any side effects you may have. We may ask that you have additional 
office visits and/or laboratory testing if you have symptoms or side effects. An EKG will be done 
28 days after your first dose of study drug (+/- 7 days) and then only repeated if your study doctor 
feels it is necessary. 
 
A CT scan of your chest, abdomen, and pelvis or PET/CT scan will be planned every eight weeks, 
± 7 days from cycle 1 day 1 while you are receiving the study drug. If your study doctor is following 


Levine Cancer Institute / Protocol Number LCI-GU-URO-CRI-001 
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Earle Burgess, MD 
Advarra IRB Approved Version 6 Jul 2018 
 
 
your disease using CT scan, a bone scan will also be done at the same interval if you had evidence of 
bone metastases (spread) to your bones at your screening scans. Also, a bone scan may be done if 
you have new bone pain or other signs that the cancer may be spreading or worsening in your 
bones. 
 
You will continue to receive the study drug until your cancer gets worse, until side effects become 
unbearable even if they are being medically treated, or until you are too ill to continue. You also 
have the option to voluntarily discontinue study treatment and withdraw from the study at any time.  
 
Your study doctor may also choose to withdraw you from the study for any reason.  
 
After you complete the intervention (Follow-up) 
 
Within 30 days of your last dose of study drug, you will come in and meet with your study doctor 
and/or clinical study staff. At this visit, you will have blood drawn.  
 
Following this visit, study staff will contact you every six months after you stop taking the study 
drug for follow-up. 
 
RISKS 
 
Crizotinib has been approved by the FDA for the treatment of certain metastatic lung cancers, so 
the risks of the drug have been studied extensively for these other disease types. While you are on 
this study, you are at risk for the side effects listed below. Most people do not experience all of the 
side effects listed. A side effect may get worse during the course of study treatment, or more side 
effects may develop as the study treatment goes on. Your study doctor will closely monitor and 
treat/prevent the side effects you might have through the study period. The side effects of crizotinib 
are:  
 
Most Common (25% or more of patients):  
• 
Vision problems. These problems usually happen within 1 week of starting the study drug. 
Vision problems can be severe and may cause partial or complete loss of vision in one or 
both eyes. Tell your study doctor right away if you have any change in vision, such as double 
vision, flashes of light, blurred vision, light hurting your eyes, new or increased floaters. 
• 
Swelling and redness of the eyelids 
• 
Change or loss of taste 
• 
Decreased appetite 
• 
Dizziness 
• 
Nausea 
• 
Diarrhea 
• 
Vomiting 
• 
Constipation 
• 
Edema or swelling of your hands and feet 
• 
Abnormal liver function or damage 
• 
Low white blood cells, which can cause infection 


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Earle Burgess, MD 
Advarra IRB Approved Version 6 Jul 2018 
 
 
• 
Fatigue or feeling tired 
• 
Upper Respiratory Infection 
• 
Damage to the nerves that may interfere with walking or organ function which may cause 
numbness, tingling, weakness, or pain in the muscles 
Less Common (less than 25% of patients):  
• Slowing of heart rate or irregular heart rhythm; may cause fainting 
• Acid reflux (heartburn) 
• Blood clot in the lung that may cause pain or shortness of breath 
• Muscle spasms 
• Rash 
• Fever 
• Increased or decreased weight 
• Headache 
• Blood testosterone decreased 
• Esophagitis (inflammation of the esophagus) 
 
Some other rare but serious risks include but are not limited to: 
 
Hepatotoxicity (Abnormal liver function or damage) 
Symptoms of abnormal liver function may include yellowing of your eyes, decreased appetite, 
darkening or change to your urine color to orange or brown, bleeding or bruising more easily, 
abdominal pain, itching, nausea or severe fatigue.  You must report these symptoms and inform 
your study doctor immediately.  
 
Pulmonary Symptoms (Lung problems or pneumonitis) 
If you experience any new or worsening pulmonary symptoms such as difficulty breathing, shortness 
of breath, cough with or without mucus, or fever, you must report these symptoms and inform your 
study doctor immediately. Crizotinib can cause scarring of the lungs.  
 
Bradycardia (slow heart rate) 
Symptoms of bradycardia include dizziness, lightheadedness, and syncope or fainting. If you 
experience any of these while taking the study drug, you must report these symptoms and inform 
your study doctor about the use of any heart or blood pressure medications. 
 
Other Risks 
 
Computed Tomography (CT), Positron Emission Tomography (PET) and Radionuclide 
Bone Scan Risks 
 
 The CT, PET/CT, and bone scans will expose you to some radiation.  Radiation levels are within 
acceptable limits.  Ask the study doctor about the risk from these scans in this study. IV contrast dye 
given with a CT scan may cause an allergic reaction or kidney function abnormality. 


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Earle Burgess, MD 
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Blood Drawing Risks 
 
 During this study, small amounts of blood will be drawn from a vein to perform tests that allow 
your study doctors to see how you are doing. Drawing blood may cause pain where the needle is 
inserted, and there is a small risk of bruising and/or infection at the place where the needle is 
inserted. Some people experience dizziness, upset stomach, or fainting when their blood is drawn. 
 
Reproductive Risks 
 
Because of risks of fetal harm, women who are pregnant cannot participate in this study and women 
of child-bearing potential must not become pregnant while on the study drug. Women on this study 
and the partners of men on this study must use adequate forms of contraception while on study 
treatment and for at least 90 days after last taking study drug. If you or your partner becomes 
pregnant during the study, you must inform your study doctor immediately. 
 
Highly effective methods 
• Male sterilization (vasectomy). For female subjects, the vasectomized male partner 
should be the only partner 
• True abstinence, if this is your preferred and usual lifestyle 
 
Effective methods 
• Placement of intrauterine device or intrauterine system 
• Condom with spermicidal foam/gel/film/cream/suppository 
• Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/ suppository 
• Hormonal contraceptives 
 
Unacceptable methods 
• Abstinence at certain times of the cycle only, such as during the days of ovulation or 
after ovulation (based on symptoms or temperature) 
• Pre-ejaculatory withdrawal 
 
It is not known whether the study drug is secreted in breast milk. Because many drugs are secreted 
in breast milk, women who are breastfeeding are not eligible for this study. 
 
Unknown Risks 
 
You might have side effects or discomforts that are not listed in this form.  Some side effects may 
not be known yet.  New ones could happen to you.  Tell the study doctor or study staff right away if 
you have any problems. 
 
WILL I BENEFIT FROM PARTICIPATING IN THIS STUDY? 
 


Levine Cancer Institute / Protocol Number LCI-GU-URO-CRI-001 
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Earle Burgess, MD 
Advarra IRB Approved Version 6 Jul 2018 
 
 
If you agree to take part in this study, there may or may not be direct medical benefit to you. The 
use of crizotinib in metastatic urothelial cancer is experimental and the potential benefits for its use 
are unknown. Other subjects with cancer may benefit in the future. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
 
You may choose not to participate in this study. Instead of being in this study, your options include 
but are not limited to:  
 
• Other investigational drugs  
• Treatment with other anticancer drugs  
• No therapy with comfort care only  
 
Please talk to your study doctor about these options and their potential risks and benefits. Please ask 
any questions you may have and take as much time as you need to make your decision. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
 
You and/or your health plan/insurance will need to pay for all routine care procedures. Levine 
Cancer Institute will provide you with the study drug, crizotinib, at no charge. There is no additional 
cost to you to take part in this study. Some health insurance plans may not cover certain procedures 
and medical treatments. You may wish to discuss coverage with your insurance company before 
agreeing to participate in this research study.  
 
You will not receive payment for taking part in this study.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.    
You can print a copy of the “Clinical Trials and Insurance Coverage” information from this web 
site.  Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask 
them to send you a free copy.  
 
STUDY STAFF PAYMENT/FINANCIAL DISCLOSURE 
 
None of the doctors asking you to participate in this study has received or will receive money or 
other benefits for personal use from the study sponsor.  However, the sponsor will give money or 
other benefits to a research fund, foundation, educational institution, or other organization with 
which the doctor or study staff is associated. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
 
If you become ill or are hurt while you are in the study, get the medical care that you need right 
away. 
 


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In the event that you are harmed as a result of your participation in this study, inform your study 
doctor immediately so you can access medical treatment. You and/or your health plan will be 
charged for this treatment in the usual manner. The study will not pay for standard medical 
treatment.  
 
By signing this form, you do not waive any of the legal rights that you may have. You still have the 
right to make a claim through the legal system even if you sign this form, accept medical care, or 
accept payment for medical expenses. 
 
CONFIDENTIALITY 
 
The records of this study will be kept private.  In any sort of report we might publish, we will not 
include any information that will make it possible to identify a patient.  Your record for this study 
may, however, be reviewed and/or photocopied, by Levine Cancer Institute, Carolinas HealthCare 
System, or by representatives of the Food and Drug Administration or other government agencies.  
To that extent, confidentiality is not absolute. 
 
To ensure that your information collected for this study will be kept private, your name will not be 
used whenever possible.  A code will be used instead of your name.  All of your study data will be 
kept in a secure location. 
 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
If you wish to take part in this clinical study, you will be asked to sign this consent form.  It allows 
the study sponsor and the study investigator to collect, process and pass on to the sponsor 
organizations any relevant personal health information collected from you during the study.  These 
are activities routinely carried out during all clinical studies. 
 
You have been told that personal information about you (including sensitive personal health 
information, such as your medical history and your racial/ethnic origin if relevant to the study) will 
be reviewed, collected on a computer database, stored in electronic or manual files, audited, and/or 
otherwise processed by: 
 
• the study doctor and study staff, 
• the study sponsor and/or its associated companies, Levine Cancer Institute, 
• regulatory or other governmental authorities of the United States and other countries, 
• other persons authorized by the study sponsor, 
• Carolinas HealthCare System employees, 
• other persons or agencies as required by law or allowed by federal regulations. 
 
You have been told that your personal data are being collected and processed to: 
 
• check your suitability to take part in the study, 
• monitor your treatment with the study drug, 
• compare and pool study treatment results with those of other subjects in clinical studies, 


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Earle Burgess, MD 
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• support the development of the study drug, 
• support the licensing application for regulatory approval of the study drug in the world  
• support the marketing, distribution, sale and use of the study drug anywhere in the world.    
 
You have been told that your personal information may be processed within the U.S. or elsewhere in 
the world or transferred to or from the U.S. for review, processing and/or storage by an associated 
company or a carefully selected third-party organization.  By signing this document, you explicitly 
consent to the transfer of your personal information, including sensitive personal information, 
collected during this clinical study, for review, processing and/or storage.  Your personal health 
information may be further shared by the groups above.  If shared by them, the information will no 
longer be covered by the Privacy Rule.  However, the groups are committed to keeping your 
personal health confidential. 
 
You may refuse this authorization to transfer your personal information.  If you choose not to agree 
to this authorization, you might be ineligible to participate in the study.  If you decide not to sign 
this authorization, that will not harm your relations with your doctors or with Carolinas HealthCare 
System.   
 
You have the right to inspect your medical record at any time. Your research record may be 
unavailable until the conclusion of the study. At that point, it will be available.  Please speak with the 
study doctor if you desire to access your record. 
 
You have been told that whenever your personal information is processed; it will be kept 
confidential and secure, to the best of our ability.  It will be used only for the purpose for which it 
was collected. 
 
This Authorization does not have an expiration date. You have been told that according to the 
guidelines for good clinical practice, the study investigator and sponsor will keep your personal 
information for at least 6 years. If you do not withdraw this Authorization in writing, it will remain 
in effect indefinitely.  If you wish to revoke authorization to use your personal information, you will 
notify the study doctor in writing at the address and telephone number listed on the first page of this 
form. Some of the data obtained from your record prior to your revocation may still be used if 
considered necessary for the study.   
 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study, please contact the Investigator at the telephone 
number listed on the first page of this consent document.  If you seek emergency care, or 
hospitalization is required, alert the treating physician that you are participating in this research 
study.   
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects.  If you have any questions about your rights as a research subject, and/or 
concerns or complaints regarding this research study, contact: 
 


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• By mail: 
Study Subject Adviser 
 
 
 
• or call toll free:        
 
• or by email:              
 
 
PLEASE REFERENCE THE FOLLOWING NUMBER WHEN CONTACTING THE 
STUDY SUBJECT ADVISER: PRO00015549. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
BEING A STUDY VOLUNTEER AND WITHDRAWING FROM THE STUDY 
 
Your participation in this study is completely voluntary. You should feel under no pressure to be in 
the study.  If you decide not to be in the study, that will not in any way harm your relations with 
your doctors or with Carolinas HealthCare System.  You are free to stop being in the study if you 
change your mind after entering it.  This would not harm your relations with your doctors or 
Carolinas HealthCare System. 
 
• You may always say no.  You do not have to take part in the study. 
• If you start a study, you may stop at any time.  You do not need to give a reason. 
• If you do not want to be in a study or you stop the study at a later time, you will not be 
penalized or lose any benefits. 
• If you stop, you should tell the study staff and follow the instructions they may give you. 
 
Your part in the research may stop at any time for any reason, such as: 
 
• The sponsor or the study doctor decides to stop the study. 
• The sponsor or the study doctor decides to stop your part in the study for your safety. 
• You need additional medicine. 
• You do not follow the study rules. 
• You have a new injury or illness. 
• You decide to stop. 
 
You may be asked to stop the study even if you do not want to stop.  
 
NEW INFORMATION ABOUT THE STUDY 
 
 
You will be told about any new information found during the study that may affect whether you 
want to continue to take part. 


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STATEMENT OF CONSENT  
 
I have read this form and its contents were explained to me.  I agree to be in this research study for 
the purposes listed above.  All of my questions were answered to my satisfaction.  I will receive a 
signed and dated copy of this form for my records.  I am not giving up any of my legal rights by 
signing this form.   
 
___________________________________ 
____/____/____  _________ 
Signature of Research Subject 
 
Date 
Time 
 
___________________________________ 
Printed Name of Research Subject 
 
 
STATEMENT OF PERSON EXPLAINING CONSENT  
 
I have carefully explained to the subject the nature and purpose of the above study.  There has been 
an opportunity for the subject to ask questions about this research study.  I have been available to 
answer any questions that the subject has about this study. 
 
___________________________________ 
____/____/____  _________ 
Signature of Person Explaining Consent 
Date 
 
Time 
 
___________________________________ 
Printed Name of Person Explaining Consent