Clinical trial NCT02122172
Conditions: Distal Urethral Cancer Proximal Urethral Cancer Recurrent Bladder Cancer Recurrent Urethral Cancer Stage III Bladder Cancer Stage III Urethral Cancer Stage IV Bladder Cancer Stage IV Urethral Cancer Ureter Cancer
Sponsor: University of Chicago
Start date: 2017-09-13; Completion date: 2024-04-04
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well afatinib dimaleate works in treating patients with urothelial cancer that cannot be removed surgically and has grown after treatment with standard first-line chemotherapy. Afatinib dimaleate may turn off the function of the epidermal growth factor (EGF) and human epidermal growth factor receptor 2 (HER2) receptors, which may slow the growth of cancer cells or cause some of the cells to die.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the 3-month progression free survival (PFS) rate in metastatic urothelial cancer patients receiving afatinib (afatinib dimaleate) who have progressed despite prior platinum-based chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the overall response rate (complete response \[CR\] + partial response \[PR\]), median progression free survival, and overall survival for the same treated population.

II. To determine whether tumor epidermal growth factor receptor (EGFR) and/or HER2 overexpression influences 3-month PFS in patients treated with afatinib.

OUTLINE:

Patients receive afatinib dimaleate orally (PO) once daily (QD) on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Arms: arm 1: Patients receive afatinib dimaleate PO QD on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: afatinib dimaleate intervention 2: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 
11.01.2019v.16 
 
Page 1 of 60 
 
 
Clinical Study Protocol 
 
 
Protocol No.: 
 
IRB13-0540/ 1200.171 
 
BI Investigational 
Product: 
  Afatinib 
Title:  
Afatinib in advanced refractory urothelial cancer 
Clinical Phase: 
Phase II 
 
Principal/Lead 
Investigator:   
 
Peter H. O’Donnell, M.D. 
   Drug Manufacturer: 
                            
Sponsor: 
    
   Boehringer Ingelheim Pharmaceuticals, Inc. 
 
   The University of Chicago 


 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 
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Version, and Date of 
Protocol: 
V. 1, June 3, 2012 
V.2, August 3, 2012 
V.3, September 20, 2012 
V.4, January 13, 2013 
V.5, April 26, 2013 
V.6, May 30, 2013 
V.7, August 26, 2013 
V.8, February 5, 2014 
V.9, June 16, 2014 
V.10 March 6, 2017 (CTRC re-review submission) 
V.11 April 25, 2017 (revised per CTRC review comments) 
V.12 September 12, 2017 (Administrative change in personnel and 
update to registration process) 
V.13 March 5, 2018 (page 6 revised flow chart, page 62 add 10ml 
to lavender sample) 
V.14 July 9, 2018 (page 6 updated flow chart, page 17/section 2.2 
add information to study objective, page 20/section 3.3.3 add new 
exclusion criteria statement, page 26section 4.2.2.1 clarify 
restrictions regarding concomitant treatment, page 29/section 5.1.1 
update exploratory endpoints, page 39/section 6.4 updated 
biomarker studies, page 40. update personnel, page 44/section 
7.1.2 update secondary and exploratory analysis, page 49/section 
9.1 updated IB version number, page 59 update personnel and 
administrative changes) 
V.15 November 22, 2018 (Page 2: Remove text reading “Page 1 of 
58”; Page 3: Update contact information for Regulatory Manager; 
Page 19, Section 3.3.2.4: Clarify disposition of germline genomic 
test results; Page 26, section 4.2: Update section heading; Page 27: 
Update section to clarify which subjects in whom afatinib should 
be used with caution.) 
V. 16 November 01, 2019 (Sections 3.3.2.1, 3.3.3.1, and 5.4 – 
clarified prior radiotherapy eligibility.) 
 
 
 
 


 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Protocol date: 
Protocol number: 
  
7/9/2018  
IRB13-0540/1200.171 
Title of study: 
Afatinib in advanced refractory urothelial cancer 
Principal Investigator: Peter H. O’Donnell, M.D. 
5841 S. Maryland Ave., MC 2115 
The University of Chicago 
Chicago, IL  60637 USA 
773-702-7564 
podonnel@medicine.bsd.uchicago.edu 
Statistician: 
Theodore Karrison, PhD 
5841 S. Maryland Ave., MC 2007 
The University of Chicago 
Chicago, IL  60637 USA 
Responsible Research 
Nurse: 
Dawn Conway, RN 
5841 S. Maryland Ave., MC 2115 
The University of Chicago 
Chicago, IL  60637 USA 
773-702-4135 
dbrooks@medicine.bsd.uchicago.edu 
Regulatory Manager: 
TBA 
5841 S. Maryland Ave., MC 2115 
The University of Chicago 
Chicago, IL  60637 USA 
773-702-8751 
Responsible Research 
Coordinator: 
Marah Sarrouj5841 S. Maryland Ave., MC 2115 
The University of Chicago 
Chicago, IL  60637 USA 
773-834-3567msarrouj@medicine.bsd.uchicago.edu 
Study site(s) : 
This study is being conducted by institutional members of the Personalized Cancer 
Care Consortium (PCCC), as well as additional sites. 
Sponsor: 
Drug Manufacturer: 
The University of Chicago 
Boehringer Ingelheim Pharmaceuticals, Inc. 
Clinical phase: 
phase II 


 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 
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Protocol date: 
Protocol number: 
  
7/9/2018  
IRB13-0540/1200.171 
Objective(s): 
This trial was originally designed to test the 3-month PFS rate of molecularly 
unselected urothelial cancer patients receiving afatinib. We previously completed this 
first portion of the study. Overall, five of 23 patients (21.7%) met PFS3 (two partial 
response, three stable disease). Results indicated a signal of activity for afatinib in a 
portion of patients with specific molecular alterations. Specifically, among the 21 
patients whose tumors were available, pre-specified analysis of ERBB family 
molecular alterations showed that five of six patients (83.3%) with HER2 and/or 
ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, 
respectively) versus none of 15 patients without alterations (P < 0.001). Three of four 
patients with HER2 amplification and three of three patients with ERBB3 somatic 
mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 
amplification and ERBB3 mutation never progressed on therapy, but treatment was 
discontinued after 10.3 months as a result of depressed ejection fraction. The median 
time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 
alterations versus 1.4 months in patients without alterations (P < 0.001). 
Based on these data, the study is now being amended to determine the 6-month 
progression free survival (PFS) rate in metastatic urothelial cancer patients receiving 
afatinib who have progressed despite prior platinum-based chemotherapy and who 
carry genomic ErbB family alterations. 
Methodology: 
single-arm marker-selected continuation phase II study (previous phase of this study 
allowed all patients (no marker selection) and has been completed) 
No. of patients:  
72 marker-selected patients (interim analysis after first 29 evaluable patients for 
futility assessment); the previously-enrolled 23 patients from the first portion of this 
trial (all enrolled during the first non-marker selected phase of the trial) were 
previously analyzed separately as summarized above and will not be analyzed with 
the 72 patients from this marker-selected phase 
total entered: 
95 total (72 patients in marker-selected cohort; 23 in initial cohort) 
each treatment: 
afatinib 
Indication : 
patients with platinum-refractory metastatic urothelial cancer with genomic ErbB 
molecular alterations 


 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 
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Page 5 of 60 
Protocol date: 
Protocol number: 
  
7/9/2018  
IRB13-0540/1200.171 
Main criteria 
for inclusion: 
Main criteria 
for exclusion: 
• 
Adults with urothelial carcinoma of the bladder, upper tract, or urethra 
• 
Must have tumor evidence of somatic molecular alteration in EGFR, HER2, 
ERBB3, or ERBB4 
• 
Prior treatment with a platinum-based regimen administered in the 
perioperative or metastatic setting 
• 
Evidence of disease progression prior to enrollment 
• 
Adequate hepatic and marrow function 
• 
ECOG 0-1 
 
 
 
• 
Prior therapy with afatinib 
• 
Breastfeeding or pregnant women 
• 
Uncontrolled intercurrent illness 
• 
Concurrent receipt of other investigational agents 
• 
Patients with untreated known brain metastases, or treated brain metastases 
that are clinically unstable 
• 
Uncontrolled HIV or HIV currently being treated with antiretrovirals 
 
 
Criteria for efficacy:  
Duration of treatment: 
Progression-free survival rate at 6 months in patients treated with afatinib 
Until disease progression or intolerable toxicity 
Criteria for safety: 
Criteria for efficacy:  
 
Reporting of serious adverse events 
Progression-free survival rate at 6 months in patients treated with afatinib 
Statistical methods: 
In a meta-analysis of second-line clinical trials in patients with advanced urothelial 
carcinoma (Pond et al., 2013), the estimated overall progression-free survival (PFS) 
rate at 6 months was 22.6% (95% CI:  18.8%-25.9%), although it varied from 34.6% 
in patients with no risk factors (liver metastases, ECOG 1+, Hb<10 g/dl, or time from 
previous chemotherapy <6 months) to 4.9% in patients with 3-4 risk factors.  Thus 
over three-quarters of patients will have disease progression within 6 months, and we 
propose that PFS at 6 months would be an informative endpoint for assessing drug 
activity.  A Simon, optimal two-stage design will be employed to assess the primary 
end point of 6-month PFS rate. The null hypothesis (H0), a 6-month PFS of <25%, 
will be considered representative of lack of efficacy of the drug in this biomarker-
specific patient population consisting of patients with ErbB alterations.  The 
alternative hypothesis (HA), a 6-month PFS rate of >40%, will be considered 
indicative of activity. If 23 or more of the 72 total patients (>32%) exhibit 
progression-free survival of 6 months or more the regimen will be considered 
promising and worthy of further study. 
Study duration 
Until all treatment is concluded and data is collected on enrolled patients (total = 72 
evaluable patients in marker-selected cohort) 


 
 
 
 
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IRB13-0540/ 1200.171                                                                                                                             Protocol Version:  10/22/18 v.15 
 
Page 6 of 60 
 
FLOW CHART 
  
 
Study Period 
Screening* 
Cycle 1 ** A 
Cycle 2 ** A 
Subsequent 
Cycles (3, 4, 
etc.) ** A 
End of Treatment and Post-
Study treatment  
 
   
Visit Days 
Day -21 
through day 
0 
Day 1 ‡C 
Days 15, 
29, and 
43  ‡ 
 
Day 
57(C2D1) 
‡ 
 Days 15 
and 29 ‡ 
Days 1 and 
29  ‡ 
EOT ‡ 
FU ‡ 
Add. 
FUπ ‡ 
Informed consent  
X 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Concurrent meds  
X 
X 
 
X 
 
X 
X 
 
 
Documentation of qualifying somatic 
genomic molecular alteration in 
EGFR, HER2, ERBB3, or ERBB4 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
XC 
X 
X 
X 
X 
X 
X 
 
Vital signs including O2 sat 
X 
X 
X 
X 
X 
X 
X 
 
 
Height  
X 
 
 
 
 
 
 
 
 
Weight  
X 
 
 
 
 
 
X 
 
 
Performance status  
X 
 
 
 
 
 
X 
 
 
CBC w/diff, plts  
X 
XC 
X 
X 
X 
X 
X 
 
 
Serum chemistry# 
X 
XC 
X 
X 
X 
X 
X 
 
 
Serum BHCG¥ 
X 
 
 
 
 
 
 
 
 
MUGA£ 
X 
 
 
 
X£ 
X£ 
 
 
 
Dispense study drug to subject 
 
X¶ 
 
X¶ 
 
X¶ 
 
 
 
Radiologic evaluation (CT or MRI) 
X 
 
 
X 
 
XB 
XB§ 
 
 
Tumor measurements 
X 
 
 
X 
 
XB 
X 
 
 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
 
Archival research tumor tissues% 
X ---> 
--> 
--> X 
 
 
 
 
 
 
Pharmacogenomic blood sample 
X ---> 
--> 
--> X 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
X 
X 


 
 
 
 
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IRB13-0540/ 1200.171                                                                                                                             Protocol Version:  10/22/18 v.15 
 
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*Baseline evaluations, including imaging studies, are to be conducted within 21 days prior to start of protocol therapy.   
% Archival tissues to be used for exploratory biomarker research studies described in Section 6.4. These research tissue samples are not required for eligibility nor registration and 
may be submitted during screening or after registration but must be received by the end of cycle 1. See section 6.4 for details.  
** Treatment courses continue until disease progression or unacceptable drug intolerance. 
#Comprehensive metabolic panel (Na, K, Cl, HCO3, BUN, Creatinine, Glc, Ca, Total Bilirubin, Total Protein, Albumin, AST, ALT, Alkaline Phosphatase), Mg, PO4 
¥ BHCG = beta human chorionic gonadotropin. Only required in women with intact uterus. If elevated, pt ineligible unless pregnancy otherwise proven to be excluded. 
A: Each cycle is 56 days in length. 
¶ Patient supplied with two bottles of study drug on day 1 of each 56-day cycle. Each bottle contains 30 tablets. See Section 4.3 for adherence reporting requirements (pill 
counting/pill diary). 
‡ (+/-) 4 day visit window 
C: It is encouraged that patients for whom a treating physician feels may be at higher than average risk for toxicity from afatinib should be seen at one extra in-person visit, 1 week 
after starting study therapy (on cycle 1 day 8). This visit should include physical exam and CBC with diff, plts and serum chemistry assessment. 
£ MUGA (multi-gated acquisition scan) must also be performed every 12 weeks during therapy B: Radiographic assessment of responses to be performed every 8 weeks until 
disease progression is observed or until drug intolerability.  
EOT = end of treatment 
§ A scan performed for clinical reasons mid-cycle (e.g., for clinical symptoms of possible disease progression) which indeed confirms progressive disease and which results in the 
patient being taken off study, will count as the EOT radiologic evaluation. 
FU = follow-up 
Add FU = additional follow-up 
πPatients should be followed for 3 years after end of treatment 
  


 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 11/12/18 v.15 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL SYNOPSIS ............................................... 3 
FLOW CHART ................................................................................................... 6 
TABLE OF CONTENTS ................................................................................... 8 
1. 
INTRODUCTION ................................................................................ 11 
1.2 
DRUG PROFILE ............................................................................................... 11 
1.2.1 Preclinical pharmacology and toxicology .......................................................... 11 
1.2.2 Clinical pharmacokinetic and safety ................................................................. 13 
1.2.3 Clinical efficacy .................................................................................................... 14 
2.2 
STUDY OBJECTIVES ...................................................................................... 14 
2.3 
BENEFIT-RISK ASSESSMENT ...................................................................... 17 
3.2 
OVERALL STUDY DESIGN AND PLAN ..................................................... 17 
3.3 
SELECTION OF STUDY POPULATION ...................................................... 18 
3.3.1 
Main diagnosis for study entry .................................................................... 18 
3.3.2 
Inclusion criteria............................................................................................ 19 
3.3.3 
Exclusion criteria ........................................................................................... 20 
3.3.4 
Removal of patients from therapy or assessments ..................................... 20 
4.1 
TREATMENTS TO BE ADMINISTERED .................................................... 22 
4.1.1 
Identity of investigational product ............................................................... 22 
4.1.2 
Selection of doses in the study ...................................................................... 22 
4.1.3 
Drug assignment and administration of doses for each patient ................ 22 
4.1.3.1 Afatinib ........................................................................................................... 22 
4.1.3.2.   Dose reduction/drug discontinuation scheme for afatinib ...................... 22 
4.1.4 
Packaging, labelling, and storage ................................................................. 24 
4.1.4.2 
Storage conditions ....................................................................................... 25 
4.1.5 
Drug accountability ....................................................................................... 25 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, PRECAUTIONS, AND 
RESCUE TREATMENT ................................................................................... 26 
4.2.1 
Rescue medication, emergency procedures, and additional treatment(s) 26 
4.2.2 
Restrictions..................................................................................................... 26 
4.2.2.1 
Restrictions regarding concomitant treatment ........................................ 26 
4.2.2.2 
Restrictions on diet and life style ............................................................... 26 
4.2.2.3  Precautions ..................................................................................................... 27 
4.2.3  
Concomitant therapy .................................................................................... 27 
4.2.3.1 
Management of diarrhea following treatment with afatinib .................. 27 
4.2.3.2 Management of nausea and vomiting following treatment with afatinib . 28 
4.2.3.3 
Management of rash following treatment with afatinib .......................... 29 
5.1 
EFFICACY ......................................................................................................... 30 
5.1.1 
End point(s) of efficacy ................................................................................. 30 
5.1.2 
Assessment of efficacy ................................................................................... 31 
5.2 
SAFETY .............................................................................................................. 31 
5.2.1 
Endpoint(s) of safety ..................................................................................... 31 
5.2.2 
Assessment of adverse events ....................................................................... 31 
5.2.2.1 
Definitions of adverse events ...................................................................... 31 
5.2.2.2 
 Adverse event and serious adverse event reporting ................................ 33 


 
 
 
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5.2.2.3 Responsibilities for SAE reporting ........................................................ 33 
5.2.2.3.1 Reporting Events to the UCCCC ........................................................ 33 
5.2.2.4 
Adverse Events of Special Interest ............................................................ 35 
5.2.3 
Assessment of safety laboratory parameters .............................................. 36 
5.2.4 
Assessment of other safety parameters ....................................................... 36 
5.2.4.1 
Physical examination, performance score ................................................ 36 
5.2.4.2 
Left ventricular function ............................................................................ 36 
5.2.4.3 
Vital signs ..................................................................................................... 37 
5.3 
OTHER ............................................................................................................... 37 
5.3.1 
Demographics and history ............................................................................ 37 
5.4 
APPROPRIATENESS OF MEASUREMENTS ............................................. 37 
6.1 
VISIT SCHEDULE ............................................................................................ 37 
6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ............... 38 
6.2.1 
Screening period ............................................................................................ 38 
6.3. REGISTRATION PROCEDURES .......................................................... 38 
6.3.1  
 GENERAL GUIDELINES ................................................................. 38 
6.3.2  
REGISTRATION PROCESS ............................................................. 38 
6.4  AFTER REGISTRATION ........................................................................ 40 
6.5 
Treatment period(s) ...................................................................................... 41 
6.6 
End of study treatment and follow-up period ............................................ 41 
7.1 
PLANNED ANALYSES .................................................................................... 41 
7.1.1 
Primary analyses ........................................................................................... 41 
7.1.2 
Secondary and exploratory analyses ........................................................... 44 
7.1.3 
Safety analyses ............................................................................................... 45 
7.2 
HANDLING OF MISSING DATA .................................................................. 45 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .......................................................................................................... 45 
8.2 
DATA QUALITY ASSURANCE ..................................................................... 47 
8.3 
DATA REPORTING AND RECORDS ........................................................... 49 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
 .............................................................................................................................. 49 
8.4.1 
Listedness ....................................................................................................... 49 
8.4.2 
Expedited reporting to health authorities and IRB ................................... 49 
9. 
REFERENCES ..................................................................................... 51 
9.1 
UNPUBLISHED REFERENCES ..................................................................... 51 
9.2 
PUBLISHED REFERENCES ........................................................................... 51 
10. 
APPENDICES ...................................................................................... 55 
10.1 
APPENDIX 1 ECOG SCALE ........................................................................... 55 
10.2 
APPENDIX 2 TUMOUR RESPONSE ASSESSMENT ACCORDING TO 
RECIST 1.1 ......................................................................................................... 56 
10.3 
APPENDIX 3 STUDY REPORT AND PUBLICATION POLICY .............. 57 
10.3.1  
Study Report .................................................................................................. 57 
10.3.2  
Publication Rules ........................................................................................... 57 
10.3.3  
Registration with clinical registry database ................................................ 58 
10.4  APPENDIX 4 ............................................................................................ 59 


 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 11/12/18 v.15 
 
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PATIENT REGISTRATION FORM .............................................................................. 59 
10.5  APPENDIX 5 ............................................................................................ 60 
PHARMACOGENOMIC BLOOD SAMPLE COLLECTION FORM ...................... 60 


 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 11/12/18 v.15 
 
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1. 
INTRODUCTION 
1.2 
DRUG PROFILE 
 
Afatinib is a novel, oral, irreversible, ErbB family blocker (ErbB1/EGFR, ErbB2/HER2, and 
ErbB4/HER4) that offers the chance to control both recurrent as well as distant metastatic 
disease on an outpatient basis with continuous treatment. Afatinib final formulation is 
available in 20, 30, 40 and 50 mg film-coated tablets to be used for clinical studies up to 
Phase III. 
Afatinib is a potent, irreversible, ErbB family blocker, both in vitro and in vivo. Receptor 
tyrosine kinases other than the EGFR (Class I) family and non-receptor type tyrosine kinases 
were not inhibited. Afatinib is bioavailable after oral administration in several species. 
 
1.2.1 Preclinical pharmacology and toxicology 
In mice, afatinib reaches efficacious plasma exposure with once-daily dosing throughout the 
treatment period. Afatinib displays antitumor activity, including tumor regression, against 
established subcutaneous xenografts in nude mice either as a single agent or in combination 
with a cytotoxic agent like docetaxel. The necessary maximum plasma concentrations were 
between 80 to 285 nM for single agent activity. The absolute bioavailability was medium-
high in rats (45%). The median tmax after oral administration was 4 hours and the terminal 
half-life was 4.5 hours. The terminal half-life of the radiolabelled compound was 
considerably longer indicating persistence of metabolites in the system. The exposure was 
dose proportional without gender-related effects. Some accumulation in the 13-week and 26-
week toxicology study appeared more pronounced in males. In minipigs there was a slight 
tendency towards supra-proportional increases in AUC0-24h with increasing doses, which was 
considered to be of minor relevance. A consistent effect on accumulation was not seen. 
In the whole body autoradiography in rats, afatinib was distributed in all organs with the 
exception of the CNS after oral administration. The highest concentrations were found in the 
kidney, liver, lung, and spleen. In general, a slow elimination of radioactivity was seen. The 
major excretion pathway is via faeces (91%). Afatinib covalently binds to plasma proteins. 
Whether such protein haptens are immunogenic and capable of inducing allergic reactions is 
unknown. 
Afatinib did not show relevant inhibition or induction of cytochrome P450 isoenzymes, and it 
appears unlikely that drug-drug interactions as based on this mechanism will occur. In vivo, 
afatinib was metabolized only to a minor extent and the metabolism was governed by adduct 
formation to proteins or nucleophilic small molecules. It was found that metabolism is of 
subordinate role for afatinib and that enzyme-catalyzed metabolic reactions play a negligible 
role for the metabolism of afatinib in vivo. Only approximately 2 % of the dose were 
metabolized by FMO3 in vivo. The CYP3A4-dependent N-demethylation was even too low 
to be quantitatively detected in human volunteers. Therefore, intrinsic (e.g. genetic 
predisposition) or extrinsic (e.g. by comedications) effects on the activity of FMO3 or 


 
 
 
IRB13-0540/1200.171                                                                          Protocol Version: 11/12/18 v.15 
 
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CYP3A4 in vivo are expected to be of little, if any, relevance for the pharmacokinetics of 
afatinib. 
In vitro, afatinib was found to be a P-gp substrate (estimated Km 10-30 µM) and a moderate 
to weak inhibitor of P-gp (estimated Ki of 3.4 µM). It cannot be excluded that concomitant 
treatment with other P-gp substrates or P-gp inhibitors may alter the plasma concentrations of 
afatinib.  Since I/Ki of afatinib is resulting in values considerably below 0.1 which would be 
the defined “cut off” value for considerable drug-drug interactions based on P-gp (afatinib 
acting as a P-gp inhibitor) it is unlikely that afatinib may alter the plasma concentrations of 
other P-gp substrates. 
Safety pharmacology studies (GLP) in rats indicate no adverse effects on behavior or 
respiratory function. In minipigs, minor effects on heart rate (tachycardia) and the ECG (QT-
shortening) were observed.  Cardiovascular systemic effects observed were non-significant, 
with the exception of reduced contractility at higher intravenous doses.  An effect on renal 
and liver function was seen with a very high oral dose of 300 mg/kg in rats. Furthermore, a 
dose dependent effect on gastrointestinal function was seen, leading to a substantial inhibition 
at the highest dose. 
In repeat-dose toxicity studies in mice (up to 13 weeks), rats (up to 26 weeks) and minipigs 
(up to 52 weeks), the main target organs were the skin (mice and rats; inflammatory 
changes), the gastrointestinal tract (mice, rats and minipigs; diarrhea and epithelial changes) 
and the kidneys (rats; papillary necrosis). This spectrum is in line with findings reported for 
other ErbB targeting drugs.  Changes were generally minimal to moderate and often fully 
reversible or ameliorated after drug withdrawal (skin, kidneys); they are most likely related to 
the EGFR-inhibiting effect of afatinib. 
In the gastrointestinal tract, increasing systemic exposure was associated with dose dependent 
atrophy of the epithelium and concomitant focal erosions/ulcerations in the stomachs of rats 
and minipigs. Clinically, this was characterized by diarrhea in both species and faecal occult 
blood in a single minipig. Other organs affected by the epithelial atrophy in the rat were the 
skin, prostate, uterus, and vagina. In minipigs, the upper respiratory tract, seminal vesicles, 
and the corneal epithelium were affected by epithelial atrophy. In the gastrointestinal and 
respiratory tract, atrophy of the mucinous glands, e.g. salivary glands, was also found. These 
atrophic changes were minimal to slight and fully reversible during the recovery periods and 
are most likely related to the pharmacodynamic mechanism of afatinib. 
Afatinib is not irritating to intact skin but may have a phototoxic potential. Afatinib is slightly 
mutagenic in a single bacteria strain, but it did not show genotoxic potential in vivo when 
tested up to overt toxic/lethal doses. The reproductive and developmental toxicity studies 
showed no marked adverse effects on fertility and early embryonic development, and only a 
small effect on birth weight and bodyweight gains of offspring in rats.  No indication of 
teratogenicity was identified in rats and rabbits.  Because systemic drug exposure in the 
studies generally was only slightly above clinical exposure (rat embryo-fetal development, 
male rat fertility) or below, in the absence of safety margins, a final conclusion on the 
potential of afatinib for adverse reproductive and developmental effects in humans is not 
possible. 


 
 
 
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Based on these toxicological findings and the experience with other EGFR- and HER2-
inhibitors, the risks of anti-EGFR and anti-HER2 therapy with afatinib might primarily 
consist of gastrointestinal effects (including diarrhea) and skin rash. 
1.2.2 Clinical pharmacokinetic and safety 
PK data available from clinical trials until now indicate that afatinib was moderately fast 
absorbed after oral administration, with median tmax values mainly between 1 and 6 hours. 
For afatinib there was no deviation from dose-proportionality detectable. However, moderate 
to high inter- and intra-individual differences in plasma concentrations were seen. Afatinib 
was highly distributed out of the blood and had a moderate to high clearance. The mean 
terminal half-life was mainly in the range of 13-57 h. Steady state was reached no later than 8 
days after the first administration. The major route of elimination of afatinib was via the 
faeces. After food intake, a decreased systemic exposure was observed compared to 
administration of afatinib under fasted conditions. Therefore, afatinib should be taken without 
food (i.e. afatinib should be taken at least 1 hour before or at least 2 hours after a meal).  
Typically, an accumulation ratio based on AUC values between 1.8 and 4.0 has been 
observed. At doses of 40 mg and above individual Cmax,ss and AUCτ,ss values were mainly in 
the same range as those found to demonstrate anti-tumor activity in nude mouse tumor 
xenograft models. 
Adverse events observed with afatinib are consistent with those reported for other EGFR 
inhibitors and include predominantly gastrointestinal (GI) and dermatological AEs which are 
dose-dependent. Diarrhea usually occurred within the first 2 weeks of treatment.  Grade 3 
diarrhea most frequently occurred within the first 6 weeks of treatment.  Patients of low body 
weight, females, and patients with low baseline renal function appear to be at increased risk 
for developing Grade 3 diarrhea.  A small number of patients experienced dehydration and 
prerenal insufficiency, most likely secondary to GI AEs, particularly diarrhea. 
Rash/acne occurs at a high frequency; with half of the cases beginning within 4 weeks of 
exposure to afatinib.  Those at higher risk for Grade 3 rash/acne appear to be the patients of 
low body weight/body surface area and patients with low baseline renal function. 
Early, proactive, and effective management of these adverse events is mandated in ongoing 
and forthcoming clinical trials with early intervention to manage diarrhea and skin toxicities.  
Interstitial lung disease (ILD) is a rare and serious (potentially fatal) AE reported with other 
EGFR tyrosine kinase inhibitors.  Considering reports of suspected cases of ILD on afatinib, 
ongoing trials have been amended to exclude patients with known or pre-existing ILD from 
treatment with afatinib.  Careful assessment of all patients with acute onset and/or 
unexplained worsening of pulmonary symptoms (including dyspnea, cough, and fever) are 
emphasized.  Interventions including interruptions of study drug pending investigations and 
permanent discontinuation if ILD has been diagnosed must be considered. 
Besides diarrhea, other GI AEs include nausea, vomiting, stomatitis, mouth ulceration, dry 
mouth, and oral pain.  Besides acne/rash, other dermatological AEs include dermatitis 
acneiform, dry skin, pruritus, and skin reaction.  Other AEs seen in clinical trials of afatinib 


 
 
 
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include general disorders such as fatigue/asthenia; mucosal inflammation; infections and 
infestations such as paronychia and folliculitis; respiratory disorders such as epistaxis and 
rhinorrhea; eye disorders such as conjunctivitis and keratitis; and metabolism and nutritional 
disorders, such as anorexia and dehydration. Other AEs were in the expected range for 
patients with advanced malignancies. 
 
1.2.3 Clinical efficacy 
Efficacy of afatinib has been demonstrated in multiple studies of NSCLC patients and has 
FDA approval in this disease for patients with specific EGFR mutations. 
Objective responses have been observed in phase II studies in selected breast cancer patients 
and patients with squamous cell cancer of the head and neck. 
Objective responses and durable stable disease in patients with advanced solid tumors have 
been observed in phase I monotherapy studies as well as in phase I combination studies.   
Afatinib demonstrated activity in platinum-refractory urothelial cancer patients in the first 
stage of this study, with all responders bearing ErbB family molecular alterations.  
2. 
Rationale, objectives, and Benefit - Risk Assessment 
2.2 
STUDY OBJECTIVES 
Therapy for Urothelial Cancer as an Unmet Need 
Despite the fact that urothelial carcinoma of the bladder is often a curable disease with 
surgical intervention alone, a significant number of patients will relapse and die of their 
disease.  In fact, urothelial cancer of the bladder is the 6th most common cancer and the 8th-
leading cause of cancer death in the United States1.  Each year, approximately 80,000 
individuals are diagnosed with urothelial cancer in the U.S. alone, and over 17,000 die1.  
Cisplatin-based therapy and immunotherapy remain the only accepted standards of care for 
treatment of metastatic disease2,3.  Despite these therapies, the median overall survival 
remains short4,5.  Therefore, novel agents are desperately needed. 
 
We hypothesize that a targeted, tolerable novel agent like afatinib could delay disease 
progression (and thereby potentially increase overall survival rates) for patients with this 
difficult disease. 
 
EGFR Targeting as a Rational Therapeutic Strategy 
The concept of targeting the epidermal growth factor receptor (EGFR/ErbB1/HER1) pathway 
in urothelial cancer has been the subject of intense study over the past two decades6.  Recent 
successes when targeting this pathway in other tumors (head and neck, colon, and lung 
cancers) also encourage its continued exploration in other relevant tumor types. 
 
First, it is known that EGFR overexpression is increased in urothelial cancer compared to the 
normal urothelium7, and the majority of invasive urothelial cancers (in contrast to non-
invasive tumors) overexpress EGFR8.  In a comparison of primary bladder urothelial tumors 


 
 
 
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versus sites of metastasis in the same patients from one study, EGFR expression levels in the 
primary tumors were generally found to correlate with expression levels in the metastatic 
sites9.  Importantly, EGFR was found to be significantly expressed in 65% of the metastatic 
sites9.  EGFR expression has also been shown to correlate with higher tumor grade8, muscle 
invasiveness8, tumor recurrence10,11, and overall survival11,12 in patients with urothelial 
cancer.  These composite pre-clinical and clinical data support the putative significance of the 
EGFR pathway in urothelial cancer and led to the development and initial clinical testing of 
EGFR-targeted therapies in this disease over the past 5-10 years. 
 
Clinical data on EGFR inhibition have been mixed.  Two prior trials have demonstrated lack 
of activity for the anti-EGFR drug gefitinib in patients with metastatic disease13,14.  These 
negative studies could simply be due to the fact that gefitinib may be an inferior agent within 
the anti-EGFR family (as perhaps also suggested by its ultimate failure in lung cancer).  This 
possibility may be suggested by the recent promising data reported by Pruthi et al15 in their 
phase II trial of the EGFR inhibitor erlotinib as neoadjuvant monotherapy in patients with 
cT2 urothelial cancer.  Demonstrating a pathologic downstaging rate of 35% and a pT0 rate 
of 25%, Pruthi et al. concluded that erlotinib “may have activity” in the neoadjuvant setting 
for urothelial cancer15.  As theirs was a single-arm study, we are forced to rely on historical 
comparisons to interpret the results.  However, the authors’ claim of possible activity for 
erlotinib is supported by the fact that the pT0 rate in their study (25%) appears to be higher 
than in other studies where no neoadjuvant therapy was used—studies which consistently 
show pT0 at 15% or lower16,17. 
 
We believe the combination of these promising clinical data and considerable pre-clinical 
evidence strongly support further strategies aimed at EGFR inhibition in urothelial cancer in 
a randomized fashion.  We believe afatinib is an ideal choice to test not only because of its 
potent activity and role as an EGFR inhibitor, but because of its dual mechanism of HER2 
inhibition as well. 
 
HER2 Targeting as a Rational Therapeutic Strategy 
Overexpression of HER2 (ErbB2) in urothelial carcinomas has been repeatedly shown.  
Estimates of the prevalence vary, partly because of utilization of different cutoffs for 
measuring overexpression by immunohistochemistry (IHC) and partly because gene 
amplification is instead sometimes tested.  In the most prominent clinical study in which 
HER2 testing was conducted on urothelial cancer patients, 52% were designated as HER2 
“positive”, with 49% demonstrating overexpression (at least 2+) by IHC18.  
 
Another recent series by a well-respected pathology center found that among urothelial 
patients with high-grade invasive disease (a population which would mirror the proposed 
study population here), HER2 overexpression (2+ or higher by IHC) was present in 36% of 
primary tumors and 30% of metastases19.  These composite data suggesting a significant 
prevalence of HER2 positivity has led many to advocate that HER2 is one of the most 
attractive molecules for therapeutic targeting in urothelial cancer20. 
 
Further pre-clinical evidence supports this idea.  In a series of 90 patients undergoing 
cystectomy and adjuvant cisplatin-based chemotherapy, HER2 status (IHC 2+ or 3+) was 


 
 
 
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significantly related to tumor stage (P = 0.001) and lymph node involvement (77% in N+ 
versus 23% in N0; P = 0.001).  Worse disease-related survival (log rank P = 0.011) was 
found for patients with HER2 overexpressing tumors than for those without overexpression, 
and HER2 status (relative risk = 2.22) was identified as an independent predictor for disease-
related survival in a multivariate analysis (P = 0.02)21. 
 
Similarly, Fleischmann et al.22 suggested a possible concordance between HER2 
amplification and metastasis, demonstrating that HER2 amplification was significantly more 
frequent in lymph node metastases (15.3%) of patients with urothelial cancer than in matched 
primary bladder tumors (8.7%; p=0.003).  Interestingly, HER2 amplification also 
significantly predicted poor outcome (p=0.044). 
 
 
Clinical evaluation of HER2 targeting in urothelial cancer has previously been reported by a 
study which used trastuzumab combined with carboplatin, gemcitabine, and paclitaxel in 
patients with previously untreated advanced disease18.  The regimen demonstrated significant 
activity (70% response rate).  However, the design was non-randomized, making conclusions 
difficult, and furthermore there was an unexpectedly high rate of cardiac toxicity seen with 
the use of trastuzumab.   
 
Another study examined maintenance lapatinib (versus placebo) after first-line chemotherapy 
in patients with EGFR or HER-2 “positive” metastatic urothelial cancer23. Positivity was 
defined as 2+ or 3+ immunohistochemical staining. The trial failed to show any improvement 
in progression free or overall survival for lapatinib. 
 
Finally, analysis of the first 23 patients enrolled in the first phase of this study showed 
evidence for activity in urothelial cancer patients. Specifically, in the overall (molecularly 
unselected) population, five of 23 patients (21.7%) had progression-free survival at three 
months (PFS3; two partial response, three stable disease). Most importantly, five of six 
patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 
6.3, and 5.0 months, respectively) versus none of 15 patients without alterations (P < .001). 
Three of four patients with HER2 amplification and three of three patients with ERBB3 
somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 
amplification and ERBB3 mutation never progressed on therapy, but treatment was 
discontinued after 10.3 months as a result of depressed ejection fraction. The median time to 
progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 
1.4 months in patients without HER2/ERBB3 alterations (P < .001)24.  
 
The primary purpose of the expansion study is to identify which ErbB family alterations 
confer sensitivity. 
In the earlier phase of the study, no somatic nonsynonymous mutations in EGFR were 
detected in any patients, and no alterations in ERBB4 were identified in any patients, 
consistent with previously reported findings that EGFR somatic mutations and ERBB4 
alterations are rare in urothelial cancer. Response data for patients with EGFR amplification 
and/or high EGFR expression were unclear. Given this, the sensitivity of such patients to 
afatinib is unknown. However, given the mechanisms of EGFR and ERBB4, the known 
activity of afatinib in patients with select EGFR mutations and true amplifications (in lung 


 
 
 
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cancer), and the clear sensitivity seen in ERBB2- and ERBB3-altered patients in the earlier 
study, it is rational to include EGFR mutated and amplified and ERBB4 altered patients in the 
eligible group for this larger (expansion) study.  
Given the compelling scientific rationale for pursuing the ErbB family and the significant 
clinical opportunity provided by a paucity of other therapeutic options in urothelial cancer, 
we believe afatinib is therefore an attractive agent for testing in this disease.   
2.3 
BENEFIT-RISK ASSESSMENT 
This drug is inviting for testing in this setting due to its tolerability profile25 and its route of 
oral administration.  This study addresses an important unmet need in urothelial cancer.  In a 
disease which has seen the successful introduction of no new agents in the past ~20 years and 
for which outcomes remain dismal especially for high risk patients, development of novel, 
rational agents like afatinib is desperately warranted. 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION 
3.2 
OVERALL STUDY DESIGN AND PLAN 
This continuation phase II study is designed to evaluate whether afatinib has activity in 
patients with unresectable urothelial cancer who are refractory to prior platinum-based 
chemotherapy and carry somatic molecular alterations of ErbB family genes.  Patients must 
have received prior treatment with a platinum-based regimen administered in the 
perioperative or metastatic setting and must have evidence of disease progression prior to 
enrollment. 
 
In this single-arm continuation phase II study, all patients will receive afatinib at a starting 
dose of 40 mg/day given continuously.  Radiographic assessment of responses will be 
performed via CT or MRI every 8 weeks until disease progression is observed or until drug 
intolerability.  The first portion of this study (non-marker selected; already completed- Figure 
1) permitted enrollment of patients without consideration of somatic genomic ErbB status.  
The continuation portion of this trial (the ‘marker-selected’ phase) will only enroll patients 
whose tumors harbor ErbB family genomic alterations. The trial design for the new cohort of 
the study is shown in Figure 2. 
 


 
 
 
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Trial Design
Patients with unresectable urothelial cancer who are refractory to 
prior platinum-based chemotherapy
All patients receive
afatinib (40 mg/day, 
continuously)
Assess 3-month progression-free survival (PFS) rate. 
After first 23 patients, study proceeds if ≥7 patients 
exhibit 3- month PFS
3-month PFS assessed in entire study population (33 patients)
 
 
Figure 1: Trial Design for the first portion (non-marker selected phase) of the study 
Trial Design
Patients with unresectable urothelial cancer who are refractory to 
prior platinum-based chemotherapy
afatinib (40 mg/day, continuously)
Assess 6-month PFS (complete response [CR] + partial 
response [PR] + stable disease [SD])
Identification of patients with somatic 
genomic molecular alterations
in EGFR, HER2, ERBB3, or ERBB4
 
Figure 2: Trial design for the new cohort (marker selected phase) of the study 
3.3 
SELECTION OF STUDY POPULATION 
3.3.1 
Main diagnosis for study entry  
3.3.1.1  
Patients must have locally advanced or metastatic urothelial cancer that 


 
 
 
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is not amenable to surgical treatment  
3.3.1.2  
Patients must have histologically or cytologically confirmed urothelial 
tract carcinoma.  Patients with urothelial carcinoma of the bladder, upper 
tract, or urethra are eligible.  
3.3.2 
Inclusion criteria 
3.3.2.1  
Patients must have measurable disease, defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter to 
be recorded) as > 20 mm with conventional techniques or as > 10 mm with 
spiral CT scan. See Section 10.2 (Appendix 2) for the evaluation of 
measurable disease (RECIST v1.1). Lesions that have been irradiated as the 
most recent line of treatment are not eligible as RECIST target lesions. 
3.3.2.2  
Patients must have evidence of disease progression prior to enrollment. 
3.3.2.3   
All patients must have received a prior platinum-based chemotherapy 
regimen for treatment of urothelial cancer and must now be considered 
refractory to platinum-based chemotherapy.  Patients may have received the 
platinum-containing regimen either in the peri-operative or metastatic 
setting. Patients may have received any number of additional prior therapies, 
and may have received prior immune therapies. 
3.3.2.4 Patients must have tumor evidence of somatic genomic molecular alteration 
in EGFR, HER2, ERBB3, or ERBB4, from a test result generated in a 
Clinical 
Laboratory 
Improvement 
Amendments 
(CLIA)-certified 
laboratory. The tumor tissue sample used to generate the qualifying report 
must be from a muscle-invasive or higher stage urinary tract cancer 
specimen (metastatic tissue is also acceptable). Final determination about 
whether a specific tissue source or molecular genomic finding meets criteria 
as a qualifying result rests with the central study PI. Germline genomic 
findings will not be returned to patients. 
3.3.2.5  
Patients must be 18 years of age or older. 
3.3.2.6  
ECOG performance status 0-1. 
 
3.3.2.7  
Patients must have adequate organ function as defined below:  
• 
absolute neutrophil count >1,000/mcL  
• 
platelets >100,000/mcL  
• 
hemoglobin  ≥ 8.5g/dL  
• 
total bilirubin ≤ 1.5 institutional upper limit of normal (IULN)  
• 
AST(SGOT)/ALT(SGPT) ≤ 2.5 X IULN  
• 
calculated creatinine clearance > 30 mL/min by the modified Cockcroft and 


 
 
 
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Gault Formula OR glomerular filtration rate > 30 mL/min/BSA by 
Modification of Diet in Renal Disease or CKD-EPI formula 
 
3.3.2.8  
Women and men of child-bearing potential must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating 
physician immediately.  
3.3.2.9  
Patients must have the ability to understand and the willingness to 
sign a written informed consent document.  
3.3.3 
Exclusion criteria 
3.3.3.1  
Patients may not receive any other anti-cancer treatments while on 
study. Patients cannot have received another anti-cancer chemotherapy or 
immunotherapy or radiotherapy or investigational agent within 2 weeks 
prior to the first dose of study treatment. 
3.3.3.2  
Patients with untreated known brain metastases, or treated brain 
metastases that are clinically unstable.  
 
3.3.3.3  
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, or psychiatric illness/social situations that would limit compliance 
with study requirements.   
3.3.3.4  
Women known to be pregnant. 
3.3.3.5  
Women who are breastfeeding and who are unwilling to stop 
breastfeeding prior to study entry. 
 
 
 
3.3.3.6  
Patients with known prior HIV-positive status on combination 
antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions.  Known prior HIV-positive patients with 
CD4
+ ≤ 500/mm
3 are ineligible because of the potential increased risk of 
infection.  (HIV testing is not required as part of this study). 
3.3.3.7  
Pre-existing interstitial lung disease 
3.3.3.8  
Inability to take oral medications 
3.3.3.9  
Prior therapy with afatinib  
3.3.4 
Removal of patients from therapy or assessments  
In the absence of treatment delays due to adverse event(s), treatment may continue until 


 
 
 
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one of the following criteria applies:  
• Disease progression,  
• Intercurrent illness that prevents further administration of treatment,  
• Pregnancy, 
• Unacceptable adverse event(s),  
• Patient decides to withdraw from the study,  
• General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
3.3.5 Specifics regarding tumor testing for study enrollment 
 
 
 
Analysis of results of tumor somatic testing from a CLIA-certified laboratory is 
required for study eligibility determination. Such testing may have been performed 
historically (previously), or testing may be conducted specifically for the purposes of study 
eligibility screening. If the latter, it is encouraged that patients consider signing the consent in 
advance of desired study entry so as to allow time for tumor results to become available 
(tissue pre-screening). It is permissible to consent patients even while they are receiving other 
anti-cancer therapy as long as such patients have unresectable metastatic urothelial 
carcinoma. Patients without measurable metastatic disease are not eligible for genomic pre-
screening under the auspices of this study. A central (sponsor-provided) CLIA-certified 
laboratory is available to conduct tumor sample pre-screening for this study. If testing is 
sought through this dedicated (sponsor-provided) central laboratory, a turn-around time of at 
least 14 days from the time of receipt of the sample should be expected. If a result from a 
local CLIA-certified laboratory is proposed for eligibility screening, the local laboratory must 
be first approved by the central study PI. No new (fresh) tumor biopsies should be sought 
under the auspices of this study, however such biopsies may of course be performed for 
standard of care reasons or if felt to be clinically appropriate as part of routine care in the 
view of the treating physician. 


 
 
 
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4. 
TREATMENTS 
 
4.1 
TREATMENTS TO BE ADMINISTERED 
Patients will receive afatinib. 
4.1.1 
Identity of investigational product  
Substance (INN): 
 
afatinib 
 
4.1.2 
Selection of doses in the study 
All patients will receive afatinib at a starting dose of 40 mg/day given continuously.   
4.1.3 
Drug assignment and administration of doses for each patient 
4.1.3.1 Afatinib 
For administrative purposes treatment will be divided into treatment courses, which are each 
8 weeks (56 days) in duration. Patients will take a single oral dose of 40 mg afatinib each day 
(56 days/cycle).  All patients will start with 40 mg tablets and in the event that dose reduction 
is necessary, the patient will return to the clinic and new medication will be dispensed. 
Dose reductions should be performed according to Table 4.1.3.2:1. 
 
The medication should be taken at approximately the same time each day (± 2 hours) and 
should be taken without food (i.e. afatinib should be taken at least 1 hour before or at least 2 
hours after a meal). 
 
Missed doses of afatinib can be made up if taken within 6 hours of the regularly scheduled 
time. Otherwise, the dose should be skipped and patients should take the next scheduled dose 
at the usual time. Patients with emesis should not take a replacement dose. 
 
4.1.3.2.   Dose reduction/drug discontinuation scheme for afatinib 
In the event of treatment-related toxicities, the treatment with afatinib should be handled 
according to the schedule in Table 4.1.3.2:1. 
 
 
 
 


 
 
 
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Table 4.1.3.2:1  
Dose reduction/dose discontinuation scheme 
AE Type and grade 
Action 
Dose reduction/ discontinuation 
scheme 
Grade 4 rash 
Permanently discontinue afatinib 
Permanently discontinue afatinib 
Grade ≥3 interstitial lung disease 
Permanently discontinue afatinib 
Permanently discontinue afatinib 
Grade 4 hepatic impairment 
Permanently discontinue afatinib 
Permanently discontinue afatinib 
Grade ≥3 keratitis 
Permanently discontinue afatinib 
Permanently discontinue afatinib 
Grade 2 left ventricular dysfunction 
(i.e., new resting ejection fraction of 
40-50%; OR a 10-19% drop from 
baseline)4 
Pause treatment with afatinib for 14 
days and then repeat MUGA scan.  If 
the ejection fraction has resolved to 
grade 1 or better at the time of the 
repeat MUGA, study drug will be 
resumed.  If the toxicity has not 
resolved, afatinib should be 
permanently discontinued. 
If patient was receiving 40 mg, 
resume treatment at 30 mg3.  If patient 
was receiving 30 mg, resume 
treatment at 20 mg3.  If patient was 
receiving 20 mg, discontinue afatinib. 
Any symptomatic (grade ≥3) left 
ventricular dysfunction5 
Permanently discontinue afatinib 
Permanently discontinue afatinib 
CTCAE grade ≥2 diarrhea persisting 
for 2 or more consecutive days (48 
hours) despite adequate anti-diarrheal 
medication/hydration 
Pause treatment with afatinib until 
toxicity has recovered to CTCAE 
grade ≤1 or baseline1.  If patient has 
not recovered to CTCAE grade ≤1 
within 14 days, study treatment 
should be permanently discontinued2 
If patient was receiving 40 mg, 
resume treatment at 30 mg3.  If patient 
was receiving 30 mg, resume 
treatment at 20 mg3.  If patient was 
receiving 20 mg, discontinue afatinib. 
CTCAE grade ≥2 nausea and/or 
vomiting persisting for 3 or more 
consecutive days despite anti-emetic 
treatment/hydration 
CTCAE grade 2 or grade 3 worsening 
of renal function as measured by 
serum creatinine, newly developed 
proteinuria, or newly developed 
decrease in glomerular filtration rate 
of more than 50% from baseline 
CTCAE grade 4 worsening of renal 
function 
Permanently discontinue afatinib 
Permanently discontinue afatinib 
Any other drug related AE CTCAE 
grade ≥3 
Pause treatment with afatinib until 
toxicity has recovered to CTCAE 
grade ≤1 or baseline1.  If patient has 
not recovered to CTCAE grade ≤1 
within 14 days, study treatment 
should be permanently discontinued2 
If patient was receiving 40 mg, 
resume treatment at 30 mg3.  If patient 
was receiving 30 mg, resume 
treatment at 20 mg3.  If patient was 
receiving 20 mg, discontinue afatinib. 
1 Baseline is defined as the CTCAE grade until start of treatment 
2 In the event that the patient is deriving obvious clinical benefit in the opinion of the investigator, but has not recovered 
within 14 days, the further treatment of the patient will be decided by the lead PI who may consult with the appropriate 
individuals at BI. 
3 Once a dose reduction is applied, the reduced dose is maintained unless further dose reduction is needed. 
4 Defined according to CTCAE version 4.0, page 109, adverse event denoted as “ejection fraction decreased”  


 
 
 
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5 Defined according to CTCAE version 4.0, page 9, adverse event denoted as “left ventricular systolic dysfunction”  
 
Dose reduction should always follow a treatment pause. In the event of a treatment pause, 
subsequent visits/courses should not be delayed. 
 
In the event of a prolonged (≥7 consecutive days) Grade 2 drug-related event not listed in 
Table 4.1.3.2:1, which is poorly tolerated by the patient, the treating investigator may choose 
to pause the medication for up to 14 days to allow the patient to recover followed by a dose 
reduction according to the schedule in Table 4.1.3.2:1. 
In the event of any unrelated adverse events or unrelated serious adverse events, the treating 
investigator may choose to pause the medication for up to 7 days to allow the patient to 
recover, but no dose reduction should occur. If the treating investigator chooses to pause the 
medication for more than 7 days and believes that the patient would derive clinical benefit 
from continuing medication, the decision to continue medication will be made by the lead   
investigator who may consult with BI’s medical monitor. 
4.1.4 
Packaging, labelling, and storage 
Medication numbers will be unique to each bottle and will be used for tracking purposes 
only.  
4.1.4.1  
Afatinib dispensing 
Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 40, 30, 
and 20 mg. Tablets will be supplied in HDPE, child-resistant, tamper-evident bottles. 
Bottles/boxes will be labelled according to local regulations and will include the following as 
a minimum; 
• Study number (13-0540/ 1200.171) 
• Product name: afatinib 
• Contents of the bottle (30 tablets) 
• Tablet strength (mg) 
• Batch number 
• Medication number 
• Use-by date 
• Storage information 
• Instructions for use 
• Sponsor name and address 
• A statement that the medication is for clinical study use only 
• A caution statement 


 
 
 
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Since pill bottles contain #30 tablets, patients will be given two pill bottles on day 1 of the 
first cycle (to have adequate supply to complete the entire cycle), and two bottles on day 1 of 
each subsequent cycle. All patients will start with 40 mg tablets and in the event that dose 
reduction is necessary, the patient will return to the clinic and new medication will be 
dispensed. 
4.1.4.2 Storage conditions 
Afatinib must be stored in the original packaging. Film-coated tablets are humidity and light 
sensitive and therefore bottles must be kept tightly closed. Tablets will be stored at the study 
site in a limited access area and must be stored in accordance with the instructions on the 
label.  
4.1.5 
Drug accountability 
Drug supplies, which will be provided to the study sites by Boehringer Ingelheim, will be 
kept in a secure, limited access storage area under the storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. 
The responsible person must maintain records of the product’s delivery to the study site, the 
inventory at the site, the use by each patient, and the return to the Boehringer Ingelheim or 
alternative disposition of unused product(s).  
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and study patients. The 
responsible person will maintain records that document adequately that the patients were 
provided the doses specified and reconcile all investigational product(s) received from 
Boehringer Ingelheim.  The responsible person must verify that all unused or partially used 
drug supplies have been returned by the clinical study patient. 
 
 
 
 
 
 


 
 
 
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4.2 
CONCOMITANT THERAPY, RESTRICTIONS, PRECAUTIONS, AND 
RESCUE TREATMENT 
4.2.1 
Rescue medication, emergency procedures, and additional treatment(s) 
Rescue medications to reverse the actions of afatinib are not available. Side effects of these 
treatments should be treated symptomatically. Growth factor support will be used following 
ASCO Guidelines. 
The current version of the investigator brochure lists the AEs expected with afatinib. 
Suggested treatments for diarrhea, nausea, vomiting and rash/acne are described in Section 
4.2.3.  
During study participation symptomatic treatment of tumor associated symptoms is allowed. 
Treatment with corticosteroids is allowed. Concomitant medications or therapy to provide 
adequate care may be given as clinically necessary. All concomitant (non-oncological) 
medications which are taken between study informed consent and the first follow-up visit 
should be recorded in the case report form (CRF) with the start and end of treatment dates, 
the total daily dose, the respective unit and the reason for use. 
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnea, cough, fever) should be performed to exclude ILD. 
Study drug should be interrupted pending investigation of these symptoms. If 
interstitial lung disease is diagnosed, study drug should be permanently discontinued 
and appropriate treatment instituted as necessary. 
4.2.2 
Restrictions 
4.2.2.1 Restrictions regarding concomitant treatment 
Patients may not receive any other anti-cancer treatments while on study (bone-directed 
supportive therapies such as bisphosphonates or RANKL inhibitors are permitted). Patients 
cannot have received another anti-cancer chemotherapy or immunotherapy or investigational 
agent within 2 weeks prior to the first dose of study treatment, and cannot have received 
radiotherapy within 4 weeks prior to the first dose of study treatment.  
4.2.2.2 Restrictions on diet and life style 
For afatinib: 
Afatinib should be taken without food (i.e. afatinib should be taken at least 1 hour before or 
at least 2 hours after a meal). 
In the event of diarrhea, patients should be advised to avoid lactose-containing products or 
any foods known to aggravate diarrhea. 
To prevent skin related adverse events it is currently proactively recommended to avoid 
intense irradiation with UV light, e.g. sunbathing or visiting a solarium, and to use strict sun 


 
 
 
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protection during the treatment period of the study. In case of sun exposure a sunscreen of 
Sun Protection Factor 15 (SPF 15) or higher, preferably containing zinc oxide, should be 
used, preferably a thick, alcohol-free emollient cream. Harsh detergents should be avoided. 
4.2.2.3  Precautions 
Keratitis is a known adverse event associated with afatinib, and it should be used with caution 
in patients with a known history of keratitis, ulcerative keratitis, or severe dry eye. Although 
contact lens use is a risk factor for keratitis and ulceration, the use of contact lenses will not 
preclude patient enrollment to this study.   
4.2.3  
Concomitant therapy 
4.2.3.1 Management of diarrhea following treatment with afatinib 
Close monitoring and proactive management of diarrhea is essential for successful treatment 
of patients with afatinib. Early and appropriate intervention can prevent the development of 
more severe diarrhea. In most cases, loperamide controls diarrhea caused by afatinib. 
Loperamide should be available at the start of therapy and kept with the patient at all times; it 
is therefore advisable that patients be given a prescription at the time of initiating treatment 
with afatinib. 
The recommendations for management are as follows (see also Section 4.2.2.2): 
• If any diarrhea is experienced (CTCAE Grade 1), two 2 mg loperamide tablets should 
be taken immediately, followed by one 2 mg tablet with every loose bowel 
movement, up to a maximum daily dose of 10 tablets (20 mg). 
• Oral hydration is essential regardless of severity; appropriate rehydration (1.5 
L/m²/day plus equivalent of actual fluid loss) and electrolyte replacement has to be 
ensured in the event of CTCAE Grade 2 and Grade 3 adverse events. 
• For CTCAE Grade ≥2 diarrhea lasting ≥ 2 days (48 hours) despite adequate 
antidiarrheal treatment, afatinib must be paused until recovery to CTCAE ≤ Grade 1. 
Upon recovery, afatinib should be resumed at a reduced dose according to the dose 
reduction scheme outlined in Section 4.1.3.2. 
The occurrence of diarrhea and the outcome of treatment will be recorded in the AE section 
of the CRF.  
If despite optimal supportive care and a treatment pause diarrhea does not resolve to CTC 
Grade ≤ 1 within 14 days, the patient must not receive any further afatinib treatment.  
 


 
 
 
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4.2.3.2 Management of nausea and vomiting following treatment with afatinib 
Nausea and vomiting may significantly affect patients’ adherence to the treatment and their 
quality of life. In order to reduce the occurrence and the intensity of emesis, the patients 
should be treated according to the recommendation given in Table 4.2.3.2:1. 
 
 
 
 
Table 4.2.3.2: 1 
 
Management of nausea and vomiting 
 
CTCAE Grade 
Antiemetic treatment 
Nausea = grade 0  
and 
Vomiting = grade 0 
No antiemetic prophylactic treatment 
Nausea = grade 1 
and 
Vomiting = grade 0 
Antiemetic treatment if deemed necessary 
by the investigator 
Nausea = grade 2 
and 
Vomiting = grade 0 
 
Nausea = grade 0, 1 or 2 
and 
Vomiting = grade 1 or 2 
Antiemetic treatment1 
 
Pause afatinib treatment if grade 2 vomiting 
or grade 2 nausea persists for 3 or more 
consecutive days despite optimal supportive 
care. Resume treatment when CTCAE 
grade ≤ 1. 
Vomiting ≥ grade 3 
or 
Nausea ≥ grade 3 
Antiemetic treatment1 
 
Pause afatinib treatment until return to 
CTCAE grade ≤ 1 or baseline2. 
 
 
1 
Antiemetic treatment should follow the recommendations given in the Consensus Statement of the 
Antiemetic 
Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC): Prevention of 
chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference (R06-
0986). 
2 
Baseline is defined as the CTCAE grade at the start of treatment. 
 
After a treatment pause the dose of afatinib should be reduced according to the dose 
reduction scheme in Table 4.1.3.2:1. 
The occurrence of nausea and/or vomiting and the outcome of treatment will be recorded in 
the AE section of the CRF.  
In case of nausea and/or vomiting ≥ CTCAE grade 2, appropriate hydration (1.5 L/m²/day 
plus hydration deficit) must be ensured. 


 
 
 
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4.2.3.3 Management of rash following treatment with afatinib 
A proactive and early approach to management of rash is crucial. Rash can be managed by a 
variety of treatment options to relieve symptoms and to reduce the rash.  
The recommendations for management are as follows: 
• General/Prevention: see Section 4.2.2.2 
• CTCAE Grade 1 rash: mild rash may not need treatment. However, if treatment is 
considered necessary, topical hydrocortisone (1% or 2.5%) cream and/or clindamycin 
1% gel can be used. 
• CTCAE Grade 2 rash: relief from major symptoms caused by CTCAE Grade 2 skin-
related adverse events should be achieved by a combination of local and systemic 
therapies including: 
o Systemic antibiotics (e.g. doxycycline or minocycline, etc.). 
o Topical treatment (e.g. hydrocortisone 2.5% cream, clindamycin 1% gel, 
pimecrolimus  1% cream) 
and / or 
o Antihistamines (e.g. diphenhydramine, etc.) 
• Oral corticosteroid (low dose and short term, i.e. < 10 days treatment) may be added 
at the investigator’s discretion. 
o Systemic and topical treatment should be initiated at the start of CTCAE 
Grade 2 rash and continued until improvement or resolution to CTCAE Grade 
≤ 1. If grade 2 rash persists for ≥ 7 days despite treatment and is poorly 
tolerated by the patient, the investigator may choose to pause treatment for up 
to 14 days followed by a reduction in the dose of afatinib according to the 
dose reduction scheme in Table 4.1.3.2: 1. 
• CTCAE Grade 3 rash: may be treated in a manner similar to CTCAE Grade 2 rash. In 
the event of CTCAE Grade 3 rash, treatment with afatinib should be paused until 
recovery to CTCAE Grade ≤ 1. Treatment should be resumed at a reduced dose (see 
Section 4.1.3.2). If CTCAE Grade 3 rash does not resolve to CTCAE Grade ≤ 1 
within 14 days of stopping afatinib treatment and despite optimal supportive care, the 
patient should not receive any further treatment with afatinib. 
• CTCAE grade 4 rash:  permanently discontinue afatinib. Treatment should be in a 
manner similar to CTCAE Grade 2/3 rash 
 


 
 
 
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 4.3 
TREATMENT COMPLIANCE 
 
Assessment for compliance will be conducted using pill counting at the end of each 
cycle.  Remaining pills at the end of the cycle will be noted in the patient’s research chart and 
discarded prior to provision of study drug for the subsequent cycle.  A pill diary will be used 
and completed by the study nurse after each cycle.  
5. 
VARIABLES AND THEIR ASSESSMENT 
5.1 
EFFICACY  
5.1.1 
End point(s) of efficacy 
The first portion of this trial which aimed to determine PFS3 in an unselected population of 
urothelial cancer patients has been fully accrued, analyzed, and published24. Based on those 
data, the below end points reflect those of the new amendment for this study. 
Primary endpoint: 
To determine the 6-month PFS rate of molecularly-selected metastatic urothelial cancer 
patients treated with afatinib who have progressed despite prior platinum-based 
chemotherapy. 
Radiographic assessment of responses will be performed via CT or MRI every 8 weeks until 
disease progression is observed or until drug intolerability.   
Secondary endpoints: 
To determine the overall response rate (CR + PR), median progression free survival, and 
overall survival for the same treated population. 
To examine the role of different ErbB alterations in determining afatinib activity in urothelial 
cancer. 
Exploratory Endpoints: 
To determine the PFS6 rate, overall response rate, and OS among the predefined subset of 
patients with qualifying alterations exclusive of EGFR alterations. 
To determine whether tumor EGFR and/or HER2 expression, or, alternatively, whether 
certain microRNAs, influence 6-month PFS in patients treated with afatinib. 
This exploratory endpoint is based on the hypothesis that the level of EGFR and/or HER2 
expression may influence drug activity. One study which required expression of either EGFR 
or HER2 prior to enrollment examined the variability of these markers in patients with 
refractory advanced/metastatic urothelial cancer26. For EGFR, the respective percentages of 
patients with each expression quartile were 12% (0), 35% (1), 33% (2), and 19% (3).  For 
HER2, the quartile percentages were 23% (0), 32% (1), 37% (2), and 7% (3).  Notably, 71% 


 
 
 
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of patients had high overexpression (defined as 2+ or 3+) of at least one of the targets.  
Additionally, 22% of patients had high co-overexpression (2+ or 3+ for both EGFR and 
HER2). The method used for quantifying expression will follow standard commercially 
developed assays. 
Alternatively, studies have suggested that epithelial-to-mesenchymal transition, a cellular 
development process that is associated with cellular invasion and migration, may confer 
resistance to EGFR-directed therapy27,28.  Specifically, in cell line models, expression of the 
microRNA miR-200 has been shown to induce mesenchymal-phenotype bladder cancer cells 
to adopt a phenotype resembling their epithelial counterparts, and to simultaneously increase 
sensitivity to EGFR inhibition29. We will therefore consider evaluation of tumor tissue for 
determination of whether tumor microRNAs like miR-200 have bearing on the 6-month PFS 
in this study. 
Finally, RNA profiling of available tissue may be performed if technically feasible. On a 
DNA level, specific genomic alterations may be confirmed/investigated post-hoc for 
scientific purposes (not for eligibility purposes), and overall mutational profiling may be 
assessed. 
5.1.2 
Assessment of efficacy 
5.2 
SAFETY 
5.2.1 
Endpoint(s) of safety 
Safety of afatinib will be evaluated as indicated by intensity and incidence of adverse events, 
graded according to US NCI CTCAE Version 4.0. Safety endpoints include: 
• events leading to dose reduction 
• events leading to permanent treatment discontinuation 
• the overall incidence and CTC criteria grade of adverse events, as well as relatedness of 
adverse events to treatment 
• causes of death 
5.2.2 
Assessment of adverse events 
5.2.2.1 Definitions of adverse events 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment. 
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability/incapacity, requires or prolongs 
patient hospitalization, is a congenital anomaly/birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 


 
 
 
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judgement which may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions. 
Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
A serious adverse event is considered to be a suspected adverse reaction (SAR) if there 
evidence to suggest a causal relationship to the study agent.  This may include a single 
occurrence of an event strongly associated with drug exposure (e.g. Stevens-Johnson 
Syndrome), one or more occurrence of an event otherwise uncommon in the study 
population, or an aggregate analysis of specific events occurring at greater frequency than 
expected. 
Unexpected events are those not listed at the observed specificity or severity in the listed 
adverse event section of the investigator brochure for the product. 
 
ALL SUSARS occurring on this clinical trial must be reported to the FDA by the University 
of Chicago/IND Holder.  Participating institutions that are not the University of Chicago will 
report SUSARS to the University of Chicago who will then report to the FDA. Refer to 
Sections 5.2.2.2 - 5.2.2.3 for full reporting guidelines.  
 
Intensity of adverse event 
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 in the University of Chicago 
CRF (eVelos system).  
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms.  
Yes: 
There is a reasonable causal relationship between the investigational product 
 
administered and the AE.  
No: 
There is no reasonable causal relationship between the investigational product 
 
administered and the AE.  
Worsening of the underlying disease or other pre-existing conditions 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF. 
 
Changes in vital signs, MUGA, physical examination, and laboratory test results 
Changes in vital signs, MUGA, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator. 
 


 
 
 
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5.2.2.2  Adverse event and serious adverse event reporting 
Upon inclusion into the study, the patient’s condition is assessed (e.g. documentation of 
history / concomitant diagnoses and diseases), and relevant changes from baseline are noted 
subsequently. 
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the 28 days follow-up period) will 
be collected, documented and reported to the sponsor by the investigator on the appropriate 
CRFs / SAE reporting forms (BI SAE report form or alternatively the CIOMS 
form/MEDWATCH form). 
 
Serious Adverse Event reporting will be done according to the specific definitions and 
instructions detailed in Section 5.2.2.3 below.  
For each adverse event, the treating investigator will provide the onset date, end date, CTC 
AE grade, treatment required, outcome, seriousness, and action taken with the investigational 
drug. The treating investigator will determine the relationship of the investigational drug to 
all AEs as defined in Section 5.2.2.1.  
Adverse events with onset within first administration of afatinib therapy and 28 days after last 
administration of afatinib will be considered as on treatment. All AEs, including those 
persisting after end of study treatment must be followed up until they have resolved or have 
been sufficiently characterized or the principal investigator decides to not further pursue 
them. 
Serious and non-serious adverse events occurring later than 28 days after last administration 
of trial drugs will only be reported in case they are considered drug-related or trial 
(procedure) related. 
Deaths (unless they are considered drug-related or trial related) will not be reported as SAE 
when they occur later than 28 days after last administration of the trial. 
5.2.2.3 Responsibilities for SAE reporting 
All SAEs occurring on this trial must be reported to the Study Chair/IND Holder, University 
of Chicago Comprehensive Cancer Center (UCCCC), and Boehringer Ingelheim 
Pharmaceuticals.  Events meeting the additional reporting criteria noted below will be 
reported to the Institutional Review Board and/or the FDA as applicable.   
 
5.2.2.3.1 Reporting Events to the UCCCC 
All serious adverse events and protocol violations/deviations must be reported to the UCCCC 
Cancer Clinical Trials Office (CCTO) in accordance with the UCCCC Data Safety 
Monitoring Plan.   
 
All serious adverse events occurring on this study require expedited reporting to the 
University of Chicago Comprehensive Cancer Center (UCCCC) Clinical Trials Office 
(CCTO).  The responsible Research Nurse or other designated individual at the treating site 


 
 
 
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should report the SAE to the CCTO by the end of the business day when s/he becomes aware 
of the event.  Events occurring after business hours should be reported to the CCTO by 12pm 
(noon) the next business day.  Reports should be made using the ‘Serious Event Report’ 
Form.  Please scan and send via email (preferred) or FAX to: 
 
University of Chicago Phase II CRA General 
PhaseIICRA@medicine.bsd.uchicago.edu 
Phone:  773-834-1746 
FAX:  773-702-4889 
 
UC CCC Cancer Clinical Trials Office of Quality Assurance 
qaccto@bsd.uchicago.edu 
 
All unexpected adverse reactions must be reported to both the IND holder and FDA.  The 
responsible Research Nurse or other designated individual at the treating site should also 
provide a more complete written report using the FDA MedWatch 3500A form/CIOMS form.  
The completed form should be sent to the CCTO at qaccto@bsd.uchicago.edu and to the 
Phase II CRA at PhaseIICRA@medicine.bsd.uchicago.edu, within the timelines specified 
below regardless of whether all information regarding the event is available.  If applicable, a 
follow-up report should be provided to the CCTO if additional information on the event 
becomes available.   
 
Fatal or Life-threatening Events: within 4 calendar days from treating investigator 
knowledge of the event 
 
All Other Reportable Events: within 10 calendar days of treating investigator 
knowledge of the event 
 
Participating sites should not forward any adverse event reports directly to the FDA.  The 
UCCCC CCTO will report all events to the FDA as per the current FDA guidelines.  
 
5.2.2.3.2  Reporting Events to the Institutional Review Board 
 
Events meeting current UChicago IRB reporting criteria must be submitted by the principal 
investigator via the IRB’s electronic submission system within the IRB’s designated 
reporting timeframes.  Details of the IRB’s current reporting policy and timelines can be 
found on their website at: http://bsdirb.bsd.uchicago.edu/forms-guidelines/up.html . 
 
The responsible UChicago research nurse and/or clinical research associate/data manager are 
responsible for entering the appropriate information into the IRB’s electronic submission 
system and forwarding the submission to the principal investigator for reporting to the IRB.  
 
Events occurring at a participating site should be reported to the local IRB of record 
according to their policies and procedures. 
 
5.2.2.3.3  Reporting Events to Boehringer Ingelheim Pharmaceuticals  


 
 
 
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Each site shall report all SAEs and non-serious AEs occurring at the same time and/or which 
are medically related to the SAE and Adverse Events of Special Interest by fax:  
 
FAX #: 203-837-4329 
 
using the BI SAE report form or alternatively CIOMS/MEDWATCH form with BI cover 
letter form to the BI Unique Entry Point in accordance with the following timelines: 
 
within five (5) calendar days upon receipt of initial and follow-up SAEs containing at least 
one fatal or immediately life-threatening event; 
within ten (10) calendar days upon receipt of any other initial and follow-up SAEs. 
 
 
5.2.2.3.5  Reporting Events to Participating Investigators 
 
It is the responsibility of the assigned CCTO Regulatory Manager on behalf of the IND 
Holder to notify all participating sites of all unexpected and serious suspected adverse 
reactions that occur on this clinical trial and which are reported to the FDA as an IND Safety 
Report (21 CFR 312.32).  A copy of the completed Form 3500A (MedWatch) and/or IND 
Safety Report Narrative will be provided to the responsible Regulatory Manager by the IND 
Coordinator for distribution to all participating sites. 
 
5.2.2.4 Adverse Events of Special Interest 
Although rare, drug-induced liver injury (DILI) is under constant surveillance by sponsors 
and regulators and is considered a protocol-specified significant adverse event.  Timely 
detection, evaluation, and follow-up of laboratory alterations of selected liver laboratory 
parameters to distinguish an effect of the underlying malignancy on liver function from other 
causes are important for patient safety.  The following are considered as Protocol-specified 
significant events: 
 
Hepatic injury defined by the following alterations of liver parameters:  
• For patients with normal liver function (ALT, AST and bilirubin within normal limits) 
at baseline, an elevation of AST and/or ALT >3 fold ULN combined with an 
elevation of bilirubin >2 fold ULN measured in the same blood draw sample.  Patients 
showing these lab abnormalities need to be followed up according to this clinical trial 
protocol. 
 
• For patients with abnormal liver function at baseline, an elevation of AST and/or ALT 
>5 fold ULN combined with an elevation of bilirubin >2 fold ULN measured in the 
same blood draw sample.  Patients showing these lab abnormalities need to be 
followed up according to this clinical trial protocol.    
   


 
 
 
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Protocol-specified significant events are to be reported in an expedited manner similar to 
Serious Adverse Events, even if they do not meet any of the seriousness criteria - for details 
please see section 5.2.2.2. 
 
If the investigator determines any protocol-specific significant event is related to study drug, 
the administration of the study drug must be managed according to section 4.1.3 of the 
protocol. 
 
5.2.3 Assessment of safety laboratory parameters 
Blood samples will be collected at the time points specified in the Flow Chart and analyzed in 
a laboratory facility at (or close to) the investigational site. Safety laboratory examinations 
include hematology and biochemistry. In case of neutropenia, blood will be examined as 
clinically indicated at the discretion of the treating investigator until recovery. 
Safety laboratory assessment may be performed according to local practice but must include 
at least the following parameters: 
Hematology 
Red blood cell count (RBC), neutrophils, hemoglobin, white blood cell 
count (WBC) and differential, platelets. 
Biochemistry 
Sodium, potassium, calcium, magnesium, creatinine, aspartate amino-
transferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase,  total bilirubin, urea (BUN), PO4. Glomerular Filtration 
Rate (GFR) will be estimated by the modified Cockroft Gault, MDRD, 
or CKD-EPI Formula utilizing serum creatinine values 
5.2.4 Assessment of other safety parameters 
5.2.4.1 Physical examination, performance score 
A physical examination will be performed at screening and at the time points specified in the 
Flow Chart.  
A full physical exam serves as a clinical tumor assessment and should include a 
cardiopulmonary examination and an assessment of the mental and neurological status. 
Additional symptoms which have not been reported during a previous examination should be 
clarified. Wherever possible the same investigator should perform this examination. 
Measurement of height (in cm), body weight (in kg) and body temperature and the evaluation 
of the ECOG performance score will be performed at the time points specified in the Flow 
Chart. 
5.2.4.2 Left ventricular function 
Left Ventricular Ejection Fraction (LVEF) as measured by Multi-Gated Acquisition Scan 
(MUGA) will be assessed at time points specified in the Flow Chart. 


 
 
 
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5.2.4.3 Vital signs 
Vital signs (blood pressure and pulse after 2 minutes supine rest) and temperature will be 
recorded at the screening visit and at the time points specified in the Flow Chart. 
5.3 
OTHER 
5.3.1 
Demographics and history 
Demographics (sex, birth date), information on smoking and alcohol history, and baseline 
conditions will be collected during the screening visit. 
The date of first histological diagnosis (month and year may be sufficient) and type of tumor 
histology will be reported in the CRF.  The number and locations of metastatic sites (liver, 
lung, peritoneum, brain, other) as well as the stage according to the tumor, (lymph) node, 
metastasis (TNM) classification will be provided as obtained at diagnosis and at the inclusion 
into the trial.  Previous surgery and radiotherapy will be reported.   
Previously administered chemo- or radiotherapy will be reported including start and end dates 
(month and year may be sufficient), the therapy protocol with the number of courses 
(chemotherapy), total radiation dose and radiation field (radiotherapy) and the best response 
obtained (complete response, partial response, stable disease, progressive disease, unknown).  
5.4 
APPROPRIATENESS OF MEASUREMENTS 
The RECIST criteria 1.1 to be used for evaluation of tumor response are well established and 
scientifically accepted. The US NCI CTCAE criteria Version 4.0 are used in the assessment 
of adverse events in cancer patients. Lesions that have been irradiated as the most recent line 
of treatment are not eligible as RECIST target lesions. 
6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
Patients must be seen to complete the informed consent process in person and to undergo a 
baseline assessment according to the Flow Chart.  After screening and registration, the patient 
will be seen on Day 1 of treatment initiation, and every 2 weeks during study treatment for 
the first 12 weeks. After 12 weeks, patients remaining on treatment will be seen in person 
monthly. It is permissible and encouraged that patients who a treating physician feels may be 
at higher than average risk for toxicity from afatinib should be seen at one extra in-person 
visit, 1 week after starting study therapy (on cycle 1 day 8). 
Radiographic assessment of responses will be performed via CT scans of the 
chest/abdomen/pelvis every 8 weeks until disease progression is observed or until drug 
intolerability.   


 
 
 
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6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS 
6.2.1 
Screening period 
Baseline evaluations are to be conducted within 21 days prior to start of protocol therapy.  
See the Flow Chart for details of required screening procedures. 
6.3. REGISTRATION PROCEDURES  
6.3.1   General Guidelines  
All eligible patients will be registered centrally by the University of Chicago Clinical 
Research Associate assigned to the study. All sites should call the CRA to verify 
availability of a slot. Following registration, patients should begin protocol treatment 
within the window specified in 6.2.1.  Issues that would cause treatment delays should be 
discussed with the Lead Principal Investigator. If a patient does not receive protocol 
therapy following registration, the patient’s registration on the study may be canceled. 
The CRA should be notified of cancellations as soon as possible. 
6.3.2  Registration Process  
Pre-registration for Screening 
 
• All patients must be pre-registered with the UC Phase II coordinator to obtain a 
screening ID number. This ID number will be used for the screening mutation 
testing involved on this trial. Please email the UC Phase II coordinator at 
PhaseIICRA@medicine.bsd.uchicago.edu to obtain this screening number.  
 
Treatment Registration 
Once the signed informed consent has been obtained, all pretreatment evaluations have 
been performed, and patient’s eligibility has been confirmed by the University of Chicago a 
patient will be registered on study.  
When a potential patient has been identified, notify the CRA via phone or email to ensure a 
reservation on the study. Reservations for potential subjects will only be held for subjects 
who have signed consent for that particular study. 
To register a patient, the research nurse or data manager must complete the 
eligibility/registration form and contact the central study office at the University of Chicago 
(Phone 773-834-1746) or fax a copy of the completed eligibility checklist, signed Informed 
Consent, medical history documents, and results from the baseline evaluations (FAX 
Number 773-702-4889) or email (email preferred) to: 
PhaseIICRA@medicine.bsd.uchicago.edu 
When registering a subject, the following must occur:  


 
 
 
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• Confirm that the institution has current IRB approval of the correct version of 
protocol/consent and has an annual update on file.  
• Submit all required materials (Eligibility Checklist, Source documentation, & signed 
consent form) to confirm eligibility and required pre-study procedures to the CRA a 
minimum of 48 hours prior to the subject’s scheduled therapy start date.  
• Source documentation includes copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source 
documentation but rather as a checklist that original source documentation exists for 
each criterion. 
• Communicate with the above CRA to ensure all necessary supporting source 
documents are received and the potential subject is eligible to start treatment on 
schedule. If there are questions about eligibility, the CRA will discuss it with the PI. 
PI may clarify, but not overturn, eligibility criteria.  
• Affiliate sites must confirm registration of subjects by obtaining a subject study ID 
number from the CRA via phone, fax or email.  
• If a subject does not start on the scheduled day 1 treatment date, promptly inform the 
CRA as the delay in start may deem the subject ineligible and/or require further or 
repeat testing to ensure eligibility.  
• The date the patient is randomized if randomization is involved or receives treatment 
for the first time will be considered the patient’s “OnStudy Date.” The patient’s 
subject ID will be assigned and a confirmation of registration will be issued by the 
CRA on this date. Subjects that sign consent and do not go “OnStudy” will be 
recorded in the database with the date they signed consent and the reason for not 
going “OnStudy” (e.g., Ineligible, Screen Failure or Withdrawn Consent).  
 
Data Reporting 
Data reporting will be performed utilizing the eVelos electronic data capture system.  Prior to 
study initiation, all participating sites must have eVelos users registered and trained on use of 
the system.  The University of Chicago CRA will provide each site with the applicable user 
registration information. 
 
All required data must be recorded in the eVelos database at the completion of each cycle.  
AEs are to be entered in real time. SAEs are to be entered on the Serious Event Form within 
24 hours of the site’s knowledge of the event and sent via email (preferred) or fax to the 
University of Chicago (PhaseIICRA@medicine.bsd.uchicago.edu or 
qaccto@bsd.uchicago.edu; Fax: 773-702-4889). All case report forms must be completed by 
designated study personnel. Each screened (consented) patient is to be entered into eVelos 
within 48 hours of patient registration. In addition to direct data entry, you may be required to 
provide supporting source documentation. Source records are original documents, data, and 
records (e.g., medical records, raw data collection forms, pharmacy dispensing records, 
recorded data from automated instruments, laboratory data) that are relevant to the clinical 
trial. Each site will prepare and maintain adequate and accurate source documents. These 
documents are designed to record all observations and other pertinent data for each subject 
enrolled in this clinical trial. Source records must be adequate to reconstruct all data 
transcribed onto the case report form. 
 


 
 
 
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6.4  After Registration 
Biomarker Studies 
As exploratory endpoints of this trial, we propose retrospective tumor testing of (1) EGFR 
and/or HER2 expression status; (2) epithelial to mesenchymal transition states30; (3) novel 
microRNAs29 since they may relate to response rates in this study; (4) post hoc 
investigational/confirmatory testing of specific somatic genomic alterations to understand the 
role of specific alterations in drug sensitivity; and (5) investigation of germline 
pharmacogenomic determinants that may be associated with drug activity and/or toxicity. 
These analyses (and the requested research tissues) are separate from those required for study 
eligibility. 
 
For each registered patient, the enrolling institution will pursue and obtain archival tumor 
tissue from the patient’s primary urothelial cancer surgery.  Patients will be asked to consent 
to release of this tissue during enrollment.  For these exploratory biomarker studies, if a 
patient’s tumor is not able to be located, this does not make the patient ineligible for the 
study, however, full attempts at procurement of this tissue for all enrolled patients is 
mandatory.  The following archival tissue types are needed (one from each below category is 
needed):  
1.  10 unstained slides cut at 5 microns for IHC purposes. 
AND 
2.  Paraffin blocks containing a tumor specimen measuring at least 0.5 cm x 0.5 cm x 100 
microns; OR 15-20 additional unstained slides cut at 10 microns; OR 8-10 core needle tissue 
punches of the tumor region deposited in a microcentrifuge tube. 
Tissue samples may be from original diagnosis or biopsy any time prior to first drug 
treatment, and as long as from a muscle-invasive or higher-stage urothelial cancer specimen 
(metastatic is permitted).  Securely label the specimens with the patient’s initials, registration 
number, and study number (University of Chicago IRB#).  Submitted tissues should be sent 
in a dry container at room temperature, boxed and labeled appropriately. 
Additionally, a single peripheral venous blood sample will be collected from each registered 
patient for the purposes of germline DNA extraction and potential future exploratory 
pharmacogenomic testing.  Whole blood (totaling 10 mL) should be drawn at one timepoint 
into ONE, 10 mL plastic lavender top tube (i.e. BD catalog # 366643).  Whenever possible, 
this blood draw should occur in conjunction with other standard of care phlebotomy.  The 
tube should be labeled with the patient’s ID#, initials, assigned study ID, date and clock time 
of sample acquisition.  The Pharmacogenomic Sample Sheet (APPENDIX 5) should be 
completed and provided with the samples. 
The above samples described in this Section, Section 6.4, should be sent by overnight 
delivery to: 
Attn:  Briana Rhodes 
Lab:  Peter H. O’Donnell (PI) 


 
 
 
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5841 S. Maryland Ave. 
MC 2115 
The University of Chicago 
Chicago, IL  60637 
 
Please notify Briana Rhodes by e-mail on the day of mailing at:    
                   brhodes@medicine.bsd.uchicago.edu  
 
6.5 
Treatment period(s) 
A cycle will be defined as 56 days (8 weeks) of continuous daily therapy.  Treatment may 
continue indefinitely in the absence of disease progression or unacceptable toxicity. 
6.6 
End of study treatment and follow-up period 
All patients must be seen for an end of study visit to occur 28 days following their date of 
treatment discontinuation.  Patients will thereafter be followed at a minimum of every 3 
months until the patient dies or refuses further follow up, or until three years of follow up are 
reached. 
7. 
STATISTICAL METHODS  
7.1 
PLANNED ANALYSES 
7.1.1 
Primary analyses 
This is a continuation of a single-arm phase II study.  The previous phase of this study 
allowed enrollment of patients without respect to genomic marker status (‘non-marker 
selected population’).  That prior phase has been fully accrued (total n=23 patients), 
completed, and has been analyzed  separately per the original statistical plan24. 
 
The present continuation portion of this phase II trial will enroll only patients whose tumors 
harbor genomic alterations in one or more of the ErbB family genes. This will comprise the 
‘marker-selected population’ of this continuation trial. 
 
In a meta-analysis of second-line clinical trials in patients with advanced urothelial 
carcinoma31, the overall estimated progression-free survival (PFS) rate at 6 months was 
22.6% (95% CI:  18.8%-25.9%), although it varied from 34.6% in patients with no risk 
factors (liver metastases, ECOG 1+, Hb<10 g/dl, or time from previous chemotherapy <6 
months) to 4.9% in patients with 3-4 risk factors. Thus over three-quarters of patients will 
have disease progression within 6 months, and we propose that PFS at 6 months would be an 
informative endpoint for assessing drug activity.   
 
For this continuation (marker-selected population) phase, a Simon31, optimal two-stage 
design will be employed to assess the primary end point of 6-month PFS rate.  The null 
hypothesis (H0), a 6-month PFS of <25%, will be considered representative of lack of 
efficacy of the drug in this biomarker-specific patient population consisting of patients with 
ErbB alterations.  The alternative hypothesis (HA), a 6-month PFS rate of >40%, will be 


 
 
 
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considered indicative of activity.  PFS will be defined as the time from enrollment until 
disease progression or death from any cause, and will be estimated using the Kaplan-Meier 
method, although we will follow the last patient entered for a minimum of 6 months to ensure 
that there is no censoring prior to 6 months.  For determination of the PFS curve, patients 
who are alive and progression-free will be censored as of the date of the last negative 
evaluation. 
 
For 90% power at one-sided alpha = 0.10, n=72 patients will be needed. Assuming the 
frequency of having an alteration in any of the four genes is 20%, this will require screening 
approximately 360 patients.  In the first stage, 29 patients will be enrolled and if 7 or fewer 
are alive and progression-free at 6 months the trial will be terminated for futility.  Otherwise 
an additional 43 patients will be enrolled.  At the end of the second stage, if 22 or fewer are 
alive and progression-free at 6 months the null hypothesis will be accepted and the treatment 
considered to be of insufficient efficacy, whereas if 23 or more (> 32%) exhibit progression-
free survival of 6 months or more the regiment will be considered promising and worthy of 
further study.  
 
Vinflunine is approved for use in urothelial cancer patients in the second-line setting in 
Europe32.  Separately, atezolizumab3, nivolumab33, durvalumab34, and pembrolizumab5 have 
recently been FDA approved and/or studied in this setting as well and have shown significant 
activity despite not showing demonstrable changes in PFS. We therefore contend that our 
chosen 6-month observed PFS rate of 32% or higher required to consider afatinib promising 
would compare afatinib very favorably in this disease. This level of activity would warrant 
consideration of further testing of afatinib in this disease and biomarker subgroup. 
 
We also considered in this statistical plan whether there are any relevant data about 
progression free survival in the subset of patients with ERBB alterations? Our prior data 
(from the first 23 patients of this trial)24 is the largest cohort we are aware of reporting PFS 
data in patients with different types of ERBB-altered tumours. However, two other prior 
studies may be additionally indirectly informative. Powles et al.23 recently examined 232 
patients with metastatic urothelial cancer who had undergone primary platinum-based 
chemotherapy and were then randomly assigned to lapatinib vs placebo. To be randomized, 
patients had to have “high expression” of HER1/2 (defined as immunohistochemistry 2+/3+ 
staining). While genomic alteration status was not reported in this study—making these data 
only tangentially pertinent to the present question—it is reasonable based on known 
correlation data between IHC and genomic amplification to assume that the trial would have 
included a higher portion of patients with true amplification than an entirely unselected 
metastatic urothelial cancer population. The authors found no difference in PFS between 
patients randomized to lapatinib (4.5 months) vs placebo (5.1 months). These PFS estimates 
correlate extremely well with the meta-analysis data that we have cited above (see also 
Sonpavde et al.37—data which showed 4.3-4.5 months as the estimated “PFS” for the 
immediate post-platinum setting in the absence of treatment). While not directly answering 
the question of a truly ERBB-altered population, the Powles et al. data therefore suggest that 
PFS is not significantly different in HER1/2-overexpressing patients compared to historical 
controls. 
 


 
 
 
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More relevant are the data from Fleischmann et al.22 which reported on 150 patients who had 
undergone cystectomy and were followed for survival. The primary tumours of these patients 
were assessed for HER2 amplification. Twelve (12) patients were found to be HER2 
amplified. While PFS data are not reported, it was interestingly noted that overall survival 
was significantly poorer in patients with HER2 amplified tumours (with an absolute 
shortening of overall survival by approximately 1 year; p=0.04). It would follow that PFS is 
also likely to be shorter (tracking with OS) in this genomic population. This would mean that 
the historical PFS estimate used in our study (which included all urothelial cancer patients 
notwithstanding genomic status) is, if anything, likely an over-estimate of the actual PFS of 
patients with ERBB alterations. We thus feel that our historical comparator assumptions in 
this statistical plan in fact thus set a very high bar (perhaps even higher than may be truly 
present for this genomic population, although the above data are very limited). This means 
that the success endpoint for detecting an effect of afatinib on PFS is likely very stringent, or, 
said another way, the above data do not suggest that the study design has an inherent bias in 
favor of detecting the effect (if anything, the bias is in the other direction). 
 
We would also argue that one of the potential values of our proposed selected cohort-
expansion study will be to better define the PFS in this only-recently appreciated population 
of patients.  
 
Secondly, afatinib treatment in the context of this trial will most likely be used as a “third 
line” therapy given the advent and FDA approval of immunotherapies in the traditional 
“second line” setting. We therefore examined recent data on immune therapy-treated patients 
to ensure that the above PFS estimates remained reasonable. 
 
First, none of the studies which have reported on the impressive activity of immunotherapies 
in the platinum-refractory setting for urothelial cancer have shown an impact on PFS 
compared to historical controls3,38,39. In fact, even in the landmark phase III pembrolizumab 
vs cytotoxic chemotherapy study for platinum-refractory patients5—which is the only study 
to show in a prospective, randomized fashion an overall survival benefit for immunotherapy 
in urothelial cancer—the PFS was not different between the two arms (median 2.1 months in 
the pembrolizumab arm and 3.3 months in the cytotoxic arm, HR 0.98 [0.81-1.19]; P=0.42). 
The PFS6 rate in both arms was approximately 26%. These PFS times compare very 
favorably to the estimates used to define our historical comparator estimate in the above 
statistical plan. Additionally, in the NEJM phase III trial5, 115 of the 542 (21%) randomized 
patients were indeed actually receiving the pembrolizumab or comparator cytotoxic 
chemotherapy in the “3rd line”, so the PFS estimates reported above in this paragraph from 
that trial do reflect the best available data from both “2nd” and “3rd” line populations. 
 
Secondly, Sonpavde et al. recently published cancer progression and survival data for patients 
in the post-PD-1/PD-L1 setting40. Reporting data from 62 patients across 4 institutions, the 
median time from last PD-1/PD-L1 inhibitor therapy to subsequent therapy (a mark which 
approximates the “PFS”, or the progression-free interval in the absence of ongoing treatment 
after immune therapy) was 58 (range 14-242) days. Additionally, of the 22/62 patients who 
received post-PD-1/PD-L1 inhibitor therapy, the median time to progression (on subsequent 
therapy) was 124 days. Both of these “3rd line” estimates overlap with the confidence 


 
 
 
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interval for the PFS data from the “second line” meta-analysis that was used for the above 
statistical assumptions.  
 
These aggregate external data suggest therefore that the statistical assumptions around PFS 
and PFS6 remain very reasonable and robustly reproducible estimates to use in the above 
afatinib statistical plan.  
 
Interim Analysis 
The interim analysis will be performed when 29 patients have either (a) completed study 
treatment or (b) have reached the 6 month time point without being removed from study 
treatment, or when the combination of (a) and (b) reaches 29. 
 
Patients remaining in the study at the time of the interim analysis will continue on treatment 
and will remain in the study, per the protocol. 
 
Enrollment of new patients will be temporarily suspended after the first 29 evaluable patients 
(satisfying the above (a) and (b) criteria) are identified, in order to perform the primary 
interim analysis needed to determine whether to proceed to stage two, unless the data are 
such that reaching (or not reaching) the first-stage boundary is determinate. 
 
7.1.2 
Secondary and exploratory analyses 
The overall response rate (CR + PR) will be calculated and reported, in addition to the 
median progression free survival and overall survival (OS) times for the study population. 
Median PFS and OS will be estimated along with 90% confidence intervals using the method 
of Brookmeyer and Crowley35.  Patients will be followed via phone calls and or medical 
records review even after coming off treatment for completion of the data for the PFS and OS 
endpoints. The PFS6, overall response rate, and OS will also be calculated among the 
predefined subset of patients with qualifying alterations exclusive of EGFR alterations. 
Exploratory analysis of tumor tissue in all patients will be conducted for determination of 
whether specific alterations (including investigation/confirmation of any alterations by 
alternative methods), tumor EGFR and/or HER2 expression status (IHC), epithelial to 
mesenchymal transition states, novel microRNAs, and/or RNA or DNA profiling have 
bearing on PFS. This will also include consideration of tumor genomic alterations found 
during screening via CLIA laboratory testing. We will also examine the rate of liver 
metastases (at enrollment) in patients reaching the PFS6 endpoint, versus those who do not. 
Cox regression models will be fit to test for associations with PFS. Additional analyses based 
on logistic regression modelling will examine associations between variables and partial or 
complete response. 
For the IHC testing secondary analysis, patients with EGFR IHC scores of 2+ and 3+ will be 
compared against patients with 0 or 1+ EGFR IHC scores for the primary endpoint (PFS).  
Similarly, patients with HER2 IHC scores of 2+ or 3+ will be compared to those with 0 or 1+ 
for the primary endpoint.  Finally, patients with overexpression of either marker (defined as 
2+ or 3+ IHC score for either EGFR or HER2) will be compared against those lacking 


 
 
 
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overexpression for both markers (EGFR and HER2 0 or 1+) for the primary endpoint.  Prior 
exploratory studies have demonstrated this to be a potentially informative stratification26. 
Somatic alteration results generated from the CLIA laboratory reports used for screening in 
this study will also be compiled and stored indefinitely in a research study database at The 
University of Chicago for the purposes of future cancer research by the study investigators. 
This will include all patients who screen for the study regardless of whether they ultimately 
receive treatment with study drug. 
7.1.3 
Safety analyses 
Safety analyses can occur at any time deemed necessary by the lead investigator or the drug 
sponsor and must occur at the first interim analysis (29 patients) and at the end of the study. 
Adverse event rates will be summarized by type, grade, and attribution and descriptive 
statistics (frequency distributions) generated. 
7.2 
HANDLING OF MISSING DATA 
A modified intention to treat (ITT) analysis will be performed which will include all patients 
who begin treatment with the drug (i.e., at least 1 dose administered). Thus patients who 
withdraw from therapy due to adverse events or for any other reason prior to 6 months will be 
counted as failures with respect to the primary endpoint (PFS).  Additional secondary 
analyses may be conducted excluding patients who discontinued treatment for reasons other 
than drug toxicity.  
8. 
Informed Consent, Data Protection, Study records 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the responsible Institutional Review Board IRB at each participating institution 
and the FDA according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and 
to ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent form 
must include all the relevant elements currently required by the FDA Regulations and local or 
state regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the 
study, the patient will be asked to give consent to participate in the study by signing an IRB 
approved consent form. 
Each signature must be personally dated by each signatory and the informed consent and any 
additional patient-information form retained by the investigator as part of the study records. 


 
 
 
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A signed copy of the informed consent and any additional patient information must be given 
to each patient or the patient’s legally accepted representative. The patient must be informed 
that his/her personal study-related data will be used by the Principal Investigator in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient. 
The patient must be informed that his / her medical records may be examined by authorized 
monitors (CRA) or Clinical Quality Assurance auditors appointed by the Principal 
Investigator, by appropriate IRB members, and by inspectors from regulatory authorities. 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be provided to 
the Cancer Clinical Trials Office (CCTO) at the University of Chicago Comprehensive 
Cancer Center. 
• A copy of the official IRB approval letter for the protocol and informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-investigators 
who will be involved in the study 
• Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(a  copy of the completed form may be sent to the CCTO and the original should be 
retained in the site regulatory files) 
• CAP and CLIA Laboratory certification numbers and institution lab normal values 
• Investigational drug accountability standard operating procedures 
• Additionally, before the study can be initiated at any site, the required executed 
research contract/subcontract must be on file with the University of Chicago. 
 
Data and Safety Monitoring 
This study will be remotely monitored by the designated University of Chicago Clinical 
Research Associate (CRA) in accordance with University of Chicago, Section of 
Hematology/Oncology standard operating procedures. 
 
Prior to subject recruitment, and unless otherwise specified, a participating site will undergo 
site initiation teleconference to be conducted by the designated University of Chicago 
research team. The site’s principal investigator and his or her study staff must attend the site 
initiation meeting.  
 
Monitoring will be conducted to verify the following: 
• Adherence to the protocol 
• Completeness and accuracy of study data and samples collected 
• Compliance with regulations 
 
Participating sites will also undergo a site close-out teleconference upon completion, 
termination or cancellation of a study to ensure fulfillment of study obligations during the 


 
 
 
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conduct of the study, and to ensure that the site Investigator is aware of his/her ongoing 
responsibilities. 
 
Unless otherwise specified, this protocol will undergo weekly review at the multi-institutional 
data and safety monitoring teleconference as per procedures specified by the UC CCC NCI-
approved Data and Safety Monitoring Plan. The conference will review: 
 
• Enrollment rate relative to expectations, characteristics of participants 
• Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
• Adherence to protocol (protocol deviations) 
• Completeness, validity and integrity of study data 
• Retention of study participants 
 
Protocol deviations are to be documented using the Protocol Deviation Form and sent via 
email to PhaseIICRA@medicine.bsd.uchicago.edu. Deviations that are considered major 
because they impact subject safety or alter the risk/benefit ratio, compromise the integrity of 
the study data, and/or affect subjects’ willingness to participate in the study must be reported 
within 
7 
days. 
Please 
contact 
the 
University 
of 
Chicago 
CRA 
(PhaseIICRA@medicine.bsd.uchicago.edu) if you have questions about how to report 
deviations.  All major protocol deviations should also be reported to the local IRB of record 
according to their policies and procedures. 
 
8.2 
DATA QUALITY ASSURANCE 
In addition to the clinical monitoring procedures, the University of Chicago Cancer Clinical 
Trials Office (CCTO) will perform routine Quality Assurance Audits of investigator-initiated 
clinical trials as described in the NCI-approved UCCCC DSM Plan. Audits provide assurance 
that trials are conducted and study data are collected, documented and reported in compliance 
with the protocol. Further, they ensure that study data are collected, documented and reported 
in compliance with Good Clinical Practices (GCP) Guidelines and regulatory requirements 
by performing annual quality assurance audits. The CCTO will review subjects enrolled at 
the University of Chicago in accordance with audit procedures specified in the UCCCC Data 
and Safety Monitoring plan. 
 
For institutions who are formal members of the PCCC, the University of Chicago 
Comprehensive Cancer Center (UCCCC) will conduct on site quality assurance audits on 
average every two years during the enrollment and treatment phase of the study. 
 
Auditing procedures for participating sites that are not full members of the PCCC must be 
specified and approved by the UCCCC Clinical Research Advisory Committee.  In general, 
for sites that are not full members of the PCCC, auditing responsibility will be delegated to 
the participating center, with the annual audit report forwarded to the University of Chicago 
for review.   
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during 
its conduct or even after its completion. If an inspection has been requested by a regulatory 


 
 
 
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authority, the site investigator must immediately inform the University of Chicago Cancer 
Clinical Trials Office and Regulatory Manager that such a request has been made. 
 
 
 
 
Amendments to the Protocol 
 
All modifications to the protocol, consent form, and/or questionnaires will be submitted to 
the University of Chicago IRB for review and approval. A list of the proposed modifications 
or amendments to the protocol and an explanation of the need of these modifications will be 
submitted, along with a revised protocol incorporating the modifications. Once a protocol 
amendment has been approved by the University of Chicago IRB, the Regulatory Manager 
will send the amended protocol and consent form to the affiliate institutions electronically. 
Upon receipt of the packet the affiliate institution is expected to do the following: 
• 
The affiliate must reply to the email from the Regulatory Manager indicating that 
the amendment was received by the institution and that it will be submitted to the 
local IRB.  
• 
The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.  
• 
The  University  of  Chicago  version  date  and/or  amendment  number  must  
appear  on  the  affiliate consent form and on the affiliate IRB approval letter.  The 
version dates can be found on the footer of every page of the protocol and consent 
form.  The amendment number can be found on the University of Chicago IRB 
amendment approval letter that is sent with the protocol/amendment mailing.  
• 
The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to the designated UC 
Regulatory Manager as soon as it is received. 
 
Annual IRB Renewals, Continuing Review, and Final Reports 
 
A continuing review of the protocol will be completed by the University of Chicago IRB and 
the participating institutions’ IRBs at least once a year for the duration of the study. The 
annual IRB renewals for participating institutions should be forwarded promptly to the 
Regulatory Manager. If the institution’s IRB requires a new version of the consent form with 
the annual renewal, the consent form should be included with the renewal letter. 
 
Obligations of the Study Site Investigators 
 
The Study Site Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Study Site Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  He/she must assure that all study site personnel, including 
sub-investigators and other study staff members, adhere to the study protocol and all 


 
 
 
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FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
 
The Study Site Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the CRFs. Periodically, 
monitoring visits or audits will be conducted and he/she must provide access to original 
records to permit verification of proper entry of data. 
 
8.3 
DATA REPORTING AND RECORDS 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. Source documents provide evidence for the existence of the patient and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the CRFs that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study; also current 
medical records must be available. 
For CRFs all data must be derived from source documents. 
Government agency regulations and directives require that all study documentation pertaining 
to the conduct of a clinical trial must be retained by the study investigator.  In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least seven years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region.  In all other cases, study 
documents should be kept on file until three years after the completion and final study report 
of this investigational study. 
 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS 
8.4.1 
Listedness 
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For afatinib, this is the current version of the Investigator’s Brochure. 
8.4.2 
Expedited reporting to health authorities and IRB 
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs), to the responsible participating site IRB will be done according to local 


 
 
 
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regulatory requirements. This study will be conducted under an IND held by Peter H. 
O’Donnell at the University of Chicago.  The University of Chicago CCTO will be 
responsible for facilitating all communications with the FDA on behalf of the IND holder. 


 
 
 
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9. 
REFERENCES  
9.1 
UNPUBLISHED REFERENCES 
U03-3218-13 BI Investigators Brochure, Version 19, 12/6/2017 
9.2 
PUBLISHED REFERENCES 
1. 
Society AC. Cancer Facts & Figures 2017. 2017; 
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-
cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Accessed March 6 2017, 
2017. 
2. 
Hussain MH, Wood DP, Bajorin DF, et al. Bladder cancer: narrowing the gap 
between evidence and practice. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2009;27(34):5680-5684.  PMCID: 4659855 
http://www.ncbi.nlm.nih.gov/pubmed/19858384. 
3. 
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with 
locally advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 
2016;387(10031):1909-1920. http://www.ncbi.nlm.nih.gov/pubmed/26952546. 
4. 
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. J Clin 
Oncol. 2000;18(17):3068-3077. http://www.ncbi.nlm.nih.gov/pubmed/11001674. 
5. 
Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for 
Advanced Urothelial Carcinoma. The New England journal of medicine. 2017. 
http://www.ncbi.nlm.nih.gov/pubmed/28212060. 
6. 
Bellmunt J, Hussain M, Dinney CP. Novel approaches with targeted therapies in 
bladder cancer. Therapy of bladder cancer by blockade of the epidermal growth factor 
receptor family. Crit Rev Oncol Hematol. 2003;46 Suppl:S85-104. 
http://www.ncbi.nlm.nih.gov/pubmed/12850530. 
7. 
Messing EM. Clinical implications of the expression of epidermal growth factor 
receptors in human transitional cell carcinoma. Cancer Res. 1990;50(8):2530-2537. 
http://www.ncbi.nlm.nih.gov/pubmed/1690599. 
8. 
Neal DE, Marsh C, Bennett MK, et al. Epidermal-growth-factor receptors in human 
bladder cancer: comparison of invasive and superficial tumours. Lancet. 1985;1(8425):366-
368. http://www.ncbi.nlm.nih.gov/pubmed/2857420. 
9. 
Bue P, Wester K, Sjostrom A, et al. Expression of epidermal growth factor receptor in 
urinary bladder cancer metastases. Int J Cancer. 1998;76(2):189-193. 
http://www.ncbi.nlm.nih.gov/pubmed/9537579. 


 
 
 
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Page 52 of 60 
 
10. 
Chow NH, Liu HS, Lee EI, et al. Significance of urinary epidermal growth factor and 
its receptor expression in human bladder cancer. Anticancer Res. 1997;17(2B):1293-1296. 
http://www.ncbi.nlm.nih.gov/pubmed/9137488. 
11. 
Neal DE, Sharples L, Smith K, Fennelly J, Hall RR, Harris AL. The epidermal growth 
factor receptor and the prognosis of bladder cancer. Cancer. 1990;65(7):1619-1625. 
http://www.ncbi.nlm.nih.gov/pubmed/2311071. 
12. 
Nguyen PL, Swanson PE, Jaszcz W, et al. Expression of epidermal growth factor 
receptor in invasive transitional cell carcinoma of the urinary bladder. A multivariate survival 
analysis. Am J Clin Pathol. 1994;101(2):166-176. 
http://www.ncbi.nlm.nih.gov/pubmed/7906919. 
13. 
Philips GK, Halabi S, Sanford BL, Bajorin D, Small EJ. A phase II trial of cisplatin 
(C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer 
and Leukemia Group B (CALGB) 90102. Ann Oncol. 2009;20(6):1074-1079.  PMCID: 
2685451 http://www.ncbi.nlm.nih.gov/pubmed/19168670. 
14. 
Petrylak DP, Tangen CM, Van Veldhuizen PJ, Jr., et al. Results of the Southwest 
Oncology Group phase II evaluation (study S0031) of ZD1839 for advanced transitional cell 
carcinoma of the urothelium. BJU Int. 2010;105(3):317-321. 
http://www.ncbi.nlm.nih.gov/pubmed/19888985. 
15. 
Pruthi RS, Nielsen M, Heathcote S, et al. A phase II trial of neoadjuvant erlotinib in 
patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and 
pathological results. BJU Int. 2010;106(3):349-356. 
http://www.ncbi.nlm.nih.gov/pubmed/20089114. 
16. 
Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus 
cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J 
Med. 2003;349(9):859-866. http://www.ncbi.nlm.nih.gov/pubmed/12944571. 
17. 
Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive 
bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19(3):666-675. 
http://www.ncbi.nlm.nih.gov/pubmed/11157016. 
18. 
Hussain MH, MacVicar GR, Petrylak DP, et al. Trastuzumab, paclitaxel, carboplatin, 
and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive 
urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin 
Oncol. 2007;25(16):2218-2224. http://www.ncbi.nlm.nih.gov/pubmed/17538166. 
19. 
Hansel DE, Swain E, Dreicer R, Tubbs RR. HER2 overexpression and amplification 
in urothelial carcinoma of the bladder is associated with MYC coamplification in a subset of 
cases. Am J Clin Pathol. 2008;130(2):274-281. 
http://www.ncbi.nlm.nih.gov/pubmed/18628098. 


 
 
 
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Page 53 of 60 
 
20. 
Black PC, Dinney CP. Growth factors and receptors as prognostic markers in 
urothelial carcinoma. Curr Urol Rep. 2008;9(1):55-61. 
http://www.ncbi.nlm.nih.gov/pubmed/18366975. 
21. 
Kolla SB, Seth A, Singh MK, et al. Prognostic significance of Her2/neu 
overexpression in patients with muscle invasive urinary bladder cancer treated with radical 
cystectomy. Int Urol Nephrol. 2008;40(2):321-327. 
http://www.ncbi.nlm.nih.gov/pubmed/17899426. 
22. 
Fleischmann A, Rotzer D, Seiler R, Studer UE, Thalmann GN. Her2 Amplification is 
Significantly More Frequent in Lymph Node Metastases From Urothelial Bladder Cancer 
Than in the Primary Tumours. Eur Urol. 2011. 
http://www.ncbi.nlm.nih.gov/pubmed/21640482. 
23. 
Powles T, Huddart RA, Elliott T, et al. Phase III, Double-Blind, Randomized Trial 
That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in 
Patients With Human Epidermal Growth Factor Receptor 1/2-Positive Metastatic Bladder 
Cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2017;35(1):48-55. http://www.ncbi.nlm.nih.gov/pubmed/28034079. 
24. 
Choudhury NJ, Campanile A, Antic T, et al. Afatinib Activity in Platinum-Refractory 
Metastatic Urothelial Carcinoma in Patients With ERBB Alterations. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2016;34(18):2165-
2171. http://www.ncbi.nlm.nih.gov/pubmed/27044931. 
25. 
Yap TA, Vidal L, Adam J, et al. Phase I trial of the irreversible EGFR and HER2 
kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol. 
2010;28(25):3965-3972. http://www.ncbi.nlm.nih.gov/pubmed/20679611. 
26. 
Wulfing C, Machiels JP, Richel DJ, et al. A single-arm, multicenter, open-label phase 
2 study of lapatinib as the second-line treatment of patients with locally advanced or 
metastatic transitional cell carcinoma. Cancer. 2009;115(13):2881-2890. 
http://www.ncbi.nlm.nih.gov/pubmed/19399906. 
27. 
Shrader M, Pino MS, Brown G, et al. Molecular correlates of gefitinib responsiveness 
in human bladder cancer cells. Molecular cancer therapeutics. 2007;6(1):277-285. 
http://www.ncbi.nlm.nih.gov/pubmed/17237287. 
28. 
Black PC, Brown GA, Inamoto T, et al. Sensitivity to epidermal growth factor 
receptor inhibitor requires E-cadherin expression in urothelial carcinoma cells. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 
2008;14(5):1478-1486. http://www.ncbi.nlm.nih.gov/pubmed/18316572. 
29. 
Adam L, Zhong M, Choi W, et al. miR-200 expression regulates epithelial-to-
mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth 
factor receptor therapy. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2009;15(16):5060-5072. 
http://www.ncbi.nlm.nih.gov/pubmed/19671845. 


 
 
 
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Page 54 of 60 
 
30. 
McConkey DJ, Choi W, Marquis L, et al. Role of epithelial-to-mesenchymal 
transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev. 
2009;28(3-4):335-344. http://www.ncbi.nlm.nih.gov/pubmed/20012924. 
31. 
Pond GR, Agarwal N, Bellmunt J, et al. A nomogram including baseline prognostic 
factors to estimate the activity of second-line therapy for advanced urothelial carcinoma. BJU 
international. 2014;113(5b):E137-143. http://www.ncbi.nlm.nih.gov/pubmed/24219029. 
32. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical 
trials. 1989;10(1):1-10. http://www.ncbi.nlm.nih.gov/pubmed/2702835. 
33. 
Vaughn DJ, Srinivas S, Stadler WM, et al. Vinflunine in platinum-pretreated patients 
with locally advanced or metastatic urothelial carcinoma: results of a large phase 2 study. 
Cancer. 2009;115(18):4110-4117. http://www.ncbi.nlm.nih.gov/pubmed/19536904. 
34. 
Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent 
metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, 
multi-arm, phase 1/2 trial. The Lancet. Oncology. 2016;17(11):1590-1598. 
http://www.ncbi.nlm.nih.gov/pubmed/27733243. 
35. 
Massard C, Gordon MS, Sharma S, et al. Safety and Efficacy of Durvalumab 
(MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in 
Patients With Advanced Urothelial Bladder Cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2016;34(26):3119-3125. 
http://www.ncbi.nlm.nih.gov/pubmed/27269937. 
36. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics. 1982;38:29-41.  
37. 
Sonpavde G, Pond GR, Fougeray R, et al. Time from prior chemotherapy enhances 
prognostic risk grouping in the second-line setting of advanced urothelial carcinoma: a 
retrospective analysis of pooled, prospective phase 2 trials. Eur Urol. 2013; 63(4):717-23. 
38. 
Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in 
patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-
randomised, open-label, phase 1b study. Lancet Oncol. 2017; 18(2):212-220. 
39. 
Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial 
carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. 
Lancet Oncol. 2017; 18(3):312-322. 
40. 
Sonpavde G, Pond GR, Mullane S, et al. Outcomes in patients with advanced 
urothelial carcinoma after discontinuation of programmed death (PD)-1 or PD ligand 1 
inhibitor therapy. BJU Int. 2017;119(4):579-584. 
 


 
 
 
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10. 
APPENDICES 
10.1 
APPENDIX 1 
ECOG SCALE 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead. 
0 
Dead. 
 
 
 


 
 
 
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10.2 
APPENDIX 2 
TUMOUR RESPONSE ASSESSMENT ACCORDING TO 
RECIST 1.1 
Response criteria for target lesions 
1.   Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have a reduction in 
short axis to < 10mm) 
2.   Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum diameters 
3.   Progression (PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as references 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 a least 5 mm (note: the appearance of one or 
more new lesions is also considered progression). 
4.   Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as references the smallest sum 
diameters while on study 
 
Response criteria for non-target lesions 
1.   Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in 
size (< 10mm short axis) 
2.   Non-CR/ Non-PD: 
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits. 
3.   Progression (PD): 
Unequivocal progression of existing non-target lesions (Note: the 
appearance of one or more new lesions is also considered 
progression) 
 
Overall response 
Target lesions 
Non-Target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


 
 
 
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10.3 
APPENDIX 3 
STUDY REPORT AND PUBLICATION POLICY 
10.3.1  Study Report 
After completion of the study, i.e. when the study has been concluded in accordance with this 
protocol and the last patient completed his/her last follow-up visit (last patient out), an 
integrated clinical and statistical study report containing a complete and detailed analysis and 
summary of all observations, results and conclusions related to or resulting from the study 
shall be written by the sponsor-investigator in consultation with the other investigators within 
twelve (12) months after completion of the study. 
The study report shall be compiled in accordance with the ICH-E3 Guideline. 
10.3.2  Publication Rules 
The primary publication shall be a full publication of the study. If such a full publication is 
not submitted within twelve (12) months after conclusion of the study, investigator(s) may 
publish individually in accordance with this Section 10.3.2. 
The Principal Investigator will have the unrestricted right to publish on data resulting from 
the study and will be given the choice to be the first author, or the last author.  
The selection and order of the subsequent authors (i.e. author(s) 2.-x.) will be based on (a) the 
numbers of recruitment, i.e. the number of subjects randomized/enrolled in the study, (b) data 
quality and (c) significant scientific input to the study, unless otherwise agreed.  
For any interim publication(s,) the order of the authors will be determined in accordance with 
(a) the numbers of recruitment and (b) data quality, after consultation with the Coordinating 
Investigator. 
Any written, oral or audio-visual publication resulting from the study, either in part or in total 
(abstracts in journals or newspapers, oral presentations, posters, etc.) by investigators and/or 
their representatives, including publications of experimental substudies, will require pre-
submission review by BIPI. BIPI is entitled to delay any publication in order to protect 
patentable inventions and/or to avoid disclosure of proprietary matters which require 
protection, including but not limited to, trade secrets and know-how (for details, see 
contract). Moreover, BIPI has the right to edit or remove confidential information, prior to 
submission for publication. In general, BIPI will not veto any publication. 
For publication(s) of experimental substudies only, co-authorship will be offered to all 
authors according to their individual contributions, unless otherwise agreed. The Principal 
Investigator will be given the choice to be the first, or the last author. 
The sponsor-investigator shall have the right to publish results of the study in whole or in part 
for regulatory purposes, unless otherwise agreed. 


 
 
 
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All publications of the results of the study shall be compiled in adherence to the rules of 
Good Scientific Practice and the guidelines for publications of clinical Study data as outlined 
e. g. by editors of the major medical journals. 
10.3.3  Registration with clinical registry database 
In accordance with the applicable statutory requirements, information about this study will be 
published with the Clinical Studies Registry of the US National Institutes of Health (ref. to 
Website clinicaltrials.gov) upon initiation of the clinical study. 
 
 
 
 


 
 
 
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10.4  APPENDIX 4 
 
PATIENT REGISTRATION FORM 
 
Afatinib in Advanced Refractory Urothelial Cancer 
 
(UNIVERSITY OF CHICAGO PROTOCOL #: 13-0540/1200.171) 
 
Today’s Date:   ___/___/____ 
 
I.1 
Patient Name:  _______________________________________________ 
 
I.2 
Enrolling institution:  __________________________________________ 
 
I.3 
Institutional Medical Record Number _____________________________ 
 
 
I.4 
Race (PATIENT must self-record this answer on this form): 
1---------- American Indian/Alaska Native  
1----------Asian 
1----------Native Hawaiian or Other Pacific Islander 
1----------Black or African American 
1----------White 
1----------More Than One Race/Other  
 
I.5 
Ethnicity (PATIENT must self-record this answer on this form): 
1----------Hispanic or Latino 
1----------Not Hispanic or Latino 
 
BELOW TO BE COMPLETED BY CENTRAL DATA MANAGEMENT: 
 
I.6 
Assigned Study ID Number:    __________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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10.5  APPENDIX 5 
Pharmacogenomic Blood Sample Collection Form 
 
Afatinib in advanced refractory urothelial cancer 
  
(University of Chicago Protocol #: 13-0540/ 1200.171) 
 
Labeling of Samples:  Ensure that each tube is labeled with the patient’s ID#, initials, study number, date, and 
time of sample acquisition.   
 
Patient Information (Name, medical record #) 
Receivers Information 
 
Attn:  Briana Rhodes 
Lab:  Peter H. O’Donnell (PI) 
5841 S. Maryland Ave. 
MC 2115 
The University of Chicago 
Chicago, IL  60637 
LABORATORY REQUISITION FORM for EDTA blood samples 
Patient Study ID# 
   
  
 
Collection date 
 
  
Collection time 
 
 
 
Completed by 
  
email 
   
Date 
  
 
Samples collected 
To be completed by person collecting 
To be completed by receiving lab 
expected specimen 
# of specimens 
included 
# of specimens 
received 
Comments 
Receiver's initials/date 
ONE 10mL 
lavender top EDTA  
tube 
 
 
 
 
DNA isolation (to be completed by receiving lab upon DNA isolation) 
Date 
mL 
blood 
barcode 
location 
ng/uL 
A260/A280 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
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