Phase II Trial of Paclitaxel Plus Gemcitabine and Cisplatin in Urothelial Cancer
Phase: PHASE2
Conditions: Urinary Bladder Neoplasms
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-13-0864 
IRB APPROVAL DATE: 05/04/2016 
 
 
 
 
 
 
 
 
 
 
 
Phase II Trial of Paclitaxel Plus Gemcitabine and Cisplatin in Urothelial Cancer 
 
NCT02560038 
 
Version Date: 05/04/2016 
 
 
 

IRB NUMBER: HSC-MS-13-0864 
IRB APPROVAL DATE: 05/04/2016 
 
 
 
 
 
 
 
 
 
Phase II Trial of Paclitaxel Plus Gemcitabine and Cisplatin in Urothelial Cancer 
 
Clinical Protocol No: GU-13-102 
 
 
 
 
Principal Investigator: 
Robert J. Amato Director and 
Professor Department of Internal 
Medicine Division of Oncology 
 
 
Collaborators: 
Urology 
Steven Canfield, M.D. 
Associate Professor 
Department of Surgery 
 
Imaging 
Varaha Tammisetti, M.D. 
Assistant Professor 
Department of Diagnostic & Interventional Imaging 
 
Pharmacy 
Nwabugwu S. Ochuwa, Pharm.D., BCOP 
Clinical Specialist in Oncology 
UT Memorial Hermann Cancer Center 
 
 
 
 
Version 1: October 1, 2014 
Version 2:  February 1, 2016 
Version 3:  April 7, 2016 
Version 4: April 25, 2016 
 
 
 
 
The study is to be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP) and other applicable regulatory requirements. 
 
 
 
 
 
 
 
 
Signature:  
 
Date:  
 
Robert J. Amato, D.O. 

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TABLE OF CONTENTS 
 
 
 
1.0 
OBJECTIVES...................................................................................................................................... 3 
 
2.0 
BACKGROUND .................................................................................................................................. 3 
 
3.0 
PATIENT ELIGIBILITY ....................................................................................................................... 6 
 
4.0 
TREATMENT PLAN ........................................................................................................................... 7 
 
5.0 
PRETREATMENT EVALUATION ...................................................................................................... 8 
 
6.0 
EVALUATION DURING STUDY ........................................................................................................ 8 
 
7.0 
CRITERIA FOR EVALUATION, ENDPOINT DEFINITIONS AND REMOVAL FROM STUDY......... 9 
 
8.0 
SAFETY MONITORING AND REPORTING ...................................................................................... 9 
 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................................. 13 
 
10.0 
DATA AND PROTOCOL MANAGEMENT....................................................................................... 13 
 
11.0 
ETHICAL CONSIDERATIONS ......................................................................................................... 14 
 
12.0 
REFERENCES.................................................................................................................................. 16 
 
APPENDIX A:  NCI Common Terminology Criteria for Adverse Events ................................................ 20 
 
APPENDIX B: ECOG Performance Status ............................................................................................... 21 
 
APPENDIX C: RECIST 1.1 Guidelines ...................................................................................................... 22 
 
APPENDIX D: Schedule of Assessments ................................................................................................ 26 

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PROTOCOL 
 
 
1.0 OBJECTIVES 
 
1.1 To determine the efficacy of paclitaxel plus gemcitabine and cisplatin administered to 
patients with advanced local or metastatic urothelial cancer. 
 
1.2.  To determine the qualitative and quantitative toxicity and reversibility of toxicity of the 
combination  of  paclitaxel  plus  gemcitabine  and  cisplatin  treatment  in  patients  with 
advanced local or metastatic urothelial cancer. 
 
2.0 BACKGROUND 
 
Although bladder cancer is one of the ten most common cancers [1], treatment options are 
suboptimal  for  metastatic  disease,  with  median  survival  under  1  year  for  untreated 
disease, despite its known chemosensitivity [2]. Remarkably, the clinical expression of 
urothelial cancer has much in common with small-cell carcinoma of the lung; front-line 
therapy for both diseases has historically been based on cisplatin, growth rates and 
response rates are high, the CNS is a common second echelon site of metastatic disease, 
and the cures of grossly metastatic disease are distinctly uncommon. Chemotherapy 
changes the expectation of median survival from about 4 months with no therapy to 
approximately 15 months with available chemotherapy. Unfortunately, there are still very few 
5-year survivors, despite front-line response rates now in the range of 70%. Non- localized 
bladder cancer remains largely incurable and usually rapidly fatal. 
 
Cisplatin-based combination chemotherapy regimens like M-VAC (methotrexate, vinblastine, 
adriamycin, and cisplatin) and CMV (cisplatin methotrexate, and vinblastine) remains a 
standard of therapy for patients with advanced carcinoma of the urothelium [3,4].  The  
overall  response  rate  (complete  plus  partial)  to  these  cisplatin-based combination 
regimens ranged from 50% to 70%, with complete responses seen in 15%- 
25% of cases [5-7]. Nonetheless, almost all responding patients ultimately relapsed within 
the first year, with a median survival of approximately 12-14 months [8]. 
M-VAC produced a modest, although significant, survival benefit compared in randomized 
trials with cisplatin as a single agent,  CAP or CISCA (cyclophosphamide, adriamycin, and 
cisplatin) [9], or a carboplatin-based regimen [10]. Long-term follow-up of M-VAC–treated 
patients showed 12.5 months median survival and >6 years disease-free survival in 3.7% 
of patients [11]. The results with M-VAC did not improve with dose-intensification of this 
combination, and adverse toxicity reactions were both frequent and severe [12-14]. The 
dismal long-term outcome these regimens led to a search for new treatment approaches. 
 
2.1 Gemcitabine in urothelial cancer 
 
 
Gemcitabine (Gemzar; Eli-Lilly and Company, Indianapolis, IN) is a pyrimidine antimetabolite 
that has single-agent activity against urothelial cancer in previously treated patients, with an 
overall response rate of 27%-28% [15,16]. Two trials evaluating gemcitabine  in  previously  
untreated  patients  showed  response  rates  of  24.3%-28% [17,18]. 

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Gemcitabine is a nucleoside analog of deoxycytidine in which two fluorine atoms have 
been inserted into the deoxyribofuranosyl ring. Once inside the cell, gemcitabine is rapidly 
phosphorylated by deoxycytidine kinase, the rate-limiting enzyme for the formation of the 
active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate 
(dFdCTP).  Gemcitabine  diphosphate  inhibits  ribonucleotide  reductase,  which  is 
responsible for producing the deoxynucleotides required for DNA synthesis and repair. 
The subsequent decrease in cellular deoxynucleotides (particularly dCTP) favors 
gemcitabine  triphosphate  in  its  competition  with  dCTP  for  incorporation  into  DNA. 
Reduction in cellular dCTP is an important self-potentiating mechanism resulting in increased 
gemcitabine nucleotide incorporation into DNA. Other self-potentiating mechanisms of 
gemcitabine include increased formation of active gemcitabine di-and triphosphates, and 
decreased elimination of gemcitabine nucleotides. After gemcitabine nucleotide is 
incorporated on the end of the elongating DNA strand, one more deoxynucleotide is added, 
and thereafter the DNA polymerases are unable to proceed. This action, termed, "masked 
chain termination," appears to lock the drug into DNA because proofreading exonucleases 
are unable to remove gemcitabine nucleotide from this penultimate position. Incorporation 
of gemcitabine triphosphate into DNA is strongly correlated with the inhibition of further 
DNA synthesis. Compared with ara-C, gemcitabine serves as a better transport substrate, is 
phosphorylated more efficiently, and is eliminated more slowly. These differences, together 
with self-potentiation, masked chain termination and the inhibition of ribonucleotide 
reductase, which are not seen with ara-C, may explain why gemcitabine is, and ara-C is 
not, active in solid tumors [19]. This unique combination of metabolic properties and 
mechanistic characteristics suggests that gemcitabine is likely to be synergistic with other 
agents in combination with either ribonucleotide reductase inhibitors to increase their 
incorporation into replicating DNA or with agents that induce DNA damage and evoke 
DNA repair processes. 
 
Previous  studies  suggested  that  the  dose  rate  should  be  considered  that  produces 
maximal nucleotide analogue formation, with increased intensity being achieved by 
prolonging the duration of infusion [20,21]. In a phase I trial at MD Anderson Cancer 
Center, 
dose 
intensification 
was 
based 
on 
studies 
of 
gemcitabine's 
cellular 
pharmacokinetics. The accumulation of gemcitabine triphosphate by mononuclear cells 
was saturated by dose rates of 10 mg/m2/min [22]. 
 
2.2 Gemcitabine combined with cisplatin 
 
The cytotoxicity of cisplatin is associated with the formation of bifunctional DNA inter- and 
intra-strand  crosslinks  [23].  An  increased  capacity  to  remove  these  crosslinks  by 
nucleotide excision repair is thought to be a mechanism of resistance to cisplatin. Yang et 
al.  demonstrated  that  the  gemcitabine  triphosphate  inhibits  the  removal  of  cisplatin 
adducts from DNA nucleotide excision repair, resulting in synergistic cytotoxicity of 
gemcitabine and cisplatin [24]. 
The combination of gemcitabine and cisplatin was evaluated in bladder cancer in phase II 
studies using different schedules of administration. In those studies, gemcitabine was 
administered on days 1, 8, and 15 every 4 weeks and cisplatin once every 4 weeks either 
on day 1 or 2 or on days 1, 8, and 15 [25-27]. In total, 116 patients were treated with this 
combination, with an overall response rate ranging from 41% to 71% and with complete 
response rates ranging from 25% to 35%. The median survival time was consistently 
reported to be 13 months in two of the studies [25,27]. 

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Because of the high response rates found in these phase II trials using the above- mentioned 
combinations, randomized phase III trials comparing M-VAC with cisplatin/gemcitabine. The 
International trial of cisplatin and gemcitabine vs. M-VAC in 405 patients was conducted 
between November 1996 and September 1998, for a median follow-up of 19 months, with 
334 progressive disease status and 274 deaths observed [28,29]. Based on this trial, there 
was no indication that cisplatin/gemcitabine was inferior to M-VAC (HR = 1.05), but it was 
substantially less toxic. Based on these data, cisplatin and gemcitabine became the 
standard chemotherapeutic option for urothelial cancer. However, given that outcomes were 
not improved over the previous M-VAC standard, the need remains for more effective 
treatment regimens [30]. 
 
 
2.3.  Addition of taxanes 
 
 
Several reports have described the antitumor activity of taxanes in combination with cisplatin 
in bladder cancer. The combination of paclitaxel and gemcitabine was shown to have a 
promising activity profile in bladder carcinoma [31]. Paclitaxel (Taxol; Bristol-Myers Squibb, 
Princeton, NJ) is extracted from the bark of the Pacific yew, Taxus brevifolia. It promotes 
tubulin assembly into the microtubules and inhibits depolymerization to free tubulin, thus 
blocking cells in the M phase of the cell cycle [32-34]. In preclinical studies, paclitaxel 
demonstrated high antitumor activity against multiple murine transplantable tumors, as well 
as against human tumor xenografts [33,34]. There have been reports of paclitaxel showing 
improved efficacy in treatment of urothelial cancer [35-37]. In patients with advanced 
urothelial carcinoma who had not received prior radiotherapy or systemic chemotherapy, 
paclitaxel given at a dose of 250 mg/m2  by 24 hours continuous infusion every 3 weeks 
resulted in a response rate of 42%, including complete responses in 27% of patients [37]. 
 
Paclitaxel given in combination with cisplatin was evaluated in several early studies [38- 
40] that included a total of 115 patients, with an overall response rate ranging from 50% to 
72%. Studies with the other widely used taxane, docetaxel, in combination with cisplatin 
has a reported response rate of 60% in one study including 25 patients [41]. Median survival 
was 13 months in one of the cisplatin/paclitaxel studies [40], 10.6 in the other, and 
13.6 months in the cisplatin/docetaxel study [41]. 
 
2.4.  Paclitaxel plus cisplatin and gemcitabine 
 
Because cisplatin, gemcitabine, and paclitaxel have differing mechanisms of action and 
somewhat  difference  toxicity  profiles,  European  researchers  studied  this  combination 
under the rationale that the combination would provide good disease control while being well 
tolerated by patients [2,42,43]. Initial results showed an overall response rate of 78% and a 
median survival of 15.6 months. The long-term, phase III trial found that after >4.5 years of 
follow-up, the regimen of all three drugs together resulted in an overall response rate of 56% 
and overall survival of 15.8 months, compared with 43.6% response and 12.7 months 
survival in patients who received only gemcitabine with cisplatin. Toxicity was similar for both 
arms, with the regimens being well tolerated [2]. However, doses have differed among all 
the studies of this regimen [44,45], from as little as 60 mg/m2 [42] to as much as 200 mg/m2 
[44], with little rationale given for choice of dose. 
 
2.5. Rationale 

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The rationale of the present study is to develop a combination based on the 
pharmacokinetics and mechanisms of action of the agents paclitaxel plus gemcitabine and 
cisplatin, which are all known active agents in urothelial tumors. Gemcitabine may be 
synergistic with DNA-damaging drugs such as paclitaxel and cisplatin because it can 
antagonize DNA repair. We will investigate the combination in this Phase II study. 
 
 
 
 
3.0  PATIENT ELIGIBILITY 
 
3.1.  Inclusion Criteria 
 
3.1.1.     All  patients  must  have  histologic  demonstration  of  metastatic  or  locally 
unresectable transitional cell carcinoma of the urothelium. Minor components 
(<50% overall) of variants such as glandular or squamous differentiation, or 
evolution to more aggressive phenotypes, such as sarcomatoid, or small cell 
changes are acceptable. However, when these atypical histologies are dominant, 
other treatment approaches may be more appropriate, and such patients are not 
eligible. 
 
3.1.2.     All patients must have measurable or evaluable disease. In general, liver and 
lung lesions should be at least 1 cm, and patients with node-only disease should 
have lesions of 1.5 cm in the largest dimension. Patients with disease confined 
to bone may be eligible if a measurable lytic defect is present. Patients with a 3- 
dimensional mass or pelvic sidewall fixation on bladder examination under 
anesthesia are considered to have measurable disease. 
 
3.1.3.     All patients must have adequate physiologic reserves as evidenced by: 
   Life expectancy of at least 12 weeks. 
   Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. 
   No clinical history of heart disease and a normal EKG or an ejection fraction 
measured by echocardiogram or MUGA scan of at least 45%. 
   Transaminase less than twice the upper limit of normal. Bilirubin <1.5 mg%. 
   Serum creatinine 2.0 mg/dL. Patients presenting with obstructive uropathy 
may be eligible if they show excellent response to nephrostomy drainage. 
   Absolute neutrophil count 1500; platelet count 100,000. 
 
3.1.4.     Patients must not have had any previous systemic chemotherapy for bladder cancer, 
including neoadjuvant or adjuvant treatment given remotely. Gemcitabine/cisplatin 
is the standard of care for metastatic urothelial cancer. Patients who have received 
treatment would be either resistant or refractory to additional doses. In addition, 
they would have residual adverse effects from treatment and would be particularly 
susceptible to further neuropathic adverse events. Any prior intravesicular therapy 
is allowed. 
 
3.1.5.     Women of childbearing potential must have a negative pregnancy test prior to 
starting therapy. Men and women of childbearing potential must be willing to 
consent using effective contraceptive while on treatment and for a reasonable 
period thereafter. 

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3.1.6. 
Patients must not have an active, or likely to become active, second malignancy. 
 
3.1.7. 
Patients must be at least 6 weeks out from pelvic irradiation, and must not have 
had more than 10% of the bone marrow irradiated. 
 
3.2 Exclusion Criteria 
 
3.2.1. 
Patients with uncontrolled CNS metastasis are not eligible. 
 
3.2.2. 
Patients with a history of peripheral neuropathy greater than grade 1 are not eligible. 
 
3.2.3. 
Pregnant women are excluded. 
 
 
 
4.0 TREATMENT PLAN 
 
4.1 Patients will be registered in the Genitourinary Oncology Program. 
 
4.2 Combination chemotherapy consisting of gemcitabine and cisplatin plus paclitaxel. 
 
4.3 The treatment will be repeated on a 21-day cycle. Patients will receive therapy in the 
Genitourinary Oncology Infusion Center or as an inpatient. 
 
4.4 The gemcitabine will be administered as an IV infusion over 10mg/m2/min. The paclitaxel 
will be administered as an IVPB over 3 hours. The cisplatin will be administered as an 
IVPB over 2 hours. 
 
4.5 Premedication for the gemcitabine infusion will consist of ondansetron 8 mg IV. 
 
4.6 Premedication for the paclitaxel and cisplatin infusion will consist of dexamethasone 12 
mg IV, ondansetron 8 mg IV, and diphenhydramine 25-50 mg IV. 
 
4.7 Treatment Group: 
 
Level 
Gemcitabine (mg/m2) Days 1, 8 Paclitaxel (mg/m2) Day 2 Cisplatin  (mg/m2) Day 2 
-2 
800 
135 
70 
-1 
1000 
135 
70 
0 
1000 
175 
70 
 
4.8 Dose modification will occur only for paclitaxel or gemcitabine.  The dose modifications will 
be based on Grade 4 hematologic toxicity. The modifications will occur consistent with 
section 4.7. 
 
For granulocyte counts <500 cells/µL over 96 hours, filgrastim 5 µg/kg/day will be adminis- 
tered subcutaneously, daily for 3 days or until granulocyte is 1000 cells/mm3. For subse- 
quent cycles, if granulocytopenia persists with filgrastim therapy, treatment dose will be 
decreased by 1 treatment level.  Patients unable to tolerate treatment level -2 will be re- 
moved from the study. 

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For platelet count <25,000 cells/m3 over 96 hours, treatment dose will be decreased by 1 
treatment level for subsequent cycles.  Patients unable to tolerate treatment level -2 will be 
removed from the study. 
 
For hemoglobin <8 g/dL, patients will be transfused with packed red blood cells to main- 
tain a hemoglobin of 8 g/dL. For non-symptomatic patients with hemoglobin between 8 
and 9.9 g/dL who have adequate iron stores, epoetin alfa will be administered at a dose of 
40,000 units subcutaneously once weekly. 
 
 
4.9   Dose modifications based on non-hematologic toxicity. The following dose modification will 
be consistent with section 4.7. If grade 3/4 stomatitis occurs or bilirubin greater than the 
upper limits of normal, and alkaline phosphatase greater than 5 times the upper limit of 
normal, or an SGOT/SGPT greater than 5 times the upper limit of normal; grade 2 
neuropathy (treatment with paclitaxel will be discontinued for grade 3/4 neuropathy). 
 
4.10 Since all of the drugs in this trial are standard of care, there may be instances when 
subjects will receive their treatment at other infusion centers as well as their standard 
blood draws due to insurance network provider determinations, cost, etc. Dr. Amato will work 
closely with referring physicians and infusion centers. The lab results and clinic/infusion 
notes will be obtained and reviewed by Dr. Amato. All subjects will still come to the cancer 
center for restaging study visits. 
 
 
 
5.0 PRETREATMENT EVALUATION 
 
5.1 All patients must have an appropriate history and physical examination. Specific details to 
be recorded include the date of original diagnosis, the date of the first documentation of 
muscle-invasive disease, prior intravesical therapies (if any), results of ―staging‖ studies at 
the time of initiation of systemic therapy (see below). The physical examination must include 
current height and weight; the presence or absence of pathologic adenopathies, the results 
of cardiovascular examination, including: the presence or absence of carotid or iliac bruits, 
an assessment of peripheral pulses and the presence or absence of peripheral edema; 
examination of the oral cavity; and palpation of the inguinal nodes, abdomen and rectal 
examination. 
 
5.2 All patients must have a complete blood count (including a differential and platelet count), 
alkaline  phosphatase,  electrolytes,  calcium,  phosphorous,  magnesium,  BUN,  albumin, 
total protein, bilirubin, transaminase (either SGOT or SGPT), glucose, creatinine, CEA, beta-
hCG, beta-2 microglobulin, and CA-125 within 3 weeks of study entry. All patients will have 
a bone scan and x-ray or CT scan of the chest, abdomen and pelvis within one month 
of study entry. An EKG within 3 months must be available. In addition, if a baseline 
measurement of ejection fraction (EF) is required, this should be obtained within 3 months 
of study entry. 
 
 
 
6.0 EVALUATION DURING STUDY 
 
These  assessments  should  be  performed  within  ±3  days  of  the  scheduled  day  of 
assessment.  Schedule of Assessments can be found in Appendix D. 

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6.1 All patients will have a clinical assessment every 3 weeks. Data on symptom status, pain 
medication use and acute accumulative toxicity will be recorded. 
 
6.2 All patients will have a weekly CBC for the first 6 weeks of therapy. Following this, the 
frequency of CBC monitoring can be tailored in light of the experience during the first 6 
weeks of therapy. 
 
6.3 All patients will have a weekly complete metabolic panel for the first 6 weeks of therapy. 
Following this, the frequency of complete metabolic profile monitoring can be tailored in light 
of the experience during the first 6 weeks of therapy. 
 
6.4 Patients with elevated tumor markers at study entry should have these repeated at the six- 
week clinical evaluations, even if they normalize. 
 
6.5 Whatever imaging is required to assess response in at least one measurable disease site 
should be repeated at the first six-week clinical evaluation. If a patient meets criteria for 
response (see 7.0 below), then all measurable sites of disease should be imaged when 
the patient returns for evaluation after 12 weeks on the same therapy. 
 
 
 
7.0 CRITERIA FOR EVALUATION, ENDPOINT DEFINITIONS AND REMOVAL 
FROM STUDY 
 
Tumor response will be determined according to the Response Evaluation Criteria in Solid Tu- 
mors (RECIST) version 1.1. 
 
 
8.0 SAFETY MONITORING AND REPORTING 
 
The investigator will monitor each patient for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study following the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.0. A link to the electronic version of the 
CTCAE can be found in Appendix A.  Investigators must document their review of labora- 
tory reports by initialing and dating each report, as well as addressing the clinical signific- 
ance (for significant abnormalities). The investigator will assess and record any adverse 
event (serious and non-serious) in detail on the adverse event form including the date of 
onset, description, severity, time course, duration, outcome and relationship to the study 
drug from the time the patient signs the informed consent until 4 weeks after the patient 
has stopped study treatment. 
 
8.1 Adverse Events 
 
All adverse events should be treated appropriately. Such treatment may include interrup- 
tion or discontinuation of study drug, starting or stopping concomitant treatments, changes 
in the frequency or nature of assessments, hospitalization, or any other medically required 
intervention. 
 
Information about common side effects already known about the study drug can be found 
in the protocol and respective package inserts. This information will be included in the pa- 
tient informed consent and should be discussed with the patient during the study as needed. 

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8.2 Adverse Event Definition 
 
An adverse event (AE) is defined as any unintended or undesirable, noxious, or pathologi- 
cal change, compared to pre-existing conditions, experienced by a patient during a clinical 
study or the follow-up period, regardless of relationship to study drug.  Adverse events in- 
clude: 
    Suspected adverse drug reactions. 
    Reactions from drug overdose, abuse, withdrawal, sensitivity, or toxicity. 
 
Significant changes or abnormalities, when compared to baseline, in structure (sign), 
function (symptom), clinical laboratory results, or physiological testing. This includes 
any worsening of a pre-existing condition temporally associated with the use of study 
drug. 
 
Other medical events, regardless of their relationship to the study drug, such as injury, 
surgery, accidents, extensions of symptomatology, or apparently unrelated illnesses. 
 
8.3 Evaluating Adverse Events 
 
Each adverse event will be evaluated to determine: 
    the severity grade (mild, moderate, severe) or (grade 1-4) 
    its relationship to the study drug(s) (suspected/not suspected) 
    its duration (start and end dates or if continuing at final exam) 
    action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication taken; non-drug therapy given; hospitalization/prolonged hospitalization) 
    outcome 
    whether it constitutes a serious adverse event (SAE) 
 
8.4 Determination of Severity 
The severity of AEs will be assessed according to CTCAE, Version 4.0. If the AE is not de- 
fined in the CTCAE, the Investigator will determine the severity of an adverse event based 
on the following definitions: 
 
Mild (Grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity. The AE does not require discontinuing administration or reducing the dose of 
the study drug. 
 
Moderate (Grade 2): The AE interferes with routine activity but responds to 
symptomatic therapy or rest. The AE may require reducing the dose but not 
discontinuing administration of the study drug. 
 
Severe (Grade 3): The AE significantly limits the patient‘s ability to perform routine 
activities despite symptomatic therapy. In addition, the AE leads to discontinuing 
administration or reducing the dose of the study drug. 
 
Life-Threatening (Grade 4): The AE requires discontinuing administration of the study 
drug. The patient is at immediate risk of death. 
 
8.5 Determination of Relatedness 
 
The Investigator will determine the relatedness of an adverse event with the study drug 
based on the following definitions: 
 
Not Related 

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This category applies to those adverse events which, after careful medical consideration, 
are felt to be due to extraneous causes (disease, environment, etc.) that are not related to 
the administration of study drug. 
 
Probably Not Related (must have first two bullets below) 
This category applies to those adverse events, which, after careful medical consideration, 
are clearly felt unlikely to be related to the administration of the study drug. The relation- ship 
of an adverse event to the study drug can be considered probably not related if: 
    It does not follow a reasonable temporal sequence from administration of the drug. 
    It could readily have been a result of the patient‘s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
    It does not follow a known response pattern to the suspected drug. 
    It does not reappear or worsen when the drug is readministered. 
 
Possibly Related (must have first two bullets below) 
This category applies to those adverse events, which, after careful medical consideration, 
are felt unlikely to be related to the administration of the study drug, but the possibility cannot 
be ruled out with certainty. The relationship of an adverse event to the study drug can be 
considered possibly related if: 
    It follows a reasonable temporal sequence from administration of the drug. 
    It could readily have been a result of the patient‘s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
    It follows a known response pattern to the suspected drug. 
 
Probably Related (must have first three bullets below) 
This category applies to those adverse events which, after careful medical consideration, 
are felt with a high degree of certainty to be related to the administration of the study drug. 
The relationship of an adverse event to the study drug can be considered probably related 
if: 
    It follows a reasonable temporal sequence from administration of the drug. 
    It could not be reasonably explained by the known characteristics of the patient‘s 
clinical state, environmental or toxic factors or other modes of therapy administered to 
the patient. 
    It disappears or decreases upon cessation of drug or reduction in dose.* 
    It follows a known response pattern to the suspected drug. 
 
Definitely Related (must have first three bullets below) 
This category applies to those adverse events, which, after careful medical consideration, 
are felt to be related to the administration of the drug. The relationship of an adverse event 
to the study drug can be considered definitely related if: 
 
It follows a reasonable temporal sequence from administration of the drug or drug 
levels have been established in body fluids or tissues. 
    It could not be reasonably explained by the known characteristics of the patient‘s 
clinical state, environmental or toxic factors or other modes of therapy administered to 
the patient. 
 
It disappears or decreases upon cessation of drug or reduction in dose and, if 
applicable, appears upon rechallenge.* 
    It follows a known response pattern to the suspected drug. 

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*There are exceptions when an adverse event does not disappear upon discontinuation of 
the drug, yet drug relatedness clearly exists; e.g., 1) tardive dyskinesia, 2) fixed drug erup- 
tions. 
 
8.6 Serious Adverse Events 
 
Information about all serious adverse events (SAEs) will be collected and recorded.   A 
SAE is an undesirable sign, symptom or medical condition which: 
    is fatal or life-threatening 
    results in persistent or significant disability/incapacity 
    constitutes a congenital anomaly/birth defect 
 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
  routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
  elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
  treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
  social reasons and respite care in the absence of any deterioration in the patient‘s 
general condition 
 
is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 
8.7 SAE Reporting 
 
The principal investigator has the obligation to report all serious adverse events to the 
IRB, DSMB and FDA according to their respective requirements.  All events reported to 
the FDA by the investigator are to be filed utilizing the Form FDA 3500A (MedWatch 
Form). 
 
Serious Adverse Events (SAE) that are determined by the PI to be unexpected + related 
will be submitted to the DSMB within 7 calendar days of the determination by telephone or 
fax; written report no later than 15 calendar days of the determination.  Deaths should be 
reported to the IRB within 24 hours of investigator knowledge.  Any unexpected, serious, 
related adverse experiences should be reported to the IRB within 7 calendar days of in- 
vestigator knowledge. 
 
Any pregnancy that occurs during study participation should be reported. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termina- 
tion, details of birth, and the presence or absence of any birth defects, congenital abnor- 
malities or maternal and newborn complications. 
 
8.8 Unanticipated Problem Reporting 
 
The Principal Investigator (PI) must notify the IRB of unexpected problems that might arise 
during the study within 7 days.  The PI must make a judgment call regarding the expec- 
tedness and causality of the problem.  Examples include: 
 
any adverse event which in the opinion of the PI is both unexpected and related and 
places patients or others at risk of harm 

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    Protocol deviation that harmed patients or placed patients in increased risk of harm 
    Unanticipated adverse device effect 
    A breach of confidentiality 
 
Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol 
    Information that indicates a change to the risks or potential benefits of the research 
 
 
 
 
 
9.0 STATISTICAL CONSIDERATIONS 
 
The primary efficacy endpoint was the objective response rate—that is, the proportion of 
patients achieving either a CR or a PR at any time during the study. Responses (CR, PR, 
PD, and SD) will be evaluated according to RECIST 1.1 criteria (see Appendix C). Simon‘s 
one-sample two-stage design will be used. Our null hypothesis is that the response rate is 
50%, and our alternative hypothesis is that the response rate is 70%. In the first stage, 23 
patients will be accrued. If ≤12 patients of the first 23 are assessable for responses, the study 
will be stopped early for futility. If ≥13 responses are observed in the first stage, accrual will 
continue for a total of 37 patients. If ≥23 responses are observed in 37 patients by the end 
of stage two, we will conclude that the treatment is warranted for further investigation. This 
design will yield a one-sided type I error rate of 0.05 and power of 80%. There will be no 
comparison group. 
 
An interim safety analysis is planned after 3 patients and again after 12 patients have 
completed 1 cycle of treatment. During this analysis, enrollment will be stopped, the DSMB 
will review the safety and toxicity information and make their recommendation, and the 
DSMB report will be given to the IRB for review prior to treatment of additional patients. 
 
In a secondary analysis, we will also assess progression-free and overall survival to 
determine the potential benefit of the study regimen. Descriptive statistics will be used for 
this analysis. 
 
Toxicity assessment will be observational. Numbers and types of events will be quantified, 
graded according to CTCAE, and reported in a summary table. 
 
 
10.0 DATA AND PROTOCOL MANAGEMENT 
 
10.1 Protocol Compliance 
 
Written informed consent must be obtained from the patient prior to study specific screening 
tests or procedures.  Results of all baseline evaluations which assure that all inclusion and ex- 
clusion criteria have been satisfied, must be reviewed by the Investigator prior to enrollment of 
that patient.  All required interim and pre-treatment data should be available and the investigator 
must have made a designation as to tumor response and toxicity grade. 
 
10.2 Data Collection 
 
Investigators or their designee must enter the data required by the protocol onto Case Report 
Forms (CRFs). A brief explanation for required but missing data should be recorded as a com- 

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ment. The Principal Investigator is ultimately responsible for assuring that data entered into the 
CRFs are accurate, authentic / original, attributable, complete, consistent, legible, timely (con- 
temporaneous), enduring and available when required. 
 
Entries made in the CRF must be either verifiable against source documents, or have been di- 
rectly entered into the CRF, in which case the entry in the CRF will be considered as the source 
data. Any corrections to entries made in the CRFs or source documents must be dated, in- 
itialed and explained (if necessary) and should not obscure the original entry.  The Investigator 
will sign the CRFs to indicate that, to his/her knowledge, they are complete and accurate. 
 
10.3 Database Management 
 
The data manager will review the CRF data entered by study staff for completeness and accu- 
racy. Data queries stating the nature of the problem and requesting clarification will be created 
for discrepancies and missing values and sent to the study coordinator. The study coordinator 
will respond promptly to queries and make any necessary changes to the CRFs. 
 
10.4 Site Monitoring 
 
To ensure that the protocol and Good Clinical Practices (GCP) are being followed and that 
study data are accurate, complete and reliable, the trial will be monitored by a Data Safety 
Monitoring Board (DSMB), Medical Monitor and CRA monitoring as specified in the Data Safety 
Monitoring Plan (DSMP) for the study and the DSMB‘s charter. 
 
11.0 ETHICAL CONSIDERATIONS 
 
11.1 Ethical Compliance 
The study will be conducted in accordance with legal and regulatory (21 CFR 50, 56, 312 
as applicable) requirements, as well as the general principles set forth in the Guidelines for 
GCP (ICH 1996) and the Declaration of Helsinki (World Medical Association 1996 and 
2008). 
 
The principal investigator is responsible for ensuring that all participating staff members 
are adequately trained and competent to perform his/her assigned tasks. 
 
11.2 IRB Review 
Before implementing this study, the protocol, the proposed informed consent form, and 
other required information, must be reviewed and approved by a properly constituted Insti- 
tutional Review Board (IRB). Any amendments to the protocol, other than administrative 
ones, must be re-viewed and approved by this committee before implementation. If an 
immediate change to the protocol is implemented for safety reasons by the investigator, 
the IRB must be informed immediately.  The study must be reviewed and approved at 
least annually as well. 
 
11.3 Recruitment 
Recruitment typically occurs from patients treated at the Cancer Center.  Recruitment may 
occur from patient self-referral from trials posted on ClinicalTrials.gov.  If the investigator 
wishes to expand recruitment, advertisements will be reviewed and approved by the IRB 
prior to use. 
 
11.4 Informed Consent 
The Investigator will be responsible for obtaining consent, documented on the Informed 
Consent Form (ICF) signed and dated by each patient or his/her legally authorized repre- 

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sentative, prior to his/her participation in the study, in accordance with ICH GCP guide- 
lines. The ICF will be written in non-technical language. The patient should read and be 
given as much time as they need to consider their participation before signing and dating 
it. 
 
The investigator or study staff designee must explain to each patient the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each patient must be informed that par- 
ticipation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or rela- 
tionship with the treating physician. 
 
Participation in the study and date of informed consent should be documented appro- 
priately in the patient‘s files. The original ICF will be maintained in the research files and a 
copy must be maintained in the institution‘s medical records. The patient or his/her legally 
authorized representative will also be given a copy of the signed consent form. 
 
11.5 Confidentiality 
All records identifying the patient will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.  Patient names 
will not be supplied to third parties. A unique study accession number will be assigned to 
each patient on study and will be used on the CRFs. Identifiable data on any document 
(e.g., pathologist report) must be redacted before a copy of the document is supplied to 
third parties. The study coordinator will maintain a list to enable patients‘ records to be 
identified for verification purposes. 
 
Study data stored electronically will be stored in zone 100, on password-protected, en- 
crypted computers. Paper study data will be maintained by the study coordinator in the 
locked research offices. 
 
11.6 Publication of Study Results 
The investigator will assure that the key elements of this protocol will be posted in a public- 
ly accessible database such as www.ClinicalTrials.gov.  In addition, upon study completion 
and finalization of the study report the results of this study will be submitted for publication 
in scientific journals and/or scientific meetings.  If the results of the study are published, 
the patient‘s identity will remain confidential. 
 
11.7 Retention of Documents 
To enable evaluations and/or audits from regulatory authorities or sponsors, the investiga- 
tor agrees to keep records, including the identity of all participating patients (sufficient in- 
formation to link records, e.g., CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, de- 
tailed records of treatment dis-position, and adequate documentation of relevant corres- 
pondence in a secure storage facility. 
 
Essential documents (written and electronic) should be retained for at least three (3) years 
after the completion of the study. The records should be retained by the investigator ac- 
cording to local regulations or as specified in the Clinical Study Agreement (CSA), whi- 
chever is longer. 

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12.0 REFERENCES 
1.  Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA: Cancer J Clin 63: 11– 
30, 2013 
 
2.  Bellmunt J, von der Maase H, Mead GM, et al.: Randomized phase III study comparing 
paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally ad- 
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group Study 30987. J Clin Oncol 30(10):1107-13, 2012 
 
3.  Harker WG, Meyers PJ, Preiha PS, et al: Cisplatin, methotrexate, and vinblastine 
(CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of 
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1468, 1985 
 
4.  Sternberg CN, Yagoda A, Scher HI, et al: M-Y AC (methotrexate,vinblastine, doxorubi- 
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461-466, 1988 
 
5.  Boutan-Larozc A, Mabjoubi M, Droz JP, et al: M-Y AC (methotrexate, vinblastine, dox- 
orubicin and cisplatin) for advanced carcinoma of the bladder. Bur J Cancer 27:1690- 
1694, 1991 EORTC Version 6.0 41/142 15 February, 2002 
 
6.  Igawa M, Obkuchi T, Ueki T, et al: Usefulness and limitations of methotrexate, vinblas- 
tine, doxorubicin and cisplatin for the treatment of advanced urothelial cancer. J Urol 
144: 662-665, 1990 
 
7.  Tannock I, Gospodarowicz M, Connolly J, et al: M- V AC (methotrexate, vinblastine, 
doxorubicin and cisplatin) chemotherapy for transitional cell carcinoma: The Princess 
Margaret Hospital experience. J Urol 142: 289-292, 1989 
 
8.  Roth BJ, Bajorin D: Advanced bladder cancer: the need to identify new agents in the 
post-M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) world. J Urol 153: 
894-900, 1995 
 
9.  Logothetis CJ, Dexeus FH, Finn L, et al: A prospective randomized trial comparing 
MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin 
Oncol 18: 1050-1055, 1990 
 
10. Bellmunt J, Ribas A, Eres N, et al: Carboplatin based versus cisplatin-based chemo- 
therapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 
80: 1966-1972, 1997 
 
11. Saxrnan SB, Propert KJ, Einhorn LH, et al: Long term follow-up of a phase III Inter- 
group study of cisplatin alone or in combination with methotrexate, vinblastine, and 
doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group 
study. J Clin Oncol 15: 2564-2569, 1997 
 
12. Seidman AD, Scher HI, Gabrilove JL, et al: Dose-intensification of MVAC with recom- 
binant granulocyte colony stimulating factor as initial therapy in advanced urothelial 
carcinoma. J Clin Oncol: 408-414, 1993 
 
13. Loehrer PJ Sr, Elson P, Dreicer R, et al: Escalated dosages of methotrexate, vinblas- 
tine, doxorubicin, and cisplatin plus recombinant human granulocyte colony-stimulating 

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factor in advanced bladder carcinoma: An Eastern Cooperative Oncology Group trial. J 
Clin Oncol 12:483- 488, 1994 
 
14. Logothetis CJ, Finn LD, Smith T, et al: Escalated MV AC with or without recombinant 
human granulocyte-macrophage colony-stimulating factor for the initial treatment of 
advanced malignant urothelial tumors: Results of a randomized trial. J Clin Oncol 13: 
2272-2277, 1995 
 
15. Pollera CF, Ceribelli A, Crecco M, et al: Weekly gemcitabine in advanced bladder can- 
cer: A preliminary report from a phase I study. Ann Oncol 15: 182-184, 1994 
 
16. Lorusso V, Pollera CF, Antimi M, et al: A phase II study of gemcitabine in patients with 
transitional cell carcinoma of the urinary tract previously treated with platinum. Italian 
Co-operative Group on Bladder Cancer. Eur J Cancer 34:1208-1212,1998 
 
17. Stadler WM, Kuzel T, Roth B, et al: Phase II study of single-agent gemcitabine in pre- 
viously untreated patients with metastatic urothelial cancer. J Clin Oncol 15: 3394- 
3398, 1997 
 
18. Moore MJ, Tannock I, Ernst S, et al: Gemcitabine: A promising new agent in the treat- 
ment of advanced urothelial cancer. J Clin Oncol 15: 3441-3445,1997 
 
19. Gandhi V, Legha J, Chen F, Hertel LW, Plunkett W: Excision of 2', 2'- 
difluorodeoxycytidine (gemcitabine) monophosphate residues from DNA. Cancer Res 
56: 4453-4459,1996 
 
20. Grunewald R, Abruzzese JL, Tarassoff P, Plunkett W: Saturation of 2', 2' 
-difluorodeoxycytidine 5-triphosphate accumulation by mononuclear cells during phase 
I trial of gemcitabine. Cancer Chemother Pharmacol 27:25862,1991 
 
21. Plunkett W: Pharmacology of gemcitabine. Ann Oncol 3:191,1992 
 
22. Abruzzese JL, Gravel, Tarassoff P, Raber M, Plunkett W: Pharmacologically-directed 
strategy for dose intensification of gemcitabine: a phase I trial. Proc Annu Meet Assoc 
Cancer Res 34: A2233, 1993. 
 
23. Cepeda V, Fuertes MA, Castilla J, et al.: Biochemical mechanisms of cisplatin cytotox- 
icity. Anticancer Agents Med Chem 7(1):3-18, 2007 
 
24. Yang LY, Li L, Liu NM, Keating MJ, Plunkett W: Gemcitabine suppresses the repair of 
cisplatin adducts in plasmid DNA by extracts of cisplatin-resistant human colon carci- 
noma cells. AACR 36:QA2124,1995 
 
25. Von der Maasse H, Andersen L, Crino L, et al Weekly gemcitabine and cisplatin com- 
bination therapy in patients with transitional cell carcinoma of the urothelium: a phase 
II clinical trial. Ann Oncol 10:1461-1465,1999. 
 
26. Moore MJ, Winquist EW, Murray M., et al Gemcitabine plus Cisplatin in patients with 
metastatic urothelial cancer, a phase II trial of the National Cancer Institute of Canada 
clinical trials Group. J Clin Oncol 17: 2876-2881,1999. K 
 
27. Kaufman D, Raghavan, Carducci Wet al. Phase II trial of gemcitabine plus cisplatin in 
patients with metastatic urothelial cancer J Clin Oncol 18: 1921-1927, 2000 

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28. von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, 
Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing 
gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in 
patients with bladder cancer. J Clin Oncol 23(21):4602-8, 2005 
 
29. von der Maase H, Hansen SW, Robert JT, et al. Gemcitabine and cisplatin versus me- 
thotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder 
cancer: results of a large, randomized, multinational, multicenter, phase III study. J 
Clin Oncol 17(17):3068-77, 2000 
 
30. Bambury RM, Rosenberg JE. Advanced urothelial carcinoma: overcoming treatment 
resistance through novel treatment approaches. Front Pharmacol 4:3, 2013 
 
31. Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. Lancet 374(9685):239-49, 
2009 
 
32. Fuchs DA, Johnson RK. Cytologic evidence that Taxol, an antineoplastic agent from 
Taxus Brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep 62:1219- 
1222,1978 
 
33. Rowinsky EK, McGuire WP: Taxol: present status and future prospects. Contemp On- 
col 29-36, 1992 
 
34. Rowinsky EK, Donehower RC:  Paclitaxel (taxol). N Engl J Med 332:1004, 1995 
 
35. Niell HB, Rangel C, Miller A, et al : The activity of antimicrotubular agents in human 
bladder tumor cell lines (HBTCL). Proc Am Assoc Cancer Res 34: 202, 1993 (abstr) 
 
36. Rangel C, Niell H, Miller A, et al: Taxol and taxotere in bladder cancer: in vitro activity 
and urine stability. Cancer Chem Phar 33: 460-464, 1994 
 
37. Roth B, Dreicer R, Einhorn LH, et al: Significant activity ofpaclitaxel in advanced transi- 
tional- cell carcinoma of the urothelium: A phase II trial of the ECOG. J Clin Oncol 12: 
2264-2270, 1994 
 
38. Murphy BA, Johnson DR, Smith J, et al: Phase II trial ofpaclitaxel and cisplarin for me- 
tastatic or locally unresectable urothelial cancer. Proc Am Soc Clin Oncol 15:245, 1996 
(abstr) 
 
39. Dreicer R, Manola J, Roth BJ, et al.: Phase II study of cisplatin and paclitaxel in ad- 
vanced carcinoma of the urothelium: an Eastern Cooperative Oncology Group Study. J 
Clin Oncol 18(5):1058-61, 2000 
 
40. Burch PA, Richardson RL, Cha SS, et al: Phase II trial combination paclitaxel and cis- 
platin in advanced urothelial carcinoma Proc Am Soc Clin Oncol 18:329a, 1999 (abstr) 
 
41. Sengelov L, Kamby C, Lund B, et al: Docetaxel and cisplatin in metastatic urothelial 
Cancer: A phase II study. J Clin Oncol 16:3392-3397 , 1998 
 
42. Bellmunt J, Albanell J, Paz-Ares L, et al.: Pretreatment prognostic factors for survival 
in patients with advanced urothelial tumors treated in a phase I/II trial with paclitaxel, 
cisplatin, and gemcitabine. Cancer 95(4):751-7, 2002 

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43. Bellmunt J, Guillem V, Paz-Ares L, et al.: Phase I-II study of paclitaxel, cisplatin, and 
gemcitabine in advanced transitional-cell carcinoma of the urothelium. Spanish Oncol- 
ogy Genitourinary Group. J Clin Oncol 18(18):3247-55, 2000 
 
44. Meluch AA, Greco FA, Burris HA III, et al.: Paclitaxel and gemcitabine chemotherapy 
for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the 
Minnie pearl cancer research network. J Clin Oncol 19(12):3018-24, 2001 
 
45. Srinivas S, Guardino AE. A nonplatinum combination in metastatic transitional cell car- 
cinoma. Am J Clin Oncol 28(2):114-8, 2005 

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APPENDIX A:  NCI Common Terminology Criteria for Adverse Events 
 
Safety and tolerability will be assessed according to Version 4.0 of the National Cancer Insti- 
tute‘s Common Terminology Criteria for Adverse Events (CTCAE).  An electronic version may 
be found at:  http://ctep.cancer.gov/reporting/ctc.html. 
 
In brief: 
 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; inter- 
vention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age- 
appropriate instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
 
A Semi-colon indicates ‗or‘ within the description of the grade. A single dash (-) indicates a 
grade is not available. 
 
Activities of Daily Living (ADL) 
 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the tele- 
phone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 

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APPENDIX B:  ECOG Performance Status 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 

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APPENDIX C:  RECIST 1.1 Guidelines 
 
Tumor response and progression will be defined according to RECIST 1.1 criteria. Electronic guidelines 
may be found at: http://www.eortc.be/recist/documents/RECISTGuidelines.pdf. 
 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference: 
 
Eligibility 
 
• 
Only patients with measurable disease at baseline should be included in protocols where objective 
tumor response is the primary endpoint. 
 
Measurable disease - the presence of at least one measurable lesion. If the measurable disease 
is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
 
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter ≥20 mm using conventional techniques or ≥10 mm with spiral CT scan. 
 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and. 
 
• 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
• 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
Methods of Measurement 
 
• 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 10 
mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen and pelvis. Head and neck 
tumors and those of extremities usually require specific protocols. 
 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable. 
 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should 
not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US 
might also be useful to confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination. 
 
• 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully 
and widely validated. Their uses in this specific context require sophisticated equipment and a high 
level of expertise that may only be available in some centers. Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological response 
when biopsies are obtained. 

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• 
Tumor markers alone cannot be used to assess response. If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response when 
all lesions have disappeared. 
 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor 
types such as germ cell tumors). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
 
• 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline. 
 
• 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or clinically). 
 
• 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to characterize the 
objective tumor. 
 
• 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or absence 
of each should be noted throughout follow-up. 
 
 
Response Criteria 
 
 
Evaluation of target lesions 
* Complete Response (CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of 
target lesions, taking as reference the baseline sum 
LD 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum 
LD recorded since the treatment started or the 
appearance of one or more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment 
started 
 
 
Evaluation of non-target lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
* Incomplete Response/Stable Disease (SD): 
Persistence of one or more non-target lesion(s) 
or/and maintenance of tumor marker level above 
the normal limits 

IRB NUMBER: HSC-MS-13-0864 
IRB APPROVAL DATE: 05/04/2016 
Confidential 
Protocol No. GU-13-102 
Page 24 of 26 
Ver. 4, dated 04/25/16 
 
 
 
 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions (1) 
 
(1) 
Although a clear progression of ―non target‖ lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be confirmed later 
on by the review panel (or study chair). 
 
Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria 
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
 Any  
Any  
Yes  
PD  
 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having ―symptomatic 
deterioration‖. Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
• 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
 
Confirmation 
 
• 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed. In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed. 
 
• 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate. 
 
• 
In the case of SD, follow-up measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study 
protocol 
 
 
Duration of overall response 
 
• 
The duration of overall response is measured from the time measurement criteria are met for CR or 
PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment 
started. 

IRB NUMBER: HSC-MS-13-0864 
IRB APPROVAL DATE: 05/04/2016 
Confidential 
Protocol No. GU-13-102 
Page 25 of 26 
Ver. 4, dated 04/25/16 
 
 
 
Duration of stable disease 
 
• 
SD is measured from the start of the treatment until the criteria for disease progression are met, 
taking as reference the smallest measurements recorded since the treatment started. 
• 
The clinical relevance of the duration of SD varies for different tumor types and grades. Therefore, it 
is highly recommended that the protocol specify the minimal time interval required between two 
measurements for determination of SD. This time interval should take into account the expected 
clinical benefit that such a status may bring to the population under study. 
 
Response review 
 
• 
For trials where the response rate is the primary endpoint it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study‘s completion. 
Simultaneous review of the patients‘ files and radiological images is the best approach. 
 
Reporting of results 
 
• 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). 
 
• 
All of the patients who met the eligibility criteria should be included in the main analysis of the 
response rate. Patients in response categories 4-9 should be considered as failing to respond to 
treatment (disease progression). Thus, an incorrect treatment schedule or drug administration 
does not result in exclusion from the analysis of the response rate. Precise definitions for 
categories 4-9 will be protocol specific. 
 
• 
All conclusions should be based on all eligible patients. 
 
• 
Subanalyses may then be performed on the basis of a subset of patients, excluding those for whom 
major protocol deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.). However, these subanalyses may not 
serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis should be clearly reported. 
 
• 
The 95% confidence intervals should be provided. 

 
Confidential 
Page 26 of 26 
Protocol No. GU-13-102 
Ver. 4, dated 04/25/2016 
 
APPENDIX D:  Schedule of Assessments 
 
Protocol Activity 
Pretreat- 
ment 
timeframe 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Visit Name 
C1 D1 
C1 
D2 
C1 
D8 
C1 
D15 
C2 
D1 
C2 
D2 
C2 
D8 
C2 
D15 
C3-6 
D1 
C3-6 
D2 
C3-6 
D8 
C4,6 
D15 
Informed consent 
-21 to -1 
Documentation of histologic di- 
agnosis and extent of cancer 
-21 to -1 
Inclusion/Exclusion criteria 
-21 to -1 
History & Physical exam with 
height and weight 
-7 to -1 
X 
Interim physical assessment with 
AEs, con meds, and toxicity 
X 
X 
ECOG Performance status 
-7 to -1 
X 
X 
CBC with diff, plts* 
-21 to -1 
X 
X 
X 
X 
X 
X 
X* 
X 
Comprehensive metabolic panel* 
-21 to -1 
X 
X 
X 
X 
X 
X 
X* 
X 
Electrolytes* 
-21 to -1 
X 
X 
X 
X 
X 
X 
X* 
X 
Beta 2 microglobulin 
-21 to -1 
X 
X** 
X 
Beta HCG 
-21 to -1 
X 
X** 
X 
CEA 
-21 to -1 
X 
X** 
X 
CA-125 
-21 to -1 
X 
X** 
X 
CT or x-ray of Chest, Abdomen 
and Pelvis with RECIST tumor 
measurements 
-28 to -1 
X 
X*** 
X*** 
Bone Scan 
-28 to-1 
X 
X*** 
X*** 
12 Lead EKG 
-90 to +3 
Echo or MUGA Scan 
-90 to +3 
Chemotherapy (Gemcitabine) 
X 
X 
X 
X 
X 
X 
Chemotherapy (Cisplatin, Pacli- 
taxel) 
X 
X 
X 
 
*Follow-up frequency of monitoring after the first 6 weeks to be tailored based on the first 6 weeks of therapy. 
**Subjects with elevated tumor markers at study entry should have them repeated every 6 weeks. 
***Whatever imaging is required to assess response in at least 1 measurable disease site should be repeated at the first 6 -week evaluation. If subject meets crite- 
ria for response, all measurable sites of disease should be reimaged after 12 weeks of therapy. 
 
 
IRB NUMBER: HSC-MS-13-0864 
IRB APPROVAL DATE: 05/04/2016