Clinical trial NCT01589094
Conditions: Bladder Cancer
Keywords: CISPLATIN GEMCITABINE GM-CSF radical cystectomy 12-071
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2012-04-01; Completion date: 2018-08-01
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out if standard chemotherapy (gemcitabine and cisplatin) given on a dose-dense treatment schedule (with less time between treatments) can help shrink the tumor better than standard chemotherapy given on a standard treatment schedule before the patient undergoes surgery for bladder cancer.

Detailed description:

Arms: arm 1: This is a Multicenter Phase II study of dose-dense (DD) gemcitabine and cisplatin (GC) neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer (MIBC) who are candidates for radical cystectomy.
Interventions: intervention 1: Gemcitabine and Cisplatin (DD GC)
Intervention descriptions: intervention 1: Patients will receive six cycles of GC administered every 14 days. Gemcitabine 2,500 mg/m2 will be administered intravenously on day 1 and cisplatin 35 mg/m2 will be administered intravenously on days 1 and 2 of a 14 days cycle (with Peg GCSF). A total of six cycles of therapy will be administered followed by radical cystectomy with bilateral pelvic lymph node dissection (PLND)

Protocol documents:
Prot_SAP_000.pdf: 
MEMORIAL SLOANKETTERING CANCER CENTER 
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Phase II Study of Neoadjuvant Dose Dense Gemcitabine and Cisplatin (DD GC) In 
Patients with Muscle-Invasive Bladder Cancer 
 
MSKCC THERAPEUTIC/DIAGNO STIC PROTOCOL 
Principal 
Investigator/Department: 
Dean F. Bajorin, MD 
Department of Medicine, Genitourinary 
Oncology Service 
Co-Principal 
Investigator(s)/Department: 
Jonathan E. Rosenberg, MD 
Department of Medicine, Genitourinary 
Oncology Service 
Investigator(s)/Department: 
Lewis Kampel, MD 
Jason Koutcher, MD 
Dana Rathkopf, MD 
Howard Scher, MD 
Susan Slovin, MD, PhD 
David Solit, MD 
Daniel Danila, MD 
Yu Chen, MD, PhD 
Gopa Iyer, MD 
Martin Voss, MD 
Michael Morris, MD 
Darren Feldman, MD 
Robert Motzer, MD 
Karen Autio, MD 
Chung-Han Lee, MD 
Wassim Abida, MD, PhD 
Ephraim Casper, MD 
Kenneth Ng, MD 
Marina Shcherba, DO 
Shree Chalasani, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Han Xiao, MD 
Asma Latif, MD 
Afsheen Iqbal, MD 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
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Medicine: Basking Ridge 
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Medicine: Basking Ridge 
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Avni M. Desai, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Marisa Siebel, MD 
Jahan Aghalar, MD 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Philip Caron, MD PhD 
Michelle Boyar, MD 
Nancy Mills, MD 
Carolyn Wasserheit-Lieblich, MD 
Stephanie Smith-Marrone, MD 
Michael Fanucchi, MD 
Chau Dang, MD 
Diana Lake, MD 
Elizabeth Won, MD 
Karen Cadoo, MD 
Hani Hassoun, MD 
Andrew Zelenetz, MD 
Harry Herr, MD Bernard 
Bochner, MD Jonathan 
Coleman, MD Guido 
Dalbagni, MD 
S. Machele Donat, MD 
James Eastham, MD 
Paul Russo, MD 
Joel Sheinfeld, MD 
Pramod Sogani, MD 
Behfar Ehdaie, MDIrina 
Ostrovnaya, PhD 
Victor Reuter, MD 
Hikmat A. Al-Ahmadie, MD 
Medicine: Commack 
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Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
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Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Biostatistics, 
Epidemiology Service 
Department of Pathology 
Department of Pathology 
Consenting 
Professional(s)/Department: 
Dean F. Bajorin, MD 
Robert J. Motzer MD 
Lewis Kampel, MD 
Jason Koutcher, MD 
Dana Rathkopf, MD 
Howard Scher, MD 
Susan Slovin, MD, PhD 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 


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David Solit, MD 
Daniel Danila, MD 
Yu Chen, MD, PhD 
Gopa Iyer, MD 
Martin Voss, MD 
Michael Morris, MD 
Darren Feldman, MD 
Jonathan E. Rosenberg, MD 
Karen Autio, MD 
 
Chung-Han Lee, MD 
Wassim Abida, MD, PhDEphraim 
Casper, MD Kenneth 
Ng, MD Marina 
Shcherba, DO Audrey 
Hamilton, MD Mila 
Gorsky, MD 
Han Xiao, MD 
Shree Chalasani, MD 
Asma Latif, MD 
Afsheen Iqbal, MD 
Avni M. Desai, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Marisa Siebel, MD 
Jahan Aghalar, MD 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Philip Caron, MD PhD 
Michelle Boyar, MD 
Nancy Mills, MD 
Carolyn Wasserheit-Lieblich, MD 
Stephanie Smith-Marrone, MD 
Michael Fanucchi, MD 
Chau Dang, MD 
Diana Lake, MD 
Elizabeth Won, MD 
Karen Cadoo, MD 
Hani Hassoun, MD 
Andrew Zelenetz, MD 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
Department of Medicine, Genitourinary 
Oncology Service 
 
Medicine: All Network Sites 
Medicine: All Network Sites 
Medicine: All Network Sites 
Medicine: All Network Sites 
Medicine: Basking Ridge 
Medicine: Basking Ridge 
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Medicine: Basking Ridge 
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Medicine: Basking Ridge 
Medicine: Basking Ridge 
Medicine: Commack 
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Harry Herr, MD Bernard 
Bochner, MD Jonathan 
Coleman, MD Guido 
Dalbagni, MD 
S. Machele Donat, MD 
James Eastham, MD 
Paul Russo, MD 
Joel Sheinfeld, MD 
Pramod Sogani, MD 
Behfar Ehdaie, MD 
Medicine: West Harrison 
 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
Department of Surgery, Urology Service 
 
 
 
 
Participating Institution(s): 
PI’s Name: 
Site’s Role: 
University of North Carolina at 
Chapel Hill 
Matthew I. Milowsky, MD 
Data Collection 
New York University 
Arjun Balar, MD 
Data Collection 
 
 
Please Note: A Consenting Professional must have completed the mandatory 
Human Subjects Education and Certification Program. 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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MEMORIAL SLOANKETTERING CANCER CENTER 
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Table of Contents 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL ....................................................................1 
 
Table of Contents...........................................................................................................................5  
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA.......................................................................7 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS................................................................................7 
 
3.0 
BACKGROUND AND RATIONALE .................................................................................... .7 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...........................................................13 
 
4.1 
Design ................................................................................................................................13 
 
4.2 
Intervention........................................................................................................................13  
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ...........................................................................13 
 
5.1 Gemcitabine (GEMZAR®):......................................................................................................13 
 
5.2 Cisplatin .................................................................................................................................14 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ...........................................................................14 
 
6.1 
Subject Inclusion Criteria .................................................................................................14 
 
6.2 
Subject Exclusion Criteria............................................................................................... .15 
 
7.0 
RECRUITMENT PLAN .......................................................................................................15 
 
8.0 
PRETREATMENT EVALUATION ..................................................................................... .16 
 
9.0 
TREATMENT/INTERVENTION PLAN............................................................................... .16 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ...................................................21 
 
11.0 TOXICITIES/SIDE EFFECTS .............................................................................................22 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................23 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY .......................................................................23 
 
14.0 BIOSTATISTICS ................................................................................................................ .24 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
………………………………………………………………………………………………………24 
 
15.1 Research Participant Registration ...................................................................................24 
 
15.2 Randomization.................................................................................................................25 
 
16.0 DATA MANAGEMENT ISSUES ........................................................................................ .26 
 
16.1 Quality Assurance ...........................................................................................................28 
 
16.2 Data Safety and Monitoring .............................................................................................29 
 
16.3 Regulatory Documentation ..............................................................................................30 
 
16.4 Noncom pliance ................................................................................................................32 
 
17.0 PROTECTION OF HUMAN SUBJECTS ............................................................................32 
 
17.1 Privacy .............................................................................................................................32 


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17.2 Serious Adverse Event (SAE) Reporting .........................................................................32 
 
17.3 Safety Reports .................................................................................................................33 
 
18.0 INFORMED CONSENT PROCEDURES ............................................................................34 
 
18.1 For Participating Sites .....................................................................................................35 
 
19.0 REFERENCES ......................................................................................................................36 
 
20.0 Appendices...........................................................................................................................39 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a Multicenter Phase II study of dose-dense (DD) gemcitabine and cisplatin (GC) 
neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer (MIBC) who 
are candidates for radical cystectomy. Patients will receive six cycles of GC administered 
every 14 days. Gemcitabine 2,500 mg/m2 will be administered intravenously on day 1 and 
cisplatin 35 mg/m2 will be administered intravenously on days 1 and 2 of a 14 days cycle 
(with Peg G-CSF). A total of six cycles of therapy will be administered followed by radical 
cystectomy with bilateral pelvic lymph node dissection (PLND). The primary objective of 
this phase II trial will be to determine the pathologic response rate (< pT2) of this regimen. 
 
 
 
12 w eeks of GC therapy 
 
 
 
 
MIBC 
Cystoscopy/ 
EUA/TURBT 
 
Cycl e 
1 
 
Cycl e 
2 
 
Cycl e 
3 
 
Cycl e 
4 
 
Cycl e 
5 
 
Cycl e 
6 
 
Cystectomy to 
assess pathologic 
response 
 
 
 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 Primary Objective: 
 
• 
To define the pathologic response rate (<pT2) of neoadjuvant DD GC 
regimen in patients with MIBC. 
 
2.2 Secondary Objectives: 
 
• 
To determine the safety and tolerability of the DD GC regimen in patients 
with MIBC. 
• 
To determine the progression-free survival in patients with MIBC treated 
with DD GC followed by radical cystectomy. 
 
3.0 
BACKGROUND AND RATIONALE 
 
Bladder cancer is the second most common genitourinary malignancy. The American 
Cancer Society estimates 69,250 new cases and 14,990 deaths in the United States for 
the  year 2011.1   The prevalence of  bladder cancer is  estimated to  be  approximately 
600,000 cases and management of this disease costs $3 billion in healthcare expenditure 
annually compared with  $1  billion  for  prostate cancer. The  most  difficult patients  to 
manage are those with muscle-invasive disease; despite surgery with curative intent 
(radical cystectomy and bilateral pelvic lymph node dissection), approximately 50% of 
patients  with  muscle-invasive  bladder  cancer  will  develop  distant  metastases  and 
succumb to their disease.2  Over the past two decades, attempts to improve outcomes 
have focused on the addition of  perioperative chemotherapy in  hopes of  eradicating 


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micrometastatic disease and reducing the risk of relapse. Trials exploring chemotherapy in 
the adjuvant setting have yielded inconclusive results as these trials were largely 
underpowered  and/or  utilized  suboptimal  chemotherapeutic  regimens.3-5   Neoadjuvant 
cisplatin-based chemotherapy prior  to  radical  cystectomy has  been  demonstrated to 
reduce the risk of relapse and improve overall survival (OS) in multiple clinical trials and a 
meta-analysis. 
 
3.1 Neoadjuvant Cisplatin-Based Chemotherapy for MIBC Improves Outcomes 
 
Cisplatin is the only chemotherapeutic agent associated with a survival benefit in any 
urothelial cancer disease state. In the neoadjuvant setting, a survival benefit with cisplatin- 
based combination chemotherapy has been confirmed in two large randomized clinical 
trials and a meta-analysis of over 3,000 patients.6-8 These data clearly establish cisplatin- 
based neoadjuvant chemotherapy as the standard of care for patients with MIBC who are 
being considered for radical cystectomy. 
 
The most commonly studied neoadjuvant regimen reported in the literature is MVAC 
(methotrexate, vinblastine, doxorubicin, and cisplatin), a standard of care for patients with 
metastatic disease.9    The Southwest Oncology Group (SWOG)-8710 trial randomized 
patients with stage T2–T4aN0 bladder cancer to receive either three cycles of MVAC 
followed by radical cystectomy or radical cystectomy alone.10  Disease specific survival 
was superior for patients receiving neoadjuvant MVAC (HR=1.66, 95% CI, 1.22–2.45, 
p=0.002). There was a trend toward superior OS (HR=1.33, 95% CI, 1.00–1.76) for 
patients treated with MVAC as compared to patients managed with surgery alone, with an 
OS of 57% and 43% at 5 years, respectively (p=0.06). Furthermore, pathologic response 
to neoadjuvant chemotherapy predicted for clinical outcomes.  Patients without residual 
disease (pT0) at cystectomy had an improved 5-year survival (85%) over those who had 
residual disease, and patients in the MVAC arm more frequently achieved pT0 status 
(38% vs 15%, p<0.001).10 
 
Recently, updated long-term results from the MRC/EORTC randomized Phase III trial of 
neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) reported improved outcomes 
associated with neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) prior to 
definitive therapy for MIBC.   Neoadjuvant CMV was associated with a 16% relative 
improvement in survival (p=0.037) and 23% relative improvement in metastasis-free 
survival (p=0.001) at 10 years.11  Notably, the survival benefit observed with neoadjuvant 
chemotherapy in bladder cancer is similar to the survival benefit observed with adjuvant 
chemotherapy in early studies performed in breast and colon cancer (Table 1). 
 
Table 1:   Summary of Survival Benefit Associated with Perioperative Chemotherapy in 
Breast, Bladder, and Colon Cancer 
Breast 
Lancet 199812 
Bladder 
Eur Urology 200513 
Colon 
J Clin Oncology 
200414 
N=17,723 
N=3,005 
N=3,302 
Abs. Difference 
in Survival (yrs) 
7% (10) 
5% (5) 
7% (5) 
HR, Disease- 
Free Survival 
0.77 
0.78 
0.70 


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3.2 Role for Gemcitabine and Cisplatin in the Neoadjuvant Setting 
 
The MVAC regimen has long represented a standard of care for the treatment of patients 
with advanced/metastatic urothelial cancer.9      With the advent of newer agents, 
investigators focused on developing regimens with similar efficacy but less toxicity than 
MVAC. In a large randomized trial, the combination of gemcitabine and cisplatin (GC) 
proved to have similar efficacy and less toxicity than MVAC and now represents the 
standard of care for patients with metastatic urothelial cancer.15    While tolerability of 
chemotherapy improved with the GC regimen, the efficacy of therapy (response and 
survival) for patients with metastatic urothelial cancer did not change substantially. 
 
As GC is better tolerated and achieves similar response and survival rates to MVAC in 
metastatic urothelial cancer, it is frequently used as a substitute for MVAC in the 
neoadjuvant setting.   However, GC has not been prospectively evaluated in the 
neoadjuvant setting. At MSKCC, pathologic response rate in 42 patients treated with 
neoadjuvant GC was retrospectively compared to pathologic response rate in 54 patients 
treated with neoadjuvant MVAC prior to definitive surgery.16 Pathologic response rate, 
defined as eradication of muscle invasive disease (<pT2) at cystectomy, was similar for 
patients receiving GC (15/42; 36%, 95% CI 21-52%) and MVAC (19/54; 35%, 95% CI 23- 
49).  Furthermore, achieving complete pathologic response (pT0) for patients treated with 
GC (11/42; 26%, 95% CI 14-42) was also similar to MVAC (15/ 54; 28%, 95% CI 16-42). 
 
Patients treated with GC received 4 cycles of therapy on one of two 21-day dosing 
schedules for 12 weeks: 1.) a standard single dose schedule with gemcitabine 1000 
mg/m2 and cisplatin 70 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on day 8; or 2.) a 
“split-dose” schedule with gemcitabine 1000 mg/m2 and cisplatin 35 mg/mg2 on day 1 and 
day 8.   Under these two dosing schedules, the achieved median dose delivered for 
cisplatin was 91% and for gemcitabine was 90%. Treatment was well-tolerated. These 
data support the use of a 21-day schedule of GC in the neoadjuvant setting for MIBC. 
Unfortunately, despite the use of better tolerated neoadjuvant chemotherapy, outcomes 
have not significantly changed and a large proportion of patients ultimately recur. Novel 
neoadjuvant treatment strategies are needed to improve outcomes. 
 
3.3 Rationale for Dose Dense Chemotherapy 
 
Potential incremental benefits in disease-free survival (DFS) and OS have been observed 
in clinical trials utilizing higher doses (dose intense) and more frequent administration 
(dose dense) of chemotherapeutic agents.17 This is especially true for women with high- 
risk breast cancer, where dose dense therapy has become a mainstay in the adjuvant 
setting.18 
 
The Cancer and Leukemia Group B (CALGB) 9741 phase III randomized trial evaluated a 
dose-dense chemotherapy approach using concurrent doxorubicin and cyclophosphamide 
followed by paclitaxel in the adjuvant treatment of women with lymph node-positive early- 
stage breast cancer.19 This trial demonstrated a significant improvement in DFS and OS in 
the dose-dense chemotherapy arm, which has subsequently become the adjuvant 
treatment standard for patients with early-stage breast cancer.18 
 
Bonilla, et al. conducted a meta-analysis of randomized trials investigating dose-dense 
chemotherapy in non-metastatic breast cancer. Ten trials met the inclusion criteria and 
were classified into two categories based on trial methodology. Three trials enrolling 3,337 
patients compared dose-dense chemotherapy with a conventional chemotherapy schedule 
using similar chemotherapeutic agents. Patients who received dose-dense chemotherapy 


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had longer OS (HR=0.84, 95% CI 0.72-0.98, p=0.03) and longer DFS (HR=0.83, 95% 
CI=0.73-0.94, p=0.005) than patients receiving similar chemotherapy on a conventional 
schedule. Seven trials enrolling 8,652 patients compared dose-dense chemotherapy with 
regimens that use standard intervals but with different agents and/or dosages in the treat- 
ment arms. Similar results were obtained for these trials with respect to OS (HR=0.85, 
95% CI 0.75-0.96, p=0.01) and DFS (HR=0.81, 95% CI 0.73-0.88, p< 0.001).18 
 
3.4 Higher Dose Density of Cisplatin May be Associated with Improved Outcomes in 
Advanced Urothelial Cancer. 
 
In metastatic urothelial cancer, Sternberg, et al. were first to report a potential benefit of 
high dose intensity chemotherapy in a phase III randomized trial of high dose MVAC (HD 
MVAC) plus G-CSF versus conventional MVAC.20     In actuality, the doses of MVAC were 
identical in both arms, but the “high dose” arm was administered at 2 week intervals rather 
than 4 week intervals for standard MVAC.   After a median follow up of 7.3 years, HD 
MVAC was associated with a significant relative reduction in the risk of progression (p= 
0.017) and death (p=0.042) compared to MVAC.21 
 
Bamias, et al. recently reported the results of a phase III randomized trial evaluating dose 
dense MVAC (DD MVAC) versus DD GC in patients with inoperable or recurrent urothelial 
cancer.22 Patients were randomized to receive MVAC (30 mg/m2; 3 mg/m2; 30 mg/m2; 70 
mg/m2) or GC (gemcitabine 2500 mg/m2 day 1 plus cisplatin 35 mg m2 days 1 and 2 with 
G-CSF) every two weeks for a planned 6 cycles.  Overall response rate and survival were 
similar for both treatment arms: 65% and median 18.4 months respectively for patients 
treated with DD GC and 63% and median 18.0 months respectively for patients treated 
with DD MVAC.   However, DD GC was better tolerated than DD MVAC, leading the 
authors to conclude DD GC could represent another treatment standard for advanced 
disease.  Importantly, the OS reported for both arms in this trial using two dose dense 
regimens appears to be substantially better than previously reported with other cisplatin- 
based regimens administered in standard schedules, suggesting a benefit to dose dense 
chemotherapy.15 
 
These data suggest that higher dose density cisplatin may be associated with improved 
response rate and survival in advanced urothelial cancer, and thus, supports its study in 
the neoadjuvant setting (Table 2). 
 
Table 2. Comparison of Cisplatin-Based Studies Utilizing Different Dose Densities in the 
Treatment of Metastatic Bladder Cancer 
Regimen 
Dose Density of 
Cisplatin (mg/m
2/week) 
N= 
Overall 
Response 
Rate (%) 
Median OS (months) 
GC15 
17.5 
203 
49.4 
14 
MVAC15 
17.5 
202 
45.7 
15.2 
MVAC21 
17.5 
129 
58 
14.9 
GC23 
17.5 
315 
46 
12.8 
DD MVAC21 
35 
134 
72 
15.1 
DD MVAC24 
35 
118 
62.7 
18.4 
DD GC24 
35 
57 
65.3 
18.0 


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3.5 Neoadjuvant Dose Dense Cisplatin-Based Chemotherapy in MIBC 
 
To date, no prospective trials have evaluated dose dense chemotherapy in the 
neoadjuvant setting in MIBC. However, two retrospective experiences using MVAC were 
recently presented at the 2011 ASCO Genitourinary Cancers Symposium and the 2011 
ASCO Annual Meeting that suggest a dose dense approach may improve clinical 
outcomes (Table 3). 
 
Table 3. Retrospective Experiences Using Dose-Dense MVAC 
Study 
Regimen 
Cisplatin Dose 
Density 
(mg/m
2/week) 
N= 
CR 
2 year 
DFS 
Blick et al. 2011 
GU ASCO25 
DD MVAC x 3-4 cycles 
35 
80 
43% 
65% 
Elmongy et al 
2011 ASCO26 
DD MVAC x 4-6 cycles 
35 
12 
50% 
100% 
 
These retrospective data suggest that neoadjuvant dose dense chemotherapy may 
increase response rate (43-50% CR rate for DD MVAC vs 38% for standard MVAC), in a 
manner similar to that observed with its use in advanced disease, further strengthening 
the rationale for the prospective approach outlined in this clinical trial. 
 
3.6 Rationale for Neoadjuvant DD GC in MIBC 
 
Neoadjuvant GC is similar to MVAC with regards to pathologic response rates and offers 
an advantage with respect to tolerability.  Administering standard doses of cisplatin-based 
chemotherapy over a shorter period of time (i.e. higher dose density) potentially improves 
response rate and offers a survival advantage without compromising safety or tolerability. 
 
The current trial seeks to explore the intensified regimen of gemcitabine and cisplatin in 
the neoadjuvant setting in patients with MIBC. This trial is supported by the following 
rationale: 
 
• 
Neoadjuvant cisplatin-based therapy has improved survival over cystectomy alone in 
patients with MIBC. 
 
• 
Since the survival benefit is greatest in patients achieving response to chemotherapy, 
strategies to increase response rates of active regimens is warranted. 
 
• 
Dose-dense cisplatin chemotherapy increases response rate for patients with 
metastatic bladder cancer. 
 
• 
DD GC is the best tolerated dose dense regimen. 
 
• 
DD GC is a logical candidate for prospective study in the neoadjuvant setting. 


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3.7 Pathologic Response to Chemotherapy as an Endpoint of Clinical Efficacy 
 
3.7.1 Pathologic Response (<pT2) 
 
Muscle-invasive bladder cancer, defined as pathologic evidence of muscle invasion (pT2) 
on biopsy specimen, is the major indication for neoadjuvant chemotherapy prior to radical 
cystectomy.   Pathologic response to neoadjuvant chemotherapy can be defined as 
absence of any residual muscle invasive disease at the time of cystectomy (< pT2) and 
includes pT1, pTcis, pTa, and T0 disease.  Due to the multi-focal nature of this disease, it 
is very common at both pre-chemotherapy and post-chemotherapy evaluations to see pre- 
existing and/or residual superficial transitional cell carcinoma such as Tcis, Ta or T1 
disease (frequently collectively defined as < pT2).  The likelihood of residual superficial 
disease is also directly related to the extent of the TURBT prior to neoadjuvant 
chemotherapy.  Superficial disease, and in particular Tcis, is typically unresponsive to 
chemotherapy, non-life threatening, and frequently included within the definition of major 
chemotherapy response. The prognostic value of defining response to neoadjuvant 
chemotherapy in MIBC as <pT2 in contrast to solely pT0 (complete pathologic response) 
was first shown in an analysis by Splinter et al. of 147 patients treated with neoadjuvant 
chemotherapy prior to radical cystectomy at eight different centers.27     This study 
demonstrated that patients with MIBC who achieved < pT2 (including pT0, pTcis, pTa, and 
pT1) after neo-adjuvant chemotherapy achieved 75% survival at 5 years in contrast to 
20% survival for those whose tumors still harbored continued muscle-invasion ( > pT2 
residual disease). 
 
The comparable survival rates of patients achieving pathological complete response (pT0) 
and patients achieving partial pathologic response (<pT2) has been validated in a prior, 
independent study at MSKCC.28   In a trial of 111 patients treated with neo-adjuvant MVAC 
at MSKCC, outcome analysis showed a similar survival benefit from chemotherapy for 
those  patients  achieving  <   pT2   (pT0,  pTa,   pTcis,  and   pT1)  after   neoadjuvant 
chemotherapy and for those achieving the status of pT0.  This experience confirms the 
findings of Splinter et al. 
 
3.7.2   Rationale for Response Rates used in Study Design 
 
This trial will aim to test a 20% improvement on the average pathologic response rate 
reported with conventional schedule cisplatin-based neoadjuvant chemotherapy regimens 
of approximately 35%.  Thus, a “promising” pathological response rate for DD GC of 55% 
would warrant further study of this regimen.    The average pathologic response rate 
associated with conventional schedule cisplatin-based chemotherapy was determined by 
data from a prior MSKCC retrospective study and two large intergroup randomized 
neoadjuvant trials.6,8,29        At MSKCC, the pathological response rate (<pT2) was 36% for 
patients treated with neoadjuvant GC and 35% for patients treated with neoadjuvant 
MVAC.  In the MRC/EORTC trial, the pathologic response rate was 27% (95% CI 21-33) 
for the 246 patients receiving neoadjuvant chemotherapy by an intent-to-treat analysis.  In 
the SWOG 8710 trial, the pathologic response rate was 32% (95% CI 25-40) for the 153 
patients randomized to neoadjuvant MVAC chemotherapy, also using an intent-to-treat 
analysis. 
 
It is well known that pathologic response rate  can be subject to the completeness of the 
initial transurethral resection of the bladder tumor (TURBT) at diagnosis, and thus, can 
vary based on the surgeon performing the procedure.  For example, in the SWOG 8710 
randomized trial, 15% of patients randomized to surgery alone had a complete pathologic 
response at the time of cystectomy.  Thus, the pathologic response rate after neoadjuvant 
chemotherapy can also similarly vary based on the completeness of the initial TURBT. 


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However, the MSKCC experience reported by Dash et al. demonstrates similar pathologic 
outcomes to those reported by prospective randomized studies. 
 
This protocol, like our prior MSKCC neoadjuvant studies and those at other centers, will 
examine pathologic response (<pT2) after chemotherapy as the endpoint of efficacy. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1     Design 
 
This is a multicenter phase II study of neoadjuvant DD GC in patients with MIBC prior to 
radical cystectomy. Patients with biopsy proven MIBC who are candidates for radical 
cystectomy will be enrolled and will receive six 14-day cycles of DD GC. Toxicity and 
interval response will be assessed during treatment. Following treatment, patients will 
undergo radical cystectomy and bilateral pelvic lymph node dissection and the surgical 
specimens will be assessed for pathologic response to therapy. Patients will be followed 
for five years or until disease recurrence/progression. 
 
4.2     Intervention 
 
Patients will receive six cycles of GC administered every 14 days followed by radical 
cystectomy. Gemcitabine 2,500 mg/m2  will be administered intravenously on day 1 and 
cisplatin 35 mg/m2 will be administered intravenously on days 1 and 2 every 14 days for 6 
cycles (for a total of 12 weeks) with G-CSF support. The primary objective of this phase II 
trial will estimate the pathologic response rate of this regimen. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Gemcitabine (GEMZAR®): 
 
5.1.1 Gemcitabine is a pyrimidine analogue of deoxycytidine in which the deoxyribose 
moiety contains 2 fluorine atoms at the 2’position. The drug acts as an inhibitor to 
ribonucleotide reductase and inhibition of DNA synthesis may result in perturbations of 
deoxynucleotide pools and interference with DNA chain elongation. The drug is cell-cycle 
specific and blocks cells in the G1/S interface. Cytotoxicity is schedule dependent and 
increases with  increasing  duration  of  exposure.  The  drug  is  rapidly  eliminated  from 
plasma, owing mainly to deamination. Renal clearance of drug is less than 10% of parent 
drug. 
 
5.1.2 Availability 
The drug is supplied as either a 200 mg or 1 gram lyophilized powder in a 50mL sterile 
single vial for reconstitution. 
 
5.1.3 Administration 
The drug is administered via a freely running intravenous catheter per local institutional 
guidelines. 
 
5.1.4 Toxicity 
Toxicities include nausea, vomiting, alopecia, stomatitis, anorexia, fatigue, elevations of 
hepatic transaminases, rash, flu-like symptoms, edema, constipation, paresthesias, 
hypersensitivity reactions, phlebitis, proteinuria, hematuria, reversible myelosuppression, 
rarely interstitial pneumonitis and ARDS, and rarely kidney damage. 


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5.2 Cisplatin: 
 
5.2.1 Cisplatin is a planar inorganic metal salt that function as an alkylating agent. In 
aqueous solution, the drug is equated to a diaquo species as the two chloride groups 
leave the molecule. The reactive diaquo species binds to N7 residues of guanine bases on 
DNA resulting in strand scission, and intra- and inter-strand crosslinking. 
 
5.2.2 Availability 
Cisplatin is commercially supplied as a lyophilized powder in 10 mg and 50 mg vials, and 
stored at room temperature. The drug should be reconstituted using 10 ml and 50 ml 
respectively of sterile water for injection, USP, to yield a concentration of 1 mg/ml. 
Prereconstituted multidose vials of 100 mg are also available. Once the multidose vial has 
been entered, the remaining cisplatin is stable for 28 days when protected from light. 
 
5.2.3 Administration 
Route of Administration: Cisplatin should be given IV drip per local institutional guidelines. 
Needles and IV sets using aluminum should not be used in the administration of cisplatin. 
 
5.2.4 Toxicity 
Potential side effects from cisplatin include cumulative nephrotoxicity, myelosuppression, 
nausea, and vomiting. Ototoxicity, manifested by tinnitus and/or high frequency hearing 
loss, is significant. Anaphylactic-like reactions to cisplatin have been reported. Facial 
swelling, bronchospasm, tachycardia, and hypotension may occur within minutes of 
cisplatin administration. Other side effects include fatigue, anorexia, weight loss, diarrhea, 
serum    electrolyte   disturbances   including    hyponatremia,   hypomagnesemia,   and 
hypocalcemia,  edema  of  the  lungs  or  extremities,  vascular  toxicities,  neurotoxicity 
including cerebral infarction, seizures and dizziness, ocular toxicity with visual 
disturbances, peripheral neuropathy, autonomic neuropathy, infertility, muscle cramps, 
and hepatic toxicity. Other rare side effects include cardiac abnormalities, hiccoughs, 
elevated serum amylase, rash, and alopecia. Local soft tissue injury has been reported 
following extravasation of cisplatin. Based on reported toxicities from completed/ongoing 
trials utilizing NCI Common Toxicity Criteria. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1     Subject Inclusion Criteria 
 
• 
Muscle invasive urothelial carcinoma of the bladder histologically confirmed at MSKCC 
or participating site. (Urothelial carcinoma invading into the prostatic stroma with no 
histologic muscle invasion is allowed, provided the extent of disease is confirmed via 
imaging and/or EUA.) 
•   Clinical stage T2-T4a N0/X M0 disease 
• 
Medically appropriate candidate for radical cystectomy, as per MSKCC or participating 
site Attending Urologic Oncologist 
•   Karnofsky Performance Status ≥ 70% 
•   Age ≥ 18 years of age 
•   Required Initial Laboratory Values: 
o Absolute Neutrophil Count ≥ 1000 cells/mm3 
o Platelets ≥ 100,000 cells/mm3 
o Hemoglobin ≥ 9.0g/dL 
o Bilirubin ≤ 1.5 the upper limit of normal (ULN) for the institution 


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o Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for the 
institution 
o Alkaline phosphatase ≤ 2.5 x ULN for the institution 
o Serum creatinine ≤ 1.5 mg/dL 
o Estimated glomerular filtration rate ≥ 60 ml/min/1.73m2 using the CKD-EPI 
equation: eGFR = 141 x min(Scr/k, 1)a x max(Scr/k, 1)-1.209 x 0.993Age 
• 
x 1.018 [if female] x 1.159 [if black] 
Scr is serum creatinine, k is 0.7 for females and 0.9 for males, a is -0.329 
for females and -0.411 for males, min indicates the minimum of Scr/k or 1, 
and max indicates the maximum of Scr/k or 1 
o If female of childbearing potential, pregnancy test is negative 
 
 
6.2     Subject Exclusion Criteria 
 
•   Prior systemic chemotherapy (prior intravesical therapy is allowed) 
•   Prior radiation therapy to the bladder 
•   Evidence of NYHA functional class III or IV heart disease 
•   Serious intercurrent medical or psychiatric illness, including serious active infection 
•   Preexisting sensory grade ≥ 2 neuropathy 
•   Preexisting grade ≥ 2 hearing loss 
•   Major surgery or radiation therapy < 4 weeks of starting study treatment 
•   Concomitant use of any other investigational drugs 
• 
Any of the following within the 6 months prior to study drug administration: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, 
symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic 
attack 
•   Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.0 grade ≥ 2 
•   Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness or other active infection 
• 
Concurrent treatment on another clinical trial; supportive care trials or non-treatment 
trials, e.g. QOL, are allowed 
• 
Pregnancy or breast-feeding. Patients must be surgically sterile, postmenopausal, or 
must agree to use effective contraception during the period of therapy. The definition of 
effective contraception will be based on the judgment of the principal investigator or a 
designated associate. Male patients must be surgically sterile or agree to use effective 
contraception. 
 
7.0 
RECRUITMENT PLAN 
 
Eligible patients with urothelial carcinoma of the bladder will be recruited from the 
Genitourinary Oncology and Urology Services at MSKCC, University of North Carolina at 
Chapel Hill, and New York University.  Every attempt will be made to recruit women and 
minorities to participate in this study. Participation is voluntary.  The consenting physician 
will inform patients of their diagnosis, current treatment options including standard 
treatment, and the risks, benefits, and experimental nature of this treatment program. 
Approximately a total of 46 evaluable patients will participate in the trial with about 26 
patients from MSKCC and 20 from University of Carolina at Chapel Hill and New York 
University. Accrual goals are feasible because neoadjuvant chemotherapy is the standard 
of care in our center. MSKCC performs over 200 cystectomies per year (130 in patients 
with MIBC) and our group has published multiple studies of neoadjuvant chemotherapy in 
patients with bladder cancer. 


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8.0 
PRETREATMENT EVALUATION 
 
The following studies must be completed within 14 days prior to initiation of treatment (unless 
otherwise indicated): 
 
• 
Complete history and physical examination 
 
• 
Vital signs including temperature, blood pressure, respiratory rate, heart rate, weight, and 
height 
 
• 
Karnofsky Performance Status 
 
• 
Complete blood count (CBC) with differential and platelets 
 
• 
Comprehensive panel (Na, K, Cl, CO2, BUN, Cr, Ca, glucose, AST, ALT, TP, Albumin, 
ALP, BT) 
 
• Coagulation profile (PT/INR/PTT) 
 
• 
Urinalysis 
 
• 
Pregnancy test in women of childbearing potential 
 
• 
Chest X-ray (a CT of chest may be performed instead if clinically relevant) within 30 days of 
enrollment 
 
• 
EKG 
 
• 
Baseline CT scan and/or MRI of the abdomen and pelvis within 30 days of enrollment. 
Diffusion-weighted MRI is preferred. 
 
• 
Cystoscopy/Transurethral Resection of Bladder Tumor (TURBT) within 60 days of 
enrollment to define clinical stage. Biopsies from that procedure must have confirmed 
invasive urothelial carcinoma of the bladder. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Dose and Schedule of GC 
 
2 weeks = 1 cycle 
Day 1 
Day 2 
Day 3 
Gemcitabine 
2,500 mg/m2 IVPB over 
approximately 1½ - 2 hrs 
Cisplatin 
35 mg/m2 IVPB over 
approximately 30 mins 
35 mg/m2 IVPB over 
approximately 30 mins 
Peg G-CSF 
6 mg SC 
1-2 liters of normal 
saline or suitable 
alternative 


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Treatment will be administered for a total of 6 cycles with each cycle given at 2 week intervals if 
criteria for initiation of subsequent cycles are met. 
 
9.1      Gemcitabine and Cisplatin (GC) 
Gemcitabine and Cisplatin will be administered on day 1 and Cisplatin will be administered 
on day 2 of each 14 day cycle as follows: 
Day 1: Gemcitabine 2500 mg/m 2 as an IV infusion per local hospital guidelines 
Cisplatin 35 mg/m 2 as an IV infusion per local hospital guidelines 
Day 2: Cisplatin 35 mg/m 2 as an IV infusion per local hospital guidelines 
Day 3: Pegylated G-CSF (6 mg) will be administered subcutaneously per local hospital 
guidelines 
1-2 liters of normal saline (or suitable alternative) will be administered per local 
hospital guidelines 
 
Suggested delayed emesis and hydration regimens are provided in Appendix 1. 
 
9.2       Toxicities Requiring Treatment Interruption for GC 
Toxicities requiring treatment interruption include one or more of the following hematologic 
or non-hematologic criteria: 
 
Hematologic: 
• 
Platelet count <100,000 cells/mm3 
 
• 
Requirement for platelet transfusion and/or other methods to increase 
platelet count 
 
• 
Febrile neutropenia (ANC <1000/mm3 concurrent with a temperature 
>38.5oC) 
 
• 
Grade 4 neutropenia without fever of >7 days duration 
 
Non-Hematologic: 
• 
Any ≥ Grade 3 non-hematologic toxicity considered by the investigator 
to be related to study drug 
  
9.3      Criteria for Continuation of Chemotherapy 
At each clinic visit prior to initiating Day 1 of each cycle of chemotherapy, patients must 
meet the following criteria. 
 
• 
Absolute neutrophil count ≥ 1000 cells/mm3 
• 
Platelets ≥ 100,000 cells/mm3 
• 
Serum creatinine ≤ 1.5 or estimated GFR ≥ 60 mL/min 
• 
Resolution of adverse events to baseline or ≤ grade 2 
 
The initiation of subsequent cycles of chemotherapy beyond the 1st cycle may be delayed 
up to 14 days from the planned day 1 of the current chemotherapy cycle to allow for 
resolution of adverse events. If the criteria for re-treatment are not met by 14 days, the 
patient will discontinue chemotherapy. 


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9.4 
Dose Modifications 
 
Dose Level 
Gemcitabine 
Starting 
2500 mg/m2 
Dose Level -1 
2250 mg/m2 
Dose Level -2 
2000 mg/m2 
Dose Level -3 
1800 mg/m2 
 
Dose Level 
Cisplatin 
Starting 
35 mg/m2 
Dose Level -1 
30 mg/m2 
Dose Level -2 
25 mg/m2 
 
9.4.1 Maximum Duration of Treatment Delays/Maximum Dose Reductions: Treatm ent 
with gemcitabine and cisplatin may be held up to a maximum of 14 days from the 
scheduled cycle initiation date to await resolution of toxicity according to the guidelines 
above.  If  more  than  14  days  are  needed  for  recovery,  the  patient  will  discontinue 
chemotherapy. 
 
Patients requiring more than 3 dose reductions of gemcitabine or 2 dose reductions of 
cisplatin will discontinue chemotherapy and be counted as treatment failures. All patients 
discontinued from chemotherapy for maximum dose reduction will be treated according to 
physician discretion. Any patients who have completed at  least 3  cycles of  protocol 
therapy will be evaluated for the primary endpoint. 
 
9.5 
Algorithm for Dose Modification and Interruption 
 
9.5.1 Dose Modifications for Hematologic Toxicity 
If the criteria for treatment on Day 1 are not met, treatment will be held one week and the 
CBC will be rechecked before proceeding. The following dose modifications of 
gemcitabine will be based on blood counts within 1 day prior to day 1 of each cycle of 
therapy. Only the gemcitabine dose will be reduced for hematologic toxicity. 
 
Table 4: Dose Interruption and Modification for Hematologic Toxicity Based on Day 1 
Counts. 
ANC 
(x109/L) 
Platelets 
(x109/L) 
If previous dose level 
of gemcitabine was: 
Day 1 level of 
gemcitabine: 
< 1.0 
or 
< 100 
Level 0* 
Level -1 
< 1.0 
or 
< 100 
Level -1* 
Level -2 
< 1.0 
or 
< 100 
Level -2* 
Level -3 
< 1.0 
or 
< 100 
Level -3 
Off-Study 
*Hold therapy for 1 week and recheck CBC 
 
9.5.2   Non-Hematologic Toxicity 
 
Renal Insufficiency/ Nephrotoxicity 
If on day 1 of any cycle, the serum creatinine > 1.5 and calculated estimated GFR < 60 
ml/min/m2, treatment will be held for one week and creatinine/eGFR will be rechecked. If 
recovery to serum creatinine < 1.5 or eGFR > 60 cc/min occurs, the patient will be 
retreated with a cisplatin dose 1 level lower than the prior cycle. Additional hydration 
should be considered on the day of treatment or on the day following treatment. 


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Neurologic Toxicity: 
If neurologic toxicity ≥ grade 2 occurs at any point of the cycle, then gemcitabine and 
cisplatin should be held for one week. If resolution to grade 1 occurs, patient will be 
retreated with a cisplatin dose 1 level lower than prior cycle. 
 
Ototoxicity: 
If ototoxicity is suspected, audiometry will be performed to assess hearing.  For loss of 
greater than 30 db in two consecutive hearing frequencies, therapy will be held for 1 week, 
and audiometry assessment will be repeated.  If hearing loss is resolved, then the patient 
will be retreated with a cisplatin dose 1 level lower than prior cycle. 
 
 
 
Cardiovascular Toxicity: 
If during any cycle of therapy a patient develops ≥ grade 3 cardiovascular toxicity, then 
treatment should be permanently discontinued and the PI or Co-PI contacted. 
 
Pulmonary Toxicity: 
If during any cycle of gemcitabine and cisplatin therapy a patient develops ≥ grade 3 
pulmonary toxicity, then the patient should discontinue chemotherapy and the PI or Co-PI 
should be contacted. 
 
Hepatic Dysfunction: 
If bilirubin > 1.5 (in the absence of Gilbert’s disease) or transaminases >2.5 X upper limit 
or normal, evaluate for progressive disease. If drug toxicity suspected, hold until toxicity < 
grade 2 and resume gemcitabine at 1 dose level lower. 
 
Gastrointestinal Toxicity: 
Patients who develop nausea, vomiting, or diarrhea that persists at Grade 3 or 4 should be 
treated with maximal medical therapy and treatment should be withheld until the patient’s 
recovery.  Once fully recovered, therapy at the same dose and schedule can resume with 
appropriate prophylactic medications. 
 
Other Non-Hematological Toxicities: 
For any grade 3 or 4 toxicity not mentioned above, the treatment should be withheld until 
the patient’s recovery and the possibility of resumption of therapy should be discussed 
with the Study PI or Co-PI. 
 
Patients who develop a symptomatic grade 4 venous thromboembolic event will not be 
eligible for retreatment. 
 
9.6      Concomitant Medications 
Radiation therapy is not allowed during the study.  Administration of other chemotherapy, 
immunotherapy,  or  anti-tumor  hormonal  therapy  during  the  study  is  not  allowed. 
Supportive care, including but not limited to anti-emetic medications, may be administered 
at the discretion of the Investigator. 
 
No other investigational drug may be used during treatment on this protocol. Other 
concomitant  therapies  considered  necessary  for  the  patient’s  well  being  may  be 
prescribed at the investigator’s discretion. Included are antiemetics, antidiarrheals, 
hematopoietic growth factors, anti-inflammatory agents, analgesics, etc. 
 
Concomitant medication data for all patients will be collected until the time of protocol 
specified surgery. 


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9.7 
Ideal Body Weight Modification 
The total chemotherapy dose for GC may be modified for patients with obesity (e.g. male 
with body surface area (BSA) >  2.1 or female with BSA > 2.0), after consultation with the 
Principal Investigator. The modification will be calculated as follows: 
Adjusted BSA= 
Ideal BSA + Actual BSA 
2 
The ideal body weight is calculated according to the formula: 
Women = 45.5kg + .9kg/cm over 152 
Men = 50kg + .9kg/cm over 152 
 
Note: In patients with severe obesity, the investigator may elect to dose based on the ideal 
BSA alone. 


 
 
 
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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
 
 
IRB#: 12-071 A(9) 
 
Baseline 
Cycle 1 
(2 weeks
3) 
Cycle 2 
(2 weeks
3) 
Cycle 3 
(2 weeks
3) 
Cycle 4 
(2 weeks
3) 
Cycle 5 
(2 weeks
3) 
Cycle 6 
(2 weeks
3) 
Post Chemo 
Follow-Up 
Surgery 
Post 
Treatme nt 
Follow-Up
4 
Day -14 to 
0 
D1 
D2 
D3 
D1 
D2 
D3 
D1 
D2 
D3 
D1 
D2 
D3 
D1 
D2 
D3 
D1 
D2 
D3 
~2-4 wks after 
chemotherapy 
~4-8 weeks 
after 
chem oth er ap y 
X
4 
History/Physical 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, KPS, 
Height and 
Weight1 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity 
Assessment 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
CBC
2
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
panel
2
 
X 
X 
X 
X 
X 
X 
X 
X 
BHCG 
(pregnancy test) 
X 
PTT/PT/INR 
X 
EKG 
X 
UA 
X 
Staging 
Chest X-ray5 
X 
X
5
 
X 
CT/MRI of 
Ab/Pelvis6 
X 
6 
X 
X 
Cystoscopy+/- 
EUA
7
 
X 
Treatment 
Gemcitabine 
X 
X 
X 
X 
X 
X 
Cisplatin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
G-CSF 
X
8
 
X
8
 
X
8
 
X
8
 
X
8
 
X
8
 
Cystectomy 
X 
1   Height and KPS will be performed only at baseline. 
2   CBC must be performed and resulted within 1 day of planned treatment. 
3   Each 2 week cycle clinic assessment and treatment should occur within a +/- 5 day window. 
4   Standard follow up evaluations and imaging will occur as determined by the investigator (i.e. every 3 months for the first 18 months, every 6 months for the next 18 months, and then yearly) until 5 years from 
the time of surgery or disease recurrence/progression. 
5   A Chest X-ray (CXR) can be omitted if a chest CT is performed. Follow-up imaging will be performed after completion of cycle 4 treatment, prior to initiating cycle 5. 
6   The baseline CT or MRI must be performed within 30 days of enrollment. Follow-up imaging will be performed after completion of cycle 4 treatment, prior to initiating cycle 5. 
7   Within 60 days of enrollment, patients must have undergone a cystoscopy and had confirmation of muscle-invasive urothelial carcinoma by pathologic review at MSKCC or participating site 
8   1-2 liters of normal saline (or suitable alternative per institutional guidelines) will be administered for renal protection. 
 
 
 
 
Amended: 7/14/15 
 
 
 
Page 21 of 39 


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10.1    Clinical Evaluation During Treatment 
Patients must undergo a complete history, physical exam, and toxicity assessment on 
day 1 of each cycle. Weight and vital signs must be recorded. Height and KPS will only 
be assessed at baseline. All clinical assessments should occur within +/- 5 days of the 
intended cycle start date. 
 
10.2    Laboratory Studies During Treatment 
Complete blood count (CBC) with differential and platelets and comprehensive panel (Na, 
K, Cl, CO2, BUN, Cr, Ca, glucose, AST, ALT, TP, Albumin, ALP, BT) must be performed 
on day 1 of each cycle. 
 
10.3    Radiographic Studies During Treatment 
Follow-up imaging (CT Chest or CXR; CT or MR of the abdomen and pelvis) must be 
performed after completion of cycle 4 treatment, prior to initiating cycle 5. Diffusion- 
weighted MRI is preferred, if available. 
 
10.4    Surgery 
Patients will undergo standard surgery consisting of radical cystectomy and bilateral 
pelvic lymph node dissection, as determined by their attending surgical urologic 
oncologist. Surgery will be performed, if possible, 4-8 weeks after completing 
chemotherapy. 
 
10.5    Post-Treatment Follow-Up 
Standard follow-up evaluations and imaging will occur as determined by the investigator 
(i.e. every 3 months for the first 18 months, followed by every 6 months for the next 18 
months, followed by yearly scans from the time of surgery). Follow-up will occur until 5 
years from the time of surgery or until disease recurrence/progression. 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Cisplatin Toxicity 
Potential side effects from cisplatin include cumulative nephrotoxicity, myelosuppression, 
nausea, and vomiting. Ototoxicity, manifested by tinnitus and/or high frequency hearing 
loss, is significant. Anaphylactic-like reactions to cisplatin have been reported. Facial 
swelling, bronchospasm, tachycardia, and hypotension may occur within minutes of 
cisplatin  administration.  Other  side  effects  include  fatigue,  anorexia,  weight  loss, 
diarrhea, serum electrolyte disturbances including hyponatremia, hypomagnesemia, and 
hypocalcemia, edema of the lungs or extremities, vascular toxicities, neurotoxicity 
including cerebral infarction, seizures and dizziness, ocular toxicity with visual 
disturbances, peripheral neuropathy, autonomic neuropathy, infertility, muscle cramps, 
and hepatic toxicity. Other rare side effects include cardiac abnormalities, hiccoughs, 
elevated serum amylase, rash, and alopecia. Local soft tissue injury has been reported 
following extravasation of cisplatin. Based on reported toxicities from completed/ongoing 
trials utilizing NCI Common Toxicity Criteria. 


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Gemcitabine Toxicity 
 
Nausea, vomiting, alopecia, stomatitis, anorexia, fatigue, elevations of hepatic 
transaminases, reversible myelosuppression, rash, flu-like symptoms, edema, 
constipation, paresthesias, hypersensitivity reactions, phlebitis, proteinuria, hematuria, 
and rarely, interstitial pneumonitis, ARDS, and hemolytic uremic syndrome. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1    Pathologic Response 
Pathologic response to neoadjuvant DD GC is the primary endpoint of this phase II study 
and is defined as the absence of muscle invasive carcinoma (<pT2 disease) and the 
absence of lymph node metastases (N0) on the final cystectomy specimen. Pathologists 
will assess surgical specimens systematically using criteria agreed upon for all 
conventional neoadjuvant treatment based on the AJCC TNM staging system. 
 
12.2    Progression Free Survival 
Progression-free survival is measured from the time of treatment initiation until the first 
date that disease progression is objectively documented. Disease progression for this 
trial  is  defined  as  either  progression of  disease  (documented clinically  or 
radiographically) before radical cystectomy, or metastatic or local pelvic recurrence after 
radical cystectomy. Due to the multifocal nature of transitional cell tumors involving other 
segments of the genitourinary tract, this definition excludes new primary tumors of the 
renal  pelvis,  ureters,  or  urethra.  The  assessment  of  disease  recurrence  versus 
development of a second primary tumor will be left to the discretion of the treating 
physician. If the patient did not progress nor die, the patient will be censored on the date 
of last follow-up. 
 
12.4    Toxicity 
Toxicity will be graded according to the National Cancer Institute Common Toxicity 
Criteria for Adverse Events version 4.0. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If, at any time, the patient develops progressive metastatic disease, he/she will 
discontinue chemotherapy and be referred for alternative therapy. This will count as a 
failure for the primary efficacy endpoint. 
 
If, at any time, the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient 
will discontinue protocol therapy and be referred for alternative therapy. 
 
The patient will discontinue chemotherapy if treatment is held for >14 days, or the patient 
requires more than 3 dose reductions of gemcitabine or 2 dose reductions of cisplatin. 
These patients will only be considered evaluable for the primary endpoint if they have 
completed at least 3 cycles of protocol therapy. 
 
The patient will be taken off study and/or discontinue chemotherapy if, at any time, the 
study doctor believes it is in the patient’s best interest to do so. 


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14.0 
BIOSTATISTICS 
 
This is a single arm phase II study of neoadjuvant DD GC in surgical candidates with 
MIBC prior to radical cystectomy.  The primary endpoint is pathologic response, defined 
as the proportion of patients who achieve absence of muscle-invasive disease at the 
time of cystectomy (<pT2).  The “uninteresting” pathologic response rate is 35%, which 
is based on a prior retrospective study (Dash et al., 2008) and two prospective 
randomized clinical trials (MRC/EORTC trial11 and Intergroup 0080 trial10) utilizing a 
conventional schedule of cisplatin-based neoadjuvant chemotherapy.   A total of 46 
patients will be accrued to the study to detect an improvement in response rate from 
35% to 55%. The study design is based on exact Binomial one-sided test, Type 1 error 
of  5%  and  power  of  87%.  Patients  that  do  not  proceed  to  have  surgery  due  to 
progression of disease, or discontinue chemotherapy due to excessive treatment delays, 
dose reductions, or toxicity will be counted as non-responders. Patients will not be 
considered evaluable for the primary objective if they receive less than 3 completed 
cycles of protocol therapy and are discontinued from protocol treatment for either 
withdrawal of consent or adverse events. These patients will be replaced. All patients will 
remain evaluable for toxicity assessment. At the end of the study, if 22 or more patients 
will have pathologic response, the treatment regimen will be considered worthy of further 
investigation. The follow-up time is at least five years for each patient. The accrual rate 
is 2-3 patients per month, and the study is expected to be completed within 2 years. 
Since it takes about 5-6 months from the enrollment date to surgery and, therefore, 
determination of patient’s response, the two stage design is not utilized. 
 
Secondary objectives include: 1.)  Safety  and  tolerability, tabulated by  NCI  CTCAE 
version 4.0; 2.) Progression free survival, defined as the time from treatment initiation to 
disease progression, local-regional or metastatic recurrence, or death analyzed using 
the Kaplan Meier method. Patients who do not proceed to have surgery due to 
documented disease progression will be counted as progression. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1    Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/). The completed signature page of the 


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written consent/RA or verbal script/RA, a completed Eligibility Checklist and other 
relevant documents must be uploaded via the PPR Electronic Registration System. 
 
15.1.1  For Participating Sites: 
Central registration for this study will take place at Memorial Sloan Kettering Cancer 
Center (MSKCC). 
  
 
To complete registration and enroll a participant from another institution, the study staff at 
that site must contact the designated research staff at MSKCC to notify him/her of the 
participant registration. The site staff then needs to e-mail registration/eligibility 
documents to the attention of 12-071 Research Staff at medmctcore@mskcc.org. 
 
The following documents must be sent for each enrollment within 24 hours of the 
informed consent form being signed: 
 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and HIPAA Authorization form 
• Supporting source documentation for eligibility questions (laboratory results, 
pathology report, radiology reports, MD notes, physical exam sheets, medical 
history, prior treatment records, and EKG report). 
 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct 
an interim review of all documents.  If the eligibility checklist is not complete, the patient 
will be registered PENDING and the site is responsible for sending a completed form 
within 30 days of the consent. 
 
If the eligibility checklist is complete, participant meets all criteria, all source 
documentation is received, the participating site IRB has granted approval for the 
protocol, and the site is in good standing with MSKCC, the MSKCC research staff will 
send the completed registration documents to the MSKCC Protocol Participant 
Registration (PPR) Office to be enrolled as stated in section 15.1. The participant will be 
registered. 
 
Once eligibility has been established and the participant is registered, the participant will 
be assigned an MSKCC Clinical Research Database (CRDB) number (protocol 
participant number). This number is unique to the participant and must be written on all 
data and correspondence for the participant. This protocol participant number will be 
relayed back to study staff at the registering site via e-mail and will serve as the 
enrollment confirmation. 
 
15.2  Randomization (if applicable) 
Participants will not be randomized for this trial. 


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16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordination 
of the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure Clinical Research 
Database. Source documentation will be available to support the computerized patient 
record. 
 
16.0.1 Data and Source Documentation for Participating Sites 
 
Data 
The participating site(s) will enter data remotely into MSKCC’s internet-based Clinical 
Research Database, termed CRDBi-Multicenter. Standardized Case Report Forms 
(CRFs) and data entry guidelines have been generated for this study. The site staff will 
receive CRDB training prior to enrolling its first patient. The participating Site PI is 
responsible for ensuring these forms are completed accurately and in a timely manner. 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered. Relevant source documentation to be submitted throughout 
the study includes: 
o Baseline measures to assess pre–protocol disease status (ex. CT, PSA, bone 
marrow) 
o Treatment records 
o Grade 3-5 toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 
 
16.0.2 Data and Source Documentation Submission for Participating Sites 
Participating sites should enter data directly into CRDBi-Multicenter and study-specific 
paper CRFs . Source documentation should be sent to MSKCC at the contact provided 
below. Submissions should include a cover page listing relevant records enclosed per 
participant. 
 
Contact for submission of Source Documentation 
 
E-mail: medmctcore@mskcc.org to the attention of 12-071 Research Staff 
 
16.0.3 Data and Source Documentation Submission Timelines for Participating 
Site 
 
Data and source documentation to support data should be transmitted to MSKCC 
according to chart below: 


 
 
 
MEMORIAL SLOANKETTERING CANCER CENTER 
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IRB#: 12-071 A(9) 
 
 
Baseline 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Post 
Chemo 
Follow-Up 
Surgery 
SAE 
Long 
Term 
Follow-Up 
SUBMISSION SCHEDULE 
 
Source Documentation 
Within 24 
hours 
(see section 
15.1.1) 
w ithin 14 days of D3 of cycle 
Within 3 days of 
event (see 
section 17.3); 
updates to be 
submitted as 
available 
Within 14 
days of visit 
CRFs 
Within 7 days 
of visit 
Required Forms 
Demographics Form 
X 
Medical History Form 
X 
Concomitant Medication 
Form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam Form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment Form 
X 
X 
X 
X 
X 
X 
X 
Surgery Form 
X 
Laboratory Form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diagnostic Test Form 
X 
X 
Disease Status Form 
X 
X 
X 
Lesion/EOD Form 
X 
X 
X 
Adverse Event Form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Status Form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Event Form 
X 
Off Study Form 
X 
 
 
 
 
 
 
 
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16.0.4 Data Review and Queries for Participating Site Data 
Research staff at MSKCC will review data and source documentation as it is submitted. 
Data will be monitored against source documentation and discrepancies will be sent as 
queries to the participating sites. Queries will be sent by MSKCC Research staff twice a 
month. 
 
Participating sites should respond to data queries within 14 days of receipt. 
 
16.1    Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period and 
potential problems will be brought to the attention of the study team for discussion and 
action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated. 
 
16.1.1 Quality Assurance for Participating Sites 
Each site participating in the accrual of participants to this protocol will be audited by the 
staff of the MSKCC study team for protocol and regulatory compliance, data verification 
and source documentation.   Audits may be accomplished in one of two ways: (1) 
selected participant records can be audited on-site at participating sites or (2) source 
documents for selected participants will be sent to MSKCC for audit. Audits will usually 
be determined by participant accrual numbers and rate of accrual, but can also be 
prompted by reported SAEs or request of MSKCC PI. 
 
Audits will be conducted at least once shortly after initiation of participant recruitment at 
a site, annually during the study (or more frequently if indicated), and at the end or 
closeout of the trial. The number of participants audited will be determined by available 
time and the complexity of the protocol. 
 
The audit will include a review of source documentation to evaluate compliance for: 
 
•   Informed consent documents and procedures 
•   Adherence to eligibility criteria 
•   Protocol defined treatment 
•   Required baseline, on study and follow-up protocol testing 
•   IRB documents (submitted amendments, annual continuing review reports, SAEs) 
•   Case Report Form submissions to MSKCC: timelines and accuracy 
 
A wrap-up session will be conducted at the participating site and preliminary findings will 
be discussed with the participating site PI and research team. The preliminary results will 
be sent to the MSKCC PI. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited 
participating site within 30 days of the audit. The report will include a summary of 
findings, participant by participant case review, specific recommendations on any 


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performance and/or shortcomings and request for corrective action, when necessary. 
When corrective action is required, the participating site must reply within 45 days of 
receipt of audit report with their corrective action plan. 
 
A copy of the audit report and corrective action plan (if applicable) submitted by the 
participating site must be sent to the MSKCC IRB/PB, CRQA and maintained in the 
department’s protocol regulatory binder. 
 
16.1.2 Response Review 
Since therapeutic efficacy is a stated primary objective, all sites participant’s responses 
are subject to review by MSKCC’s Therapeutic Response Review Committee (TRRC). 
Radiology, additional lab reports and possibly bone marrow biopsies and/or aspirates 
will need to be obtained from the participating sites for MSKCC TRRC review and 
confirmation of response assessment. These materials must be sent to MSKCC 
promptly upon request. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. .   The DSM Plans 
at MSKCC were established and are monitored by the Office of Clinical Research.  The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20 
Monitoring%20Plans.pdf 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality.  There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs.  The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials,  report to the Center’s Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
16.3 
Regulatory Documentation 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be 
approved by the MSKCC Institutional Review Board/Privacy Board (IRB/PB). Prior to 


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implementing this protocol at the participating sites, approval for the MSKCC IRB/PB 
approved protocol must be obtained from the participating site’s IRB. 
 
The following documents must be provided to MSKCC before the participating site can 
be initiated and begin enrolling participants: 
 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authorization 
• 
Participating Site IRB approved consent form 
• 
Participating Site IRB membership list 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 
• 
Curriculum vitae and medical license for each investigator and consenting 
professional 
• 
Documentation of Human Subject Research Certification training for investigators and key staff 
members at the Participating Site 
• 
Participating site laboratory certifications and normals 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant 
permission to proceed with enrollment. 
 
16.3.1 Amendments 
Each change to the protocol document must be organized and documented by MSKCC 
and first approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, 
MSKCC will immediately distribute all non expedited amendments to the participating 
sites, for submission to their local IRBs. 
 
Participating sites must obtain approval for all non expedited amendments from their IRB 
within 90 calendar days of MSKCC IRB/PB approval. If the amendment is the result of a 
safety issue or makes eligibility criteria more restrictive, sites will not be permitted to 
continuing enrolling new participants until the participating site IRB approval has been 
granted. 
 
The following documents must be provided to MSKCC for each amendment within the 
stated timelines: 
 
• 
Participating Site IRB approval 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
 
16.3.2 Additional IRB Correspondence 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most 
current approved version of the informed consent form should be submitted to MSKCC 
within 7 days of expiration. Failure to submit the re-approval in the stated timeline will 
result in suspension of study activities. 


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Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant 
who does not meet all the eligibility criteria, pretreatment evaluation, or who requires 
alteration in their study plan. If a deviation from this protocol is proposed for a potential 
or existing participant at MSKCC or a participating site, approval from the MSKCC 
IRB/PB is required prior to the action. Participating sites should contact the MSKCC PI 
who will in turn seek approval from the MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are 
identified after they occur, the participating site should report to MSKCC as soon as 
possible. The MSKCC PI will in turn report the violation to the MSKCC IRB/PB. 
 
Participating sites should report deviations and violations to their institution’s IRBs as 
soon as possible per that site’s institutional guidelines. Approvals/acknowledgments from 
the participating site IRB for protocol deviations and violations should be submitted to 
MSKCC as received. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB 
according to local guidelines, and submit copies of that correspondence to MSKCC. 
 
16.3.3 Document maintenance 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate 
records to enable the implementation of the protocol to be fully documented and the data 
to be subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB 
approval letters referencing protocol version date and amendment number, IRB approved 
protocol, appendices, informed consent forms, deviations, violations, and approval of 
continuing reviews) is maintained in the regulatory binder on site and sent to MSKCC. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be 
paper or electronic. 
 
After study closure, the participating site will maintain all source documents, study 
related documents and CRFs for 3 years. 
 
16.4 Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges may 
be suspended and/or contract payments maybe withheld, until the outstanding issues 
have been resolved. 


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17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Potential risks to human subjects include drug-related toxicity, pain and discomfort 
associated with cisplatin, gemcitabine, placement of IV catheters, phlebotomy, and 
possible psychological discomfort from the stresses associated with obtaining imaging 
studies (e.g., CT scan). The side effects and potential toxicities of cisplatin and 
gemcitabine are listed in section 5.1.4, 5.2.3 and 11. All efforts will be made to avoid 
any complication by completely reviewing patients’ symptoms, providing appropriate 
management, and monitoring blood tests. If an adverse medical event occurs, the patient 
will first contact the primary oncologist or the principal investigator. At nights and 
weekends, there is an oncology physician on call at all times. Patients may either call or 
come directly to the urgent care center at Memorial Hospital (or to their local emergency 
room) to be seen. Patients suffering serious adverse reactions must be carefully followed 
and all follow-up information recorded. 
 
Alternatives/Options for treatment 
Patients can elect to receive standard therapy for muscle invasive urothelial carcinoma 
with neoadjuvant M-VAC or standard GC. They can also elect to participate in another 
clinical trial. Participation in a clinical trial is voluntary. 
 
Costs 
The patient will be responsible for all costs related to treatment and complications of 
treatment. Costs to the patient (or third party insurer) will include the cost of 
hospitalizations, routine blood tests and diagnostic studies, office visits, baseline EKG, 
other medications such as antibiotics and doctor’s fees. 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board. 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Serious Adverse Event Definition 
 
A serious adverse event is one that at any dose (including overdose): 
 
• 
Results in death 
• 
Is life-threatening1 
• 
Requires  an  unplanned  inpatient  hospitalization  or  prolongation  of  existing 
hospitalization 
• 
Results in persistent or significant disability or incapacity2 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event3 
• 
Pregnancy 


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Amended: 7/14/15
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the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
 
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
 
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred. 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one  of  the  other  outcomes  listed  in  the  definition  above  should  also  usually  be 
considered serious.  Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.  A new diagnosis of cancer during the course of a treatment should be 
considered as medically important. 
 
Serious Adverse Event Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 
calendar days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report 
be submitted electronically to the SAE Office at sae@mskcc.org. The report should 
contain the following information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent 
form. 
 
The PI’s signature and the date it was signed are required on the completed report. 
SAEs will be collected from the time of consent until 30 days following the protocol 
specified surgery. 


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Page 34 of 39 
MEMORIAL SLOANKETTERING CANCER CENTER 
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17.3 Serious Adverse Event (SAE) Reporting for Participating Sites 
 
Responsibility of Participating Sites 
• 
Participating sites are responsible for reporting all SAEs to their local IRB per local 
guidelines 
• 
Participating sites are responsible for reporting all SAEs to the MSKCC PI via e- 
mail within 3  calendar days of learning of the event. 
▪ 
SAEs will be collected from the time of consent until 30 days following the 
protocol specified surgery 
• 
Participating sites should notify the MSKCC PI of any grade 5 event immediately. 
• 
Participating sites should use the SAE Report Form found in MSKCC’s internet- 
based Clinical Research Database, CRDBi-Multicenter, to report SAEs to MSKCC. 
 
SAE contact information for the Coordinating Center is listed below: 
Dean Bajorin, MD 
12-071 Research Staff 
bajorind@mskcc.org 
medmctcore@mskcc.org 
Ph: 646 888 1007 
 
 
Responsibility of MSKCC 
• 
The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC 
IRB/PB as specified in 17.2 
• 
The MSKCC PI is responsible for informing all participating sites about all 
unexpected SAEs that are either possibly, probably, or definitely related to the study 
intervention within 30 days of receiving the stamped SAE from the MSKCC IRB/PB. 
• 
Any report pertaining to a grade 5 event will be distributed to the participating sites 
as soon as possible. 
 
17.4 Safety Reports 
• 
MSKCC will distribute outside safety reports to the participating sites immediately 
upon receipt. 
• 
MSKCC must submit outside safety reports to the MSKCC IRB/PB according to 
institutional guidelines. 
• 
Participating sites must submit safety reports to their institution’s IRBs within 30 
days of receipt from MSKCC or per participating site guidelines. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 


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3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
18.1 
For Participating Sites 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to 
good clinical practice and protocol guidelines. 
 
Signed copies of the informed consent should be distributed as follows: One copy will be 
given to the participant to be retained for their personal records. One copy will be 
maintained on file at the MSKCC. The third copy will be confidentially maintained by the 
participating institution. 
 
A note will be placed in the medical record documenting that informed consent was 
obtained for this study, and that the participant acknowledges the risk of participation. 


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19.0 REFERENCES 
 
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Hall R, on behalf of the Intl Collaboration of Trialists of the MRC Advanced Bladder Cancer 
Group MCTU, London, UK. Updated results of a randomised controlled trial of neoadjuvant cisplatin 
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meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. 
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Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy 
compared with cystectomy alone for locally advanced bladder cancer. New Eng J Med 
2003;349:859-66. 
9.        Loehrer PJ, Sr., Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or 
in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial 
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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;349:859- 
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Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial 
assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive 
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EBCTCG. Polychemotherapy for early breast cancer: an overview of the randomised trials. 
The Lancet 1998;352:930-42. 
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Advanced Bladder Cancer (ABC) Meta-analysis Collaboration, Adjuvant chemotherapy in 
invasive bladder cancer: a systematic review and meta-analysis of individual patient data. European 
Urology 2005;48:202. 
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Gill S. Pooled Analysis of Fluorouracil-Based Adjuvant Therapy for Stage II and III Colon 
Cancer: Who Benefits and by How Much? Journal of Clinical Oncology 2004;22:1797-806. 
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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: 
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Margot Burnell MNL, Judith-Anne W. Chapman, Vivien Bramwell, Karen Gelmon, Barbara 
Walley, Ted Vandenberg, Haji Chalchal, Kathy S. Albain, Edith A. Perez, Hope Rugo, Kathleen 
Pritchard, Patti O'Brien and Lois E. Shepherd Cyclophosphamide, Epirubicin, and Fluorouracil 
Versus Dose-Dense Epirubicin and Cyclophosphamide Followed by Paclitaxel Versus Doxorubicin 
and Cyclophosphamide Followed by Paclitaxel in Node-Positive or High-Risk Node-Negative Breast 
Cancer. Journal of Clinical Oncology 2010;28:77-82. 
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Bonilla L B-AI, Vidal L, Gafter-Gvili A, Leibovici L, Stemmer SM. Dose-dense chemotherapy 


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in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled 
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conventionally scheduled and sequential versus concurrent combination chemotherapy as 
postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup 
Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21:1431-9. 
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Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose- 
intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and 
recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced 
urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 
30924. J Clin Oncol 2001;19:2638-46. 
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Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III 
trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced 
urothelial tract tumours. Eur J Cancer 2006;42:50-4. 
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A. Bamias AK, S. Lampaki, G. Aravantinos, I. Xanthakis, C. Papandreou, G. Lainakis, F. 
Zagouri, N. Soupos, E. Kostouros, E. Samantas, C. Hatzimouratidis, C. Konstantinidis, C. Deliveliotis, 
D. G. Pectasides, G. Fountzilas, M. A. Dimopoulos, Hellenic Cooperative Oncology Group; Alexandra 
Peripheral General Hospital, Athens, Greece; University of Athens, Athens, Greece; Hellenic 
Cooperative Oncology Group Data Office, Athens, Greece; University of Thessalia, 
Larisa, Greece; Agioi Anargiroi Hospital, Athens, Greece; University of Thessaloniki, Thessaloniki, 
Greece; Hellenic Cooperative Oncology Group (HeCOG), Athens, Greece Prospective, randomized 
phase III study comparing two intensified regimens (methotrexate/vinblastine/doxorubicin 
hydrochloride/cisplatin [MVAC] versus gemcitabine/cisplatin) in patients with inoperable or recurrent 
urothelial cancer. Journal of Clinical Oncology 2011;29. 
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J. Bellmunt HvdM, G. M. Mead, J. Heyer, N. Houede, L. G. Paz-Ares, E. Winquist, L. R. 
Laufman, R. de Wit, R. Sylvester, . Randomized phase III study comparing 
paclitaxel/cisplatin/gemcitabine (PCG) and gemcitabine/cisplatin (GC) in patients with locally 
advanced (LA) or metastatic (M) urothelial cancer without prior systemic therapy; 
EORTC30987/Intergroup Study. Journal of Clinical Oncology, 2007 ASCO Annual Meeting 
Proceedings Part I Vol 25, No 18S (June 20 Supplement), 2007: LBA5030 2007. 
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A. Bamias AK, S. Lampaki, G. Aravantinos, I. Xanthakis, C. Papandreou, G. Lainakis, F. 
Zagouri, N. Soupos, E. Kostouros, E. Samantas, C. Hatzimouratidis, C. Konstantinidis, C. Deliveliotis, 
D. G. Pectasides, G. Fountzilas, M. A. Dimopoulos, Hellenic Cooperative Oncology Group; Alexandra 
Peripheral General Hospital, Athens, Greece; University of Athens, Athens, Greece; Hellenic 
Cooperative Oncology Group Data Office, Athens, Greece; University of Thessalia, 
Larisa, Greece; Agioi Anargiroi Hospital, Athens, Greece; University of Thessaloniki, Thessaloniki, 
Greece; Hellenic Cooperative Oncology Group (HeCOG), Athens, Greece Prospective, randomized 
phase III study comparing two intensified regimens (methotrexate/vinblastine/doxorubicin 
hydrochloride/cisplatin [MVAC] versus gemcitabine/cisplatin) in patients with inoperable or recurrent 
urothelial cancer. Journal of Clinical Oncology 2011;29. 
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C. Blick PH, T. Pwint, N. Munro, J. Crew, T. Powles, V. M. Macaulay, F. Al-Terkait, A. 
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M. B. Elmongy MK, C. T. Reese, C. B. Algood. Feasibility and efficacy of neoadjuvant 
chemotherapy with dose-dense methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC) in 
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29. 
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20.0 Appendices 
 
Appendix 1- Suggested Delayed Emesis and Hydration Regimens 


MEMORIAL SLOANKETTERING CANCER CENTER 
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IRB#: 12-071 A(9) 
Amended: 7/14/15
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Appendix 1: Suggested Delayed Emesis and Hydration Regimens 
 
 
 
SUGGESTED DELAYED EMESIS REGIMEN 
 
MEDICATION 
Chemo 
DAY 1 
DAY 2 
DAY 3 
FOSaprepitant 
150mg IV in 
chemotherapy 
Decadron 
(dexamethasone) 
12mg (3 
tablets, 4mg 
each) will be 
given in 
chemotherapy 
12mg (3 
tablets, 4mg 
each) will be 
given in 
chemotherapy 
Take 12mg 
(3 tablets, 
4mg each) 
at home 
 
Zofran (Ondansetron) 8mg can and should be taken orally every 8 hours as needed for 
nausea/vomiting while being treated with chemotherapy. 
  
 
SUGGESTED HYDRATION REGIMEN 
 
General points: 
- 
It is helpful to weigh patients at the beginning and end of treatment on Days 1 and 2 of each 
cycle and prior to hydration on Day 3 and record strict I&Os during infusion. 
- 
It is also helpful to have a baseline ECHO to feel more comfortable with fluid shifts, etc. 
 
Days 1 and 2 of each cycle: 
Pre-Cisplatin hydration: 
- 
1000cc normal saline given over 3 hours 
- 
Mannitol 25% (12.5g IV x 1) 
 
Post-Cisplatin hydration: 
- 
Normal saline at 250 ml/hr x 3hrs = total 750 ml 
 
Day 3 of each cycle: 
- 
500-1000cc normal saline may be given if indicated at the investigator’s discretion. This is 
subject to change due to possible fluid retention on Days 1 and 2 of treatment.