Clinical trial NCT02412670
Conditions: High Grade Upper Tract Urothelial Carcinoma
Keywords: carcinoma drug therapy nephroureterectomy urinary tract urothelium
Sponsor: ECOG-ACRIN Cancer Research Group
Start date: 2015-08-27; Completion date: 2022-05-10
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well giving chemotherapy before surgery works in treating patients with aggressive upper urinary tract cancer. Drugs used in chemotherapy, such as methotrexate, vinblastine, doxorubicin hydrochloride, cisplatin, gemcitabine hydrochloride, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Removing the affected upper urinary tract by surgery is the recommended treatment for upper urinary tract cancer, but can cause loss of kidney function and prevent patients from being able to receive chemotherapy after surgery. Giving chemotherapy before surgery, when the kidneys are working at their maximum, may allow less tissue to be removed during surgery and may be more effective in treating patients with high grade upper urinary tract cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the rate of complete pathologic response (pCR = pT0pN0) as assessed by standard pathologic review attained by neoadjuvant systemic chemotherapy and nephroureterectomy.

SECONDARY OBJECTIVES:

I. To evaluate the safety of neoadjuvant systemic chemotherapy in patients with upper tract urothelial carcinoma preceding nephroureterectomy.

II. To evaluate distant recurrence-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

III. To evaluate event-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

IV. To evaluate bladder cancer-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

V. To evaluate cancer specific survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

VI. To evaluate renal functional outcomes of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

TERTIARY OBJECTIVES:

I. To collect pre-treatment and post-treatment tumor tissue, peripheral blood mononuclear cell (PBMC), peripheral blood plasma, and urine specimens for potential evaluations of markers of chemotherapy response/resistance.

OUTLINE: Patients are assigned to 1 of 2 treatment arms based on baseline renal function.

ARM A (CREATININE CLEARANCE \[CRCL\] \> 50): Patients receive methotrexate intravenously (IV) over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.

ARM B (30 =\< CRCL \<= 50): Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Arms: arm 1: Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy. arm 2: Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Interventions: intervention 1: Methotrexate intervention 2: Vinblastine intervention 3: Doxorubicin intervention 4: Cisplatin intervention 5: Gemcitabine intervention 6: Carboplatin intervention 7: Pegfilgrastim intervention 8: Nephroureterectomy
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV intervention 7: Administered subcutaneously intervention 8: Undergo nephroureterectomy and lymph node dissection

Protocol documents:
Prot_SAP_000.pdf: 
 
EA8141 
1 
A Prospective Phase II Trial of Neoadjuvant Systemic 
Chemotherapy Followed by Extirpative Surgery for 
Patients with High Grade Upper Tract Urothelial 
Carcinoma 
STUDY CHAIR: 
Vitaly Margulis, M.D. 
STUDY CO-CHAIR: 
Jean Hoffman-Censits, M.D. 
STUDY STATISTICIAN: 
Yu-Hui Chen, M.S. 
BLADDER SUBCOMMITTEE CHAIR: 
Noah Hahn, M.D. 
GU COMMITTEE CHAIR: 
Michael Carducci, M.D. 
UROLOGY TRANSLATIONAL  
SCIENCE CO- CHAIR: 
 
Edouard Trabulsi, M.D. 
TRANSLATIONAL SCIENCE CO-CHAIR: 
Elizabeth Plimack, M.D. 
 
 
 
 
Version Date:  February 11, 2019 
NCI Update Date:  October 4, 2017 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology  
April 1, 2015 
NRG / NRG Oncology 
 
Addendum #1 – 10/15 
SWOG / SWOG 
 
Addendum #2 – 10/15 
US Sites Only 
 
Update #1 – 11/15 
 
 
Addendum #3 – 6/16 
NCTN GROUP STUDY CHAMPIONS 
 
Update #2 – 10/17 
SWOG: Guilherme Godoy, M.D., Ajjai Alva,M.D. 
 
Addendum 4 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
Gemcitabine 
IND Exempt Study 
613327 
Commercially Available 
Doxorubicin 
123127 
Commercially Available 
Cisplatin 
119875 
Commercially Available 
Carboplatin 
241240 
Commercially Available 
Methotrexate 
740 
Commercially Available 
Vinblastine 
49842 
Commercially Available 
Pegfilgrastim 
725961 
Commercially Available 


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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Research Hypothesis ................................................................................. 7 
1.2 Background ............................................................................................... 7 
2. Objectives ........................................................................................................... 9 
2.1 Primary Endpoints ..................................................................................... 9 
2.2 Secondary Endpoints................................................................................. 9 
3. Selection of Patients ......................................................................................... 10 
3.1 Eligibility Criteria ..................................................................................... 10 
4. Registration Procedures.................................................................................... 13 
4.1 Registration to Treatment ....................................................................... 16 
4.2 Eligibility Verification .............................................................................. 16 
4.3 Classification Factors ............................................................................... 16 
4.4 Additional Requirements ........................................................................ 16 
4.5 Instructions for Patients who Do Not Start Assigned Protocol Treatment17 
5. Treatment Plan ................................................................................................. 18 
5.1 Administration Schedule ......................................................................... 18 
5.2 Adverse Event Reporting Requirements ................................................. 19 
5.3 Dose Modifications ................................................................................. 27 
5.4 Supportive Care ....................................................................................... 32 
5.5 Duration of Therapy ................................................................................ 33 
5.6 Duration of Follow-up ............................................................................. 34 
6. Measurement of Effect ..................................................................................... 35 
6.1 Pathologic Complete Response .............................................................. 35 
6.2 Diagnosis of Urothelial Cancer Recurrence............................................. 35 
6.3 Diagnosis of Systemic Recurrence (Distant Recurrence) ........................ 35 
6.4 Distant Recurrence-Free Surviva ............................................................. 36 
6.5 Bladder Cancer-Free Survival .................................................................. 36 
6.6 Disease Progression ................................................................................ 36 
6.7 Second Primary Cancer ........................................................................... 36 
6.8 Local, Regional Recurrence ..................................................................... 36 
6.9 Event-Free Survival ................................................................................. 36 
6.10 Overall Survival ....................................................................................... 36 
6.11 Renal Function Endpoints ....................................................................... 36 
6.12 Antitumor Effect – Solid Tumors ............................................................. 37 
7. Study Parameters .............................................................................................. 44 
7.1 Arm A: AMVAC ........................................................................................ 44 
7.2 Arm B: GCa .............................................................................................. 46 
8. Drug Formulation and Procurement ................................................................. 48 
8.1 Methotrexate .......................................................................................... 48 


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8.2 Drug Name - Vinblastine ......................................................................... 50 
8.3 Gemcitabine ............................................................................................ 51 
8.4 Doxorubicin ............................................................................................. 53 
8.5 Cisplatin ................................................................................................... 55 
8.6 Carboplatin .............................................................................................. 58 
8.7 Pegfilgrastim ........................................................................................... 60 
8.8 Neulasta .................................................................................................. 61 
9. Statistical Considerations .................................................................................. 63 
9.1 Study Design/Primary Endpoint .............................................................. 63 
9.2 Secondary Endpoints............................................................................... 63 
9.3 Accrual ..................................................................................................... 64 
9.4 Safety Monitoring ................................................................................... 64 
9.5 Gender and Ethnicity .............................................................................. 64 
10. Submission of Biospecimens for Research ....................................................... 66 
10.1 Submissions to the CBPF ......................................................................... 66 
10.2 ECOG-ACRIN Sample Tracking System .................................................... 68 
10.3 Use of Specimens in Research ................................................................ 69 
10.4 Sample Inventory Submission Guidelines ............................................... 70 
11. Electronic Data Capture .................................................................................... 71 
12. Patient Consent and Peer Judgment ................................................................ 71 
13. References ........................................................................................................ 71 
 Appendix I  Pathology Submission Guidelines........................................................ 73 
Appendix II  Patient Thank You Letter ..................................................................... 77 
Appendix III  ECOG Performance Status .................................................................. 78 
Appendix IV  Lab Study EA8141LGS1 ....................................................................... 79 
 
 


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STUDY CHAIR 
Vitaly Margulis, M.D 
University of Texas Southwestern Medical 
Center 
5339 Harry Hines Blvd 
Dallas, TX 75390 
Phone: 214-648-0567 
Fax: 214-648-8786 
vitaly.margulis@utsouthwestern.edu 
 
STUDY CO-CHAIR 
Jean Hoffman-Censits, M.D 
Thomas Jefferson University 
Department of Medical Oncology 
1025 Walnut St, Suite 700 
Philadelphia, PA 19107 
Phone: 215-503-5455 
Jean.hoffman-censits@jefferson.edu 
 
STUDY CHAIR LIAISON (SCL) 
Allison Beaver, R.N 
University of Texas Southwestern Medical 
Center 
5339 Harry Hines Blvd 
Dallas, TX 75390 
Phone: 214-645-8788 
Fax: 214-645-8766 
Allison.Beaver@UTSouthwestern.edu 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206  
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient enrollment 
section of the protocol for instructions on 
using the Oncology Patient Enrollment 
Network (OPEN) which can be accessed 
at https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  
Please see the data 
submission section of 
the protocol for further 
instructions.  
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org 
 


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Schema 
High Grade 
Urothelial CA Upper 
Urinary Tract
Accelerated Methotrexate, 
Vinblastine, Doxorubicin 
and Cisplatin and 
Pegfilgastim x 4 cycles
Accrual Goal= 60
30 Patients per arm
1. Regimen repeated every 14 days for 4 cycles.
2. Regimen repeated every 21 days for 4 cycles.
R
E
G
I
S
T
E
R
Gemcitabine, Carboplatin 
x 4 cycles
Primary Endpoint: pCR=pT0N0
Arm A1
Arm B2
Nephroureterectomy 
Regional lymph node 
dissection
mCrCI > 50
30 < mCrCI <  50
 
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1. 
Introduction 
1.1 
Research Hypothesis 
We hypothesize that neoadjuvant systemic chemotherapy in patients with high-
grade upper tract urothelial carcinoma prior to extirpative surgery will result in at 
least a 18% rate of complete pathologic response (pCR = pT0pN0). Ultimately, 
we assert that neoadjuvant systemic chemotherapy will be safe, well tolerated 
and result in improved long-term oncologic outcomes for patients with upper tract 
urothelial carcinoma. 
1.2 
Background 
Upper tract urothelial cancer (UTUC) accounts for roughly 5% of all urothelial 
cancers (UC), with 11, 000 new cases annually in United States.  At 
presentation, 30% of patients demonstrate invasive and/or locally advanced 
disease, 30-40% have regional lymph node involvement, and 20% harbor 
metastatic disease.  Systemic recurrence and progression rates after surgery 
alone for patients with advanced UTUC are high with ranges between 45-60%.  
5-year cancer specific survival (CSS) rates for pT2 and pT3 tumors are 73% and 
40%, respectively.1,2  While radical nephro-ureterectomy (RNU) represents the 
standard therapeutic option for patients with UTUC, there are significant 
challenges associated with inaccurate clinical staging, high prevalence of occult 
metastatic disease, poor baseline and worsening post-operative global renal 
function, and subsequent difficulties with administration of meaningful systemic 
therapies. 
Cisplatin based neoadjuvant chemotherapy (NAC) has shown a therapeutic 
benefit in patients with bladder UC. Patients who received neoadjuvant therapy 
had a 5% absolute improvement in CSS, compared to patients treated with 
cystectomy alone. 3 Patients also tolerated NAC better than adjuvant therapy in 
bladder cancer studies.4 Several retrospective studies have shown that the use 
of NAC prior to RNU has been associated with pathological downstaging.5 In 
Matin et al.‘s retrospective review of 150 patients who received platinum-based 
NAC treatment of biopsy proven high grade UTUC, the overall incidence of pT2 
or higher disease was significantly lower in the NAC group compared to the 
control patients (46.5% vs. 65%; p=.043).5  Moreover, a 14% pathologic 
complete response rate (pCR) was observed in that retrospective study. Finally, 
several authors report favorable oncologic outcomes in patients with advanced 
UTUC treated with pre-surgical systemic chemotherapy, compared to historic 
controls.6-8  
Of particular relevance, is the fact that UTUC patients are at an increased risk of 
baseline or future chronic kidney disease (CKD), rendering many poor 
candidates for perioperative cisplatin chemotherapy. 9 Several studies have 
shown 25-52% and 65-78% incidence of CKD before and after RNU. 9,10 Lane et 
al. evaluated 336 patients who underwent NU for UTUC and found that at 
baseline, 52% of the cohort were poor cisplatin-based chemotherapy candidates 
due to impaired renal function. Following RNU, there was a 21% reduction in 
renal function and RNU rendered 78% of the patient’s poor candidates for 
cisplatin-based therapy. In a sub-group analysis of 144 high-risk patients (T2-T4 
NX disease) at the time of RNU, who would be ideal candidates for systemic 


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treatment, impaired preoperative renal function was observed in nearly 60% of 
patients. Following RNU, the frequency of renal impairment increased to 78% 
(p=.009).  Based on this alone, 61% of all patients and 49% of high risk patients 
who could have received chemotherapy preoperatively were unable to receive 
treatment after RNU.10 Thus a strong rationale exists to optimize delivery of 
cisplatin-based regimens to patients with adequate renal function and to define 
the role of non-cisplatin regimens in the large portion of UTUC patients who are 
poor candidates for cisplatin therapy. 
The target population of this study includes patients with clinically localized high 
grade UTUC, since histologic grade is one of the few reliable and readily 
obtainable pathologic staging variables, and correlates well with advanced 
pathologic stage, and eventual oncologic outcomes.11-13  Patients will be 
assigned to a treatment arm and receive a platinum based NAC regimen based 
on their screening creatinine clearance (CrCl), determined by Cockcroft-Gault 
calculation or direct 24-hour urine measurement, followed by nephro-
ureterectomy and regional lymph node dissection.  NAC with accelerated 
methotrexate, vinblastine, doxorubicin and cisplatin (AMVAC) will be 
administered to patients with CrCl ≥ 50 mL/min, based on CrCl cut-off with 
demonstrated safety in modern neoadjuvant cisplatin studies.3,5  Patients with 30 
≤ CrCl ≤ 50 mL/min, will be offered gemcitabine/carboplatin (GCa), which has 
demonstrated response in patients with UC and impaired CrCl treated in the 
metastatic setting.14-16  As stated above, because of additional nephron loss with 
up-front surgery, many of UTUC patients with baseline CKD will not qualify for 
any additional systemic therapy after surgery, thus the rationale for including a 
non-cisplatin arm for this group. 
Pathologic complete response (pCR) is a relevant, generalizable, early end-point 
for NAC in UC of the bladder and therefore was chosen as the initial primary 
efficacy endpoint in this proposed UTUC NAC trial.3  A targeted pCR rate of 18% 
was chosen based on well characterized results of NAC in UC of the urinary 
bladder and from limited experience with NAC in UTUC.3,5,8  Upper tract urothelial 
cancers are difficult to access for initial staging and resection, thus the expected 
pCR rate in this trial is lower than the near 40% seen in bladder NAC studies, a 
rate achieved by NAC and aggressive transurethral debulking. Important 
additional endpoints of renal functional outcomes (both improvements and 
declines on therapy), bladder and systemic recurrence-free survival and cancer-
specific/overall survival will be assessed.   
Finally, the trial design permits utilization of pre-treatment and post-treatment 
tumor tissue, peripheral blood, and urine specimens to study, among others, 
biomarkers and molecular and pathways important in resistance and response to 
chemotherapy.  


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2. 
Objectives 
2.1 
Primary Endpoints 
2.1.1 
To evaluate the rate of complete pathologic response (pCR = 
pT0pN0) as assessed by standard pathologic review attained by 
neoadjuvant systemic chemotherapy and nephroureterectomy 
2.2 
Secondary Endpoints 
2.2.1 
To evaluate the safety of neoadjuvant systemic chemotherapy in 
patients with upper tract urothelial carcinoma preceding 
nephroureterectomy 
2.2.2 
To evaluate distant recurrence-free survival of patients treated with 
neoadjuvant systemic chemotherapy preceding nephroureterectomy 
2.2.3 
To evaluate event-free survival of patients treated with neoadjuvant 
systemic chemotherapy preceding nephroureterectomy 
2.2.4 
To evaluate bladder cancer-free survival of patients treated with 
neoadjuvant systemic chemotherapy preceding nephroureterectomy 
2.2.5 
To evaluate cancer specific survival of patients treated with 
neoadjuvant systemic chemotherapy preceding nephroureterectomy 
2.2.6 
To evaluate renal functional outcomes of patients treated with 
neoadjuvant systemic chemotherapy preceding nephroureterectomy 
2.3 
Tertiary Endpoints 
2.3.1 
To collect pre-treatment and post-treatment tumor tissue, peripheral 
blood mononuclear cell (PBMC), peripheral blood plasma, and urine 
specimens for potential evaluations of markers of chemotherapy 
response/resistance 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Patients must be ≥ 18 years of age. 
3.1.2 
Patients must have high grade upper tract urothelial carcinoma 
proven by one of the following: 
 
Biopsy; 
 
Urinary cytology with a 3-dimensional upper urinary tract mass on 
cross-sectional imaging; or 
 
Urinary cytology and a mass visualized during upper urinary tract 
endoscopy 
3.1.3 
Patients must have a Creatinine clearance ≥ 30 ml/min within 28 days 
of registration to be eligible for the study. 
This will be determined by Cockroft-Gault calculation and 24-hour 
urine creatinine clearance measurement. (Please note, renal function, 
measured by 24-hour urine creatinine clearance in screening and post 
operatively, are required) 
Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) / (72 * 
Cr) 
3.1.4 
Patients must have ECOG Performance Status 0 or 1 (see  
Appendix III). 
3.1.5 
Patients must have no evidence of metastatic disease or clinically 
enlarged lymph nodes on CT or MRI of the abdomen and pelvis and 
CT chest obtained within 28 days of registration (A negative biopsy is 
required for lymph nodes ≥ 1 cm in size to confirm lack of 
involvement). Patients with lymph nodes ≥ 1 cm in whom a biopsy is 
deemed not feasible are not eligible. Patients with elevated alkaline 
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phosphatase or suspicious bone pain should also undergo baseline 
bone scans to evaluate for bone metastasis. 
3.1.6 
Patients with any component of small cell carcinoma are not eligible. 
Other variant histologies are permitted provided the predominant (≥ 
50%) subtype is urothelial carcinoma. 
3.1.7 
Patients must not have peripheral neuropathy > Grade 2. 
3.1.8 
Patients must not have a history of allergy or hypersensitivity to 
methotrexate, vinblastine, doxorubicin, cisplatin, gemcitabine, 
carboplatin or filgrastim or pegfilgrastim. 
3.1.9 
Patients must have a left ventricular ejection fraction (LVEF) ≥ 50% by 
(either MUGA or 2-D echocardiogram) within 28 days of registration. 
3.1.10 
Patients must have normal organ and marrow function as defined 
below within 28 days prior to registration: 
3.1.10.1 
Absolute Neutrophil Count (ANC) ≥ 1500/mm3 
3.1.10.2 
Platelets ≥ 100,000/mm3 
3.1.10.3 
HgB ≥ 9 
3.1.10.4 
AST(SGOT)/ALT(SGPT) < 2X institutional ULN 
3.1.10.5 
 Total Bilirubin within institutional normal limits (or < 2.5 X 
the ULN for patients with Gilbert’s disease) 
3.1.11 
Patients with concomitant primaries of the bladder/urethra are 
allowed, as long as these sites are surgically resected and non-
invasive cancers (< cT1N0). 
3.1.12 
Patients must not have another active second malignancy other than 
non-melanoma skin cancers and biochemical relapsed prostate 
cancer. Patients that have completed all necessary therapy and are 
considered to be at less than 30% risk of relapse are not considered 
to have an active second malignancy and are eligible for enrollment. 
3.1.13 
For patients who have Creatinine Clearance that meets > 50 ml/min 
they must not have received prior systemic doxorubicin. 
3.1.14 
Patients with uncontrolled illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, myocardial 
infarction in last 3 months, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements are not eligible. 
3.1.15 
Patients who are known to have HIV or are on combination 
antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions with cytotoxic chemotherapy. In addition, 
these patients are at increased risk of lethal infections when treated 
with marrow-suppressive therapy. 
3.1.16 
Patients must have no prior radiation therapy to ≥ 25% of the bone 
marrow for prior systemic anthracycline therapy. Prior intravesical 
anthracycline therapy for non-muscle invasive urothelial carcinoma of 
the bladder is permitted. 
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3.1.17 
Patients may have a history of resectable urothelial cancer (including 
neoadjuvant chemotherapy) as long as patients meet one of the 
following: 
 
pT0, Tis, or T1N0 and have no evidence of disease (NED) for 
more than 2 years from surgery or chemotherapy;  
 
pT2-3aN0 and NED for more than 3 years from surgery or 
chemotherapy; or 
 
>pT3b, or N+ and NED for more than 5 years from surgery or 
chemotherapy. 
3.1.18 
Women must not be pregnant or breast-feeding due to use of 
cytotoxic chemotherapy and risk of teratogenic side effects. 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. 
A female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.19 
Women of childbearing potential and sexually active males must use 
an accepted and effective method of contraception or to abstain from 
sexual intercourse for the duration of their participation in the study.  
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 


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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
 
a current Curriculum Vitae (CV) 
 
a completed and signed Supplemental Investigator Data Form (IDF) 
 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillabe PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ website by entering 
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credentials at https://www.ctsu.org.  For sites under the CIRB initiative, IRB data will 
automatically load to RSS. 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office for initial, continuing or amendment review. However, sites must 
submit a Study Specific Worksheet for Local Context (SSW) to the CIRB (via 
IRBManager) to indicate their intention to open the study locally. The CIRB’s approval of 
the SSW is then communicated to the CTSU Regulatory Office for compliance in the 
RSS.. The Signatory site may be contacted by the CTSU Regulatory Office or asked to 
complete information verifying the participating institutions on the study. Other site 
registration requirements (i.e., laboratory certifications, protocol-specific training 
certifications, or modality credentialing) must be submitted to the CTSU Regulatory 
Office or compliance communicated per protocol instructions. 
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the [NCI protocol #] protocol page 
located on the CTSU members’ website.  Add if a restricted access protocol: Permission 
to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS. 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Click on the (state organization type e.g. P2C, CITN, NCTN Groupname) link to 
expand, then select trial protocol #[NCI Protocol #] 
 
Click on the Site Registration Documents link 
Requirements For EA8141 Site Registration: 
 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB)  
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS. 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
FAX: (215) 569-0206  
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
Required Protocol Specific Regulatory Documents 
1. CTSU Regulatory Transmittal Form. 
2. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
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3. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
 
Indicate all sites approved for the protocol under an assurance 
number. 
 
OHRP assurance number of reviewing IRB 
 
Full protocol title and number 
 
Version Date 
 
Type of review (full board vs. expedited) 
 
Date of review. 
 
Signature of IRB official 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website. 
NOTE: 
Sites will not receive formal notification of regulatory approval from the CTSU 
Regulatory Office. 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within seven working days after registration. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data {add if a Rave study: and, upon 
enrollment, initializes the patient in the Rave database.}.  OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
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additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Registration to Treatment 
The following information is to be provided at registration. 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
 
Institution and affiliate name 
 
Investigator’s name 
4.1.3 
Patient Identification  
 
Patient’s initials (first and last) 
 
Patient’s Hospital ID and/or Social Security number 
 
Patient demographics 
 
Gender 
 
Birth date (mm/yyyy) 
 
Race 
 
Ethnicity 
 
Nine-digit ZIP code 
 
Method of payment 
 
Country of residence 
4.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
4.3 
Classification Factors 
Treatment arm will be determined by baseline renal function as determined by 
Cockroft-Gault calculation or 24-hour urine creatinine clearance measurement.  
Treatment will be assigned as follows: 
 
Arm A: mCrCl > 50 
 
Arm B: 30 ≤ mCrCl ≤ 50 
4.4 
Additional Requirements  
4.4.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.4.2 
Biospecimens are to be submitted as indicated in Section 10. 
4.4.3 
Data collection for this study will be done exclusively through the 
Medidata Rave clinical data management system. Access to the trial 
in Rave is granted through the iMedidata application to all persons 
with the appropriate roles assigned in Regulatory Support System 
(RSS). To access Rave via iMedidata, the site user must have an 
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active CTEP-IAM account  
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and the 
appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.5 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the EA8141 Forms Completion Guidelines. 


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5. 
Treatment Plan 
5.1 
Administration Schedule 
Patients will receive neoadjuvant therapy according to their measured CrCl. 
Standardized protocols for administration of AMVAC and GCa will be employed. 
The doses of each drug are standard, but the infusion duration may be given in 
accordance with institutional protocol. Central venous access is recommended 
for patients in the AMVAC arm due to vesicant risk. All chemotherapy 
calculations should be based on actual body weight. Appropriate pre hydration, 
electrolyte repletion and antiemetic prophylaxis per institutional guidelines, 
supportive care guidelines for administration are included in Section 5.4.1. Use of 
erythroid stimulating agents (ESAs) is prohibited per NCCN guideline 
recommendation as treatment on this protocol is given with curative intent. 
Patients must have surgery per Section 5.1.3, within 60 days from completion of 
chemotherapy. 
NOTE: 
Weight dependent dose calculations will not require recalculation 
unless the patient’s weight changes by greater than 10% when 
compared to the weight used for the previous dose calculation. 
5.1.1 
Arm A: AMVAC 
Cycle length is 14 days. 
Methotrexate 30 mg/m2 IV day 1 over 2-3 minutes 
Vinblastine 3 mg/m2 IV day 1 infusion 
Doxorubicin 30 mg/m2 IV day 1 slow push 
Cisplatin 70 mg/m2 IV day 1 infusion over at least 2 hours 
(At the discretion of the investigator, cisplatin dose can be divided and 
given 35 mg/m2 over day 1 and 2) 
Pegfilgrastim 6 mg once 24-48 hours after completion of 
chemotherapy is required. 
NOTE: 
Auto injector, Neulasta, is permitted for use on this trial. 
Regimen repeated every cycle for a total of 4 cycles. 
5.1.2 
Arm B: GCa 
Cycle length is 21 days. 
Gemcitabine 1000 mg/m2 IV days 1 and 8 infusion over 30-60 
minutes  
Carboplatin AUC 5 IV day 1 infusion over 30-60 minutes 
Carboplatin dosing is by the Calvert formula¹⁸: 
Total Dose (mg) = (target AUC) x (CrCl + 25) 
Use of prophylactic myeloid growth factor support in the GCa arm at 
investigator discretion per NCCN guidelines for use of myeloid growth 
factors. 
Regimen repeated every cycle for a total of 4 cycles. 
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5.1.3 
Nephrectomy and retroperitoneal lymph node dissection 
Patients with continued lack of radiographic presence of metastatic 
disease following neoadjuvant chemotherapy will proceed to 
nephroureterectomy and lymph node dissection. The surgery must 
take place 21 to 60 days from completion of chemotherapy. Surgical 
approach (open, laparoscopic, robotic assistance) is left at surgeon’s 
discretion as long as the following criteria are met.  The entirety of the 
affected upper urinary tract is removed (kidney, ureter and cuff of 
urinary bladder).  Regional lymph node dissection is performed, 
preferably according to template as proposed by Kondo et al (17).  
Specifically, for the tumor of the right renal pelvis, proximal and/or mid 
ureter – hilar, paracaval, retro-caval and inter-aortocaval lymph nodes 
should be removed.  For the left-sided renal pelvis, proximal, and/or 
mid-ureter – hilar and para-aortic lymph nodes should be harvested.  
Finally, for the distal ureteral tumors, ipsilateral common iliac, external 
iliac, internal iliac and obturator lymph nodes are removed.   
Primary tumor, normal kidney/ureter tissue, and regional lymph nodes 
will be harvested at the time of surgery and the tissue examined and 
stored according to SOP for consistent handling of the tissue located 
in Appendix I. 
5.2 
Adverse Event Reporting Requirements 
NOTE: 
For this protocol, the Adverse Event Reporting period includes the 
time the patient is on chemotherapy and continues through 30 days 
post- surgery. 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.   
 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
5.2.2 
Terminology 
 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug (or surgery) in humans, whether 
or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product (or surgery), whether or not 
considered related to the medicinal product (or surgery).  
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 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
 
 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
 
Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the agent 
(or surgery). An adverse event is considered unexpected, for 
expedited reporting purposes, when either the type of event or the 
severity of the event is NOT listed in the protocol or drug package 
insert. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). The CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
 
the AE Team at ECOG-ACRIN (617-632-3610) 
 
the FDA (1-800-FDA-1088)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 


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5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
 
the phase (0, 1, 2, or 3) of the trial  
 
whether the patient has received an investigational or commercial 
agent or both 
 
the seriousness of the event 
 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
 
the relationship to the study treatment (attribution) 
 
the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EA8141 and outline the 
specific expedited adverse event reporting requirements for study 
EA8141. 
 


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5.2.5 
Steps to determine if an event is to be reported in an expedited 
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Identify the type and grade of the event 
using CTCAE v4.0. 
Determine if the event is related to the 
protocol treatment (attribution). 
With this information, review the chart in 
Section 5.2.6 to determine if event is 
reportable via CTEP-AERS. 
Refer to footnote b in 
Section 5.2.6 to determine 
if the event meets the 
protocol specific reporting 
requirements for this 
study. If so, report the 
event via CTEP-AERS. 
Is the event 
reportable?
No 
Yes 
Report the event via CTEP-
AERS 
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 


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5.2.6 
Expedited Reporting Requirements for Arms A and B on protocol 
EA8141 
Commercial Agents: Gemcitabine, Doxorubicin, Methotrexate, 
Vinblastine, Cisplatin and Carboplatin   
NOTE: 
For this protocol, the Adverse Event Reporting period 
includes the time the patient is on chemotherapy and 
continues through 30 days post- surgery.  Please continue 
to report via CTEP-AERS all adverse events that meet the 
criteria in the chart below until the patient is 30 days post-
surgery.   
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only – Arms A and B 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution.  
NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed possibly, 
probably, or definitely to the treatment must be reported within 7 calendar days of learning of 
the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar 
days of learning of the event. For instructions on how to specifically report these events via 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 301-897-
7497. This will need to be discussed on a case-by-case basis. 
5.2.7 
Other recipients of adverse event reports and supplemental data 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.8 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
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 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one ECOG-
ACRIN study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the ECOG-ACRIN 
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5.3 
Dose Modifications  
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
Dose levels for each chemotherapy agent are shown below. Please note 
that once a drug dose is reduced, there is no re-escalation to a previous 
dosing level. Skipped doses will not be made up. 
Treatment holds should be < 2 weeks. For treatment hold > 2 weeks, patient 
should proceed to surgery. The maximum total period of treatment delay 
should not exceed 4 weeks. Patients with cumulative treatment hold of > 4 
weeks should proceed to surgery. 
METHOTREXTAE 
Dose Level 
Dose 
Level 0 
30 mg/m2 
Level -1 
23 mg/m2 
Level -2 
15 mg/m2 
VINBLASTINE 
Dose Level 
Dose 
Level 0 
3 mg/m2 
Level -1 
2.3 mg/m2 
Level -2 
1.5 mg/m2 
DOXORUBICIN 
Dose Level 
Dose 
Level 0 
30 mg/m2 
Level -1 
23 mg/m2 
Level -2 
15 mg/m2 
CISPLATIN - no dose reductions 
Dose 
Level 
Dose 
CrCl ≥ 60 mL/min 
CrCl > 50 ml/min and < 60 ml/min 
Level 0 
70 mg/m2 
35 mg/m² on days 1 and 2 
CARBOPLATIN - no dose reductions 
Dose Level 
Dose 
Level 0 
AUC 5 


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GEMCITABINE 
Dose Level 
Dose 
Level 0 
1000 mg/m2 
Level -1 
750 mg/m2 
Level -2 
500 mg/m2 
AMVAC Treatment arm 
5.3.1 
Hematologic toxicity and febrile neutropenia 
For ANC < 1500 or platelets < 100,000 on Day 1, delay treatment until 
the ANC is ≥ 1500 and platelets ≥ 100,000. If delay is one week or 
less, continue at the same doses. If the delay is for more than a week, 
reduce methotrexate, vinblastine, and doxorubicin by one dose level 
for this and all subsequent cycles. Continue cisplatin at full dose. 
For febrile neutropenia, defined as ANC of < 500 and a temperature 
of 38.3°C orally (101°F) or a temperature of ≥ 38°C (100.4°F) for more 
than 1 hour, reduce methotrexate, vinblastine, and doxorubicin by one 
dose level. Continue cisplatin at full dose. 
5.3.2 
Kidney Dysfunction 
Calculate or measure the CrCl on Day 1 of each cycle. If the CrCl is  
> 50 and < 60 ml/min on Day 1 Cycle 1 of chemotherapy, administer 
cisplatin in split dosing on Days 1 and 2. If CrCl improves to ≥ 60 
ml/min on Day 1 of subsequent cycles, split dosing of cisplatin is not 
required for those cycles. 
Beyond cycle 1 if CrCl is < 50 ml/min, hold chemotherapy for up to 2 
weeks. If the CrCl improves to > 50 ml/min within 2 weeks or less of 
the scheduled Day1, proceed with split dose cisplatin administration 
on Days 1 and 2 for this and all subsequent cycles. If the CrCl does 
not improve to > 50 ml/min within 2 weeks despite hydration and other 
supportive measures, discontinue the chemotherapy and proceed to 
surgery. 
There are no cisplatin dose reductions for kidney dysfunction. 
5.3.3 
Liver Dysfunction 
Methotrexate: Bilirubin >3 to 5 mg/dL or transaminases >3 times 
ULN: reduce by one dose level. Bilirubin >5 mg/dL, avoid until bilirubin 
< 5 mg/dL. See separate recommendations for bilirubin elevations in 
Gilbert’s disease. 
Bilirubin elevations 
 
1.5 – 3 mg/dL 
> 3– 5 mg/dL 
> 5 mg/dL 
Methotrexate 
Dose level 0 
Dose level -1 
Hold 
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AST / ALT elevations 
 
2 – 3x ULN 
> 3x ULN 
Methotrexate 
Dose level 0 
Dose level -1 
Methotrexate dose reductions for Bilirubin elevations due to 
Gilbert’s Disease 
 
> 3 – 5 mg/dL) 
> 5 – 8 mg/dL 
> 8 mg/dL 
Methotrexate 
Dose level 0 
Dose level -1 
Hold 
Vinblastine: Bilirubin 1.5 to 3 mg/dL or transaminases 2 to 3x ULN: 
reduce by two dose levels. Transaminases >3x ULN, Hold. Serum 
bilirubin >3x ULN, avoid until bilirubin < 3x ULN. See separate 
recommendations for bilirubin elevations in Gilbert’s disease. 
Bilirubin elevations 
 
1.5 – 3 mg/dL 
> 3 – 5 mg/dL 
> 5 mg/dL 
Vinblastine 
Dose level -2 
Hold 
Hold 
AST / ALT elevations 
 
2 – 3x ULN 
> 3x ULN 
Vinblastine 
Dose level -2 
Hold 
Vinblastine dose reductions for Bilirubin elevations due to 
Gilbert’s Disease 
 
> 3 – 5 mg/dL 
> 5– 8 mg/dL 
> 8 mg/dL 
Vinblastine 
Dose level 0 
Dose level -2 
Hold 
Doxorubicin: Serum bilirubin 1.2 to 3 mg/dL: reduce by two dose 
levels. Serum bilirubin > 3 mg/dL, avoid until bilirubin < 3 
mg/dL.Transaminases 2 to 3x ULN: reduce by one dose level. 
Transaminases >3 times ULN: reduce by two dose levels. 
Transaminases >3x ULN, Hold. See separate recommendations for 
bilirubin elevations in Gilbert’s disease. 
Bilirubin elevations 
 
1.2 – 3 mg/dL 
>3 – 5 mg/dL 
> 5 mg/dL 
Doxorubicin 
Dose level -2 
Hold 
Hold 
AST / ALT elevations 
 
2 – 3x ULN 
>3x ULN 
Doxorubicin 
Dose level -1 
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Doxorubicin dose reductions for Bilirubin elevations due to 
Gilbert’s Disease 
 
1.5 – 3 mg/dL 
(Gilbert’s 
disease 
 3.1 – 5 mg/dL) 
3.1 – 5 mg/dL 
(Gilbert’s disease 
 5.1 – 8 mg/dL) 
> 5 mg/dL 
(Gilbert’s 
disease 
 > 8 mg/dL) 
Doxorubicin 
Dose level 0 
Dose level -2 
Hold 
Cisplatin: Cisplatin undergoes non-enzymatic metabolism and 
predominantly renal elimination; therefore, dosage adjustment for liver 
dysfunction is likely not necessary. 
5.3.4 
Neurologic toxicity 
For Grade 3 neuropathy, hold chemotherapy until this resolves to 
Grade < 2 and then resume with a one dose level reduction in 
vinblastine. For Grade 4 neuropathy, remove the patient from protocol 
treatment. 
5.3.5 
Gastrointestinal Toxicity 
For Grade 3 or 4 vomiting, despite maximal antiemetic medical 
intervention with aprepitant, corticosteroids, and 5HT-3 antagonists 
(e.g.ondansetron), split cisplatin dosing over days 1 and 2, and dose 
reduce methotrexate, doxorubicin and vinblastine by one dose level 
following resolution to grade < 1. If Grade 3 or 4 vomiting occurs 
despite cisplatin split dosing and maximal antiemetic therapy, with 
dose reduced methotrexate, doxorubicin and vinblastine, remove the 
patient from protocol treatment. 
5.3.6 
Mucositis / Stomatitis 
For Grade > 2 toxicity, delay infusion until it resolves to Grade < 1. 
Begin leucovorin 15 mg PO TID until recovery. Reduce methotrexate 
by one dose level for this and all subsequent cycles. 
5.3.7 
Other toxicities 
For all other, non-specified adverse events at Grade 2, patients 
should be treated symptomatically, as indicated. For all other Grade 3 
or 4 (excluding alopecia and skin pigment changes), hold all 
chemotherapy and monitor the subject at least weekly. If toxicity 
resolves to Grade 1 or completely resolves in ≤ 2 weeks, reduce 
methotrexate, vinblastine, and doxorubicin by one dose level for this 
and all subsequent cycles. Any single delay in chemotherapy of more 
than 2 weeks or cumulative delays of > 4 weeks will lead to removal 
from protocol treatment and referral to surgery. 
Gemcitabine and Carboplatin - Treatment arm (Arm B) 
5.3.8 
Hematologic toxicity and febrile neutropenia 
Hematologic toxicity  
Day 1: For ANC < 1,500 on Day 1, delay treatment until the ANC is  
≥ 1500. If delay is one week or less, continue at the same dose and 
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consider pegfilgrastim with subsequent cycles following day 9, if not 
receiving. If the delay is for more than a week and pegfilgrastim has 
not been used, include pegfilgrastim in this and all subsequent cycles 
following day 9. 
If there is a dose delay of more than one week due to neutropenia 
despite pegfilgrastim use, reduce gemcitabine by one dose level for 
this and all subsequent cycles and continue pegfilgrastim. 
Day 1: For platelets < 100,000 on Day 1, delay treatment until 
platelets are ≥ 100,000. If the delay is one week or less, continue at 
the same dose levels. If the delay is for more than a week, reduce the 
gemcitabine by one dose level for this and all subsequent cycles. 
Day 8:  
For ANC ≥ 500 and ≤ 999, decrease gemcitabine by two dose levels 
and include pegfilgrastim this and in all subsequent cycles following 
day 9, if not receiving. 
For ANC < 500, hold gemcitabine and include pegfilgrastim in all 
subsequent cycles following day 9, if not receiving. If ANC < 500 
despite pegfilgrastim use, reduce gemcitabine by one dose level for 
all subsequent cycles. 
Day 8:  
For platelets ≥ 75,000 - < 100,000, reduce gemcitabine by one dose 
level for this and all subsequent doses. 
For platelets ≥ 50,000 – < 75,000 reduce gemcitabine by two dose 
levels for this and all subsequent doses. 
For platelets < 50,000, hold gemcitabine and reduce gemcitabine  by 
one dose level for all subsequent doses. 
Febrile neutropenia is defined as ANC of < 500 and a temperature of 
38.3°C orally (101°F) or a temperature of ≥ 38°C (100.4°F) for more 
than 1 hour. If patient recovers in 2 weeks or less, add pegfilgrastim if 
not previously included, continuing at the same dose level. If 
pegfilgrastim had been utilized, then reduce gemcitabine by one dose 
level for all subsequent doses and continue pegfilgrastim. If recovery 
does not occur in 2 weeks, no further chemotherapy should be given 
and the patient should proceed per protocol to surgery. 
5.3.9 
Kidney dysfunction 
Calculate the CrCl on Day 1 of each cycle. If CrCl is < 30 ml/min, hold 
chemotherapy for up to 2 weeks. If the CrCl does not improve to ≥ 30 
ml/min in 2 weeks despite hydration and other supportive measures, 
discontinue the chemotherapy and proceed to surgery. 
There are no carboplatin dose reductions for kidney dysfuntion. 
5.3.10 
Liver dysfunction 
Gemcitabine: For a total bilirubin of > 1.6 (or < 2.5 X ULN in those 
with Gilbert’s syndrome), reduce one dose level. 
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Carboplatin undergoes minimal hepatic metabolism therefore dosage 
adjustment may not be needed. 
5.3.11 
Neurologic toxicity 
For Grade 3 neuropathy, hold chemotherapy until this resolves to 
Grade < 2 and resume at same dose level. For Grade 4 neuropathy, 
remove the patient from protocol treatment. 
5.3.12 
Gastrointestinal Toxicity 
For Grade 3 or 4 vomiting, despite maximal antiemetic medical 
intervention with aprepitant, corticosteroids, and 5HT-3 antagonists 
(e.g. ondansetron), proceed with a dose reduction for all subsequent 
doses of gemcitabine. If Grade 3 or 4 vomiting occurs despite one 
dose reduction in chemotherapy and maximal antiemetic therapy, 
remove the patient from protocol treatment. 
5.3.13 
Other toxicities 
For all other, non-specified adverse events at Grade 2, patients 
should be treated symptomatically. For all other Grade 3 or 4 toxicities 
(excluding alopecia and skin pigment changes), hold chemotherapy 
and monitor the patient at least weekly. If toxicity resolves to Grade 1 
or completely resolves in ≤ 2 weeks, reduce the gemcitabine by one 
dose level for this and all subsequent doses. Any single delay in 
chemotherapy of more than 2 weeks or cumulative delays of > 4 
weeks will lead to removal from protocol treatment and referral to 
surgery. 
5.4 
Supportive Care  
5.4.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. Use of erythroid stimulating agents 
(ESAs) is prohibited per NCCN guideline recommendation as 
treatment on this protocol is given with curative intent. Transfusion 
support consistent with routine clinical practice can be utilized. 
5.4.2 
Suggested supportive care for all patients on the AMVAC treatment 
arm (Arm A) are: 
Aprepitant or fosaprepitant 
Aprepitant 125 mg po day 1 and 80 mg po days 2 and 3 or 
bioequivalent Fosaprepitant 150 mg IV day 1 only 
Ondansetron  
Or 
Palonosetron 
Ondansetron 24 mg IV Day 1 
8 mg po q8 days 4-14 prn 
Palonosetron 0.25 mg IV day 1 with Ondansetron 8 mg po q8h 
PRN days 3-14. 
Dexamethasone  
12 mg  IV Day 1 
4 mg PO BID Days 2 and 3 
Compazine 
10 mg every 6 hrs prn 
Salt and Soda Mouth rinse 
1 mouthful Swish and spit 
After every meal or snack, at least 5 times daily. 
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Proton pump inhibitor  
PO Daily or BID for duration of chemotherapy 
Benzodiapine (Ativan) 
0.5 - 1 mg q 8 hrs prn 
Intravenous hydration 
Appropriate pre- and post hydration with total of 2 liters of fluid 
should be administered.  
Electrolyte support 
Pre-treatment and repletion with potassium and magnesium IV / 
po per institutional guidelines 
Diuresis 
Mannitol or furosemide diuresis recommended per institutional 
guidelines 
Myeloid growth factor support 
Neulasta 6 mg sq 24-48 hours following chemotherapy is a 
REQUIRED component of this regimen 
For patients on the Gemcitabine Carboplatin arm (Arm B) of the study, 
suggested supportive therapies should include hydration and antiemetic 
prophylaxis per institutional guidelines: 
Aprepitant or fosaprepitant 
Aprepitant 125 mg po day 1 and 80 mg po days 2 and 3 or 
bioequivalent Fosaprepitant 150 mg IV day 1 only 
May reserve in cycle 1 at investigator discretion 
Ondansetron  
Or  
Palonosetron 
Ondansetron 24 mg IV Day 1 
8 mg po q8 days 4-14 prn 
Palonosetron 0.25 mg IV day 1 with Ondansetron 8 mg po 
q8h PRN days 3-21. 
Compazine 
10 mg every 6 hrs prn 
Dexamethasone  
12 mg IV Day 1 
4 mg PO BID Days 2 and 3 at investigator discretion 
Salt and Soda Mouth rinse 
1 mouthful Swish and spit 
After every meal or snack, at least 5 times daily. 
Proton pump inhibitor  
PO Daily or BID for duration of chemotherapy at 
investigator discretion 
Benzodiapine (Ativan) 
0.5 - 1 mg q 8 hrs prn 
Intravenous hydration 
Appropriate pre- hydration with at least 500 cc normal 
saline per institutional guidelines. 
Electrolyte support 
Pre-treatment and repletion with potassium and 
magnesium IV / po per institutional guidelines 
Myeloid growth factor support 
Use of prophylactic myeloid growth factor support at 
investigator discretion per NCCN guidelines for use of 
myeloid growth factors 
5.5 
Duration of Therapy 
Patients will receive protocol therapy unless: 
5.5.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the EA8141 Forms Packet. 


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5.5.2 
Patient withdraws consent. 
5.5.3 
Patient experiences unacceptable toxicity. 
5.5.4 
Non-protocol therapies are administered. 
5.5.5 
Patient completes 4 cycles of therapy and surgery per Section 5.3. 
5.5.6 
Development of clinically evident metastatic disease during 
chemotherapy. Note: patients in whom disease progression is noted 
on post-chemotherapy preoperative imaging, may stay on study and 
proceed to surgery at discretion of the surgeon if he/she feels the 
patient can undergo surgical resection for cure. 
5.6 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed 5 years from the date of registration. Patients will be 
followed by their urologists or medical oncologists according to standard 
institutional practices. Systemic recurrence-free survival, bladder recurrence-free 
survival and overall survival information will be collected every 3 months for 2 
years, and every 6 months for 3-5 years. 
 


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6. 
Measurement of Effect 
6.1 
Pathologic Complete Response 
Pathologic proof of a clinically complete response during pathologic evaluation of 
nephrectomy/ureterectomy and any identifiable regional lymph nodes. 
6.2 
Diagnosis of Urothelial Cancer Recurrence 
The diagnosis of urothelial cancer recurrence can be made only when the clinical 
and pathology findings meet one of the following criteria. 
 
Urothelial carcinoma noted on cytology or biopsy. 
 
Radiologic evidence on CT or MRI felt to be consistent with recurrence. 
Any recurrence of malignant disease should be proven by core needle biopsy 
whenever possible. At the time of tumor recurrence the investigator should 
clearly indicate the site of tumor recurrence (e.g. bladder, contralateral upper 
tract) and whether multiple sites are involved. 
Supporting documentation (copies of radiology, pathology, and if relevant, 
surgery reports) must be submitted using Medidata Rave following diagnosis of 
urothelial carcinoma recurrence or second primary cancer. Refer to the EA8141 
Forms Completion Guidelines for data to be collected. If biopsy material is 
available, a copy of the pathology report should also accompany the materials 
submission to the CBPF. 
NOTE: 
Development of urothelial cancer of the bladder and/or contralateral 
upper urinary tract will not constitute systemic recurrence and will be 
considered as bladder recurrence. 
6.3 
Diagnosis of Systemic Recurrence (Distant Recurrence) 
The diagnosis of systemic cancer recurrence can be made only when the clinical 
and pathology findings meet one of the following criteria. 
 
Carcinoma noted on cytology or biopsy. 
 
Radiologic evidence on CT or MRI felt to be consistent with recurrence. 
Any recurrence of malignant disease should be proven by core needle biopsy 
whenever possible. At the time of tumor recurrence the investigator should 
clearly indicate the site of tumor recurrence (i.e. non-urothelial) and whether 
multiple sites are involved. 
Supporting documentation (copies of radiology, pathology, and if relevant, 
surgery reports) must be submitted using Medidata Rave following diagnosis of 
systemic carcinoma recurrence or second primary cancer. Refer to the EA8141 
Forms Completion Guidelines for data to be collected. If biopsy material is 
available, a copy of the pathology report should also accompany the materials 
submission to the CBPF. 
NOTE: 
Development of urothelial cancer of the bladder and/or contralateral 
upper urinary tract will not constitute systemic recurrence and will be 
considered as bladder recurrence. 
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6.4 
Distant Recurrence-Free Surviva 
The time from the date of surgery to distant recurrence or death from any cause. 
Patients alive without documented distant recurrence will be censored at the date 
of last disease assessment. 
6.5 
Bladder Cancer-Free Survival 
The time from the date of surgery to the earliest return of bladder cancer or death 
from any cause. Patients alive without documented bladder cancer will be 
censored at the date of last disease assessment.  
6.6 
Disease Progression 
Disease progression will be assessed using RECIST 1.1 (see Section 6.12) in 
the following settings: 
 
From registration to surgery for all patients. 
 
For patients who are not deemed disease-free after surgery. 
6.7 
Second Primary Cancer 
Second primary cancer is defined as any cancer other than localized breast 
cancer, localized prostate cancer, or non-melanoma skin cancer.  
The diagnosis of a second primary cancer must be confirmed histologically 
whenever possible. 
6.8 
Local, Regional Recurrence  
Local regional recurrence is defined as any pathologic or radiographic evidence 
of recurrent disease within the patient’s primary upper tract urothelial carcinoma 
surgical field, or in the regional lymph nodes. 
6.9 
Event-Free Survival  
The time from registration to the earliest occurrence of recurrence of any type, 
disease progression, new invasive primary cancer, or death from any cause. 
6.10 
Overall Survival  
Time from registration to date of death from any cause. 
6.11 
Renal Function Endpoints 
Renal insufficiency is defined as CrCl < 60 ml/min. 
NOTE: 
Standardized measures of renal function will be compared pre and 
post combined therapy. Thus all patients will have at least 2 
assessments by 24 hour urine for creatinine clearance. One measure 
will be in screening, and another following completion of 
chemotherapy and nephroureterectomy, and will be thus timed 
following NU. 
Assessments of renal function will occur with each cycle. Patients 
must continue to meet CrCl eligibility criteria in their chemotherapy 
group before proceeding on next cycle. This can be assessed by 
Cockroft-Gault or 24 hr urine. Thus at the least, patients with have two 
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24 hour urine assessments, and at most, 6, adding in one for every 
cycle. 
6.12 
Antitumor Effect – Solid Tumors 
Prior to patient receiving protocol surgery, response and progression will be 
evaluated in this study using the international criteria proposed by the revised 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in RECIST. 
Patients will also be evaluated according to RECIST criteria in the event that 
after protocol surgery, patient's resection status is not R0 (e.g., disease is still 
present after protocol surgery). In the event that this occurs, a new baseline 
reference point will be established based on the post-surgery scan. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. All measurements should be recorded in metric notation by use of a ruler or 
calipers. 
3. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up. 
6.12.1 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area are not considered measurable. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
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non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.12.2 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
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Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm 
in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, 
CT is preferable. 
Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
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cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 
6.12.3 
Response Criteria 
6.12.3.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
NOTE: 
For patients that have disease presence after 
protocol surgery, the new baseline reference 
point established on post-protocol surgery 
scans should be used. 
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At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progression, See Section 
6.12.3.3). 
NOTE: 
For patients that have disease presence after 
protocol surgery, refer to the smallest sum post-
surgery. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 8 weeks. 
NOTE: 
For patients that have disease presence after 
protocol surgery, stable disease can be 
assigned as a status if measurements met 
criteria at least once after surgery at a minimal 
interval of 8 weeks. 
6.12.3.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.12.3.3). Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is 


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42 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.12.3.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it: 
a) increases in size to ≥ 15 mm in the short axis, or 
b) there is new pathological confirmation that it is disease 
(regardless of size). 
6.12.3.4 
Evaluation of Best Overall Response 
Prior to protocol surgery (or for those patients who do not 
receive protocol surgery), the best overall response is the 
best response recorded from the start of the treatment until 
disease progression/recurrence or non-protocol therapy 
(taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the 
achievement of both measurement and confirmation 
criteria. 
After protocol surgery, if patient has presence of disease, 
the best overall response is the best response recorded 
from the surgery until disease/progression/recurrence or 
non-protocol therapy (taking as reference for progressive 
disease the smallest measurements recorded since the 
surgery). The patient’s best response assignment will 
depend on the achievement of both measurement and 
confirmation criteria. 


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Table 6.1: Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target 
Lesions 
New Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-
PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not 
evaluated 
No 
PR 
SD 
Non-PD***/not 
evaluated 
No 
SD 
Documented at least 
once ≥ 8 wks. from 
study entry (or surgery 
if patient had disease 
presence post-protocol 
surgery) 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease (Section 6.12.3.2) for further explanation. 
NOTE:  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 


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7. 
Study Parameters 
All required prestudy evaluations must be completed within 28 days of registration unless otherwise specified. 
7.1 
Arm A: AMVAC 
PHYSICAL 
Pre study 
Week1 C1 Week 3 C2 Week 5 C3 Week 7 C4 
Pre NU 
NU 
Post NU9 
Follow-up11 
History and Physical Exam 
(Ht/WT included) 
X 
X 
X 
X 
X 
 
 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
 
 
X 
X 
Toxicity evaluation 
X 
X 
X 
X 
X 
 
 
X 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
CBC with Differential1 
X 
X 
X 
X 
X 
X7,14 
 
X 
X 
Serum or Urine Pregnancy Test2 
X 
 
 
 
 
 
 
 
 
Comprehensive metabolic panel3 
X 
X 
X 
X 
X 
X7,14 
 
X 
X 
Creatinine clearance4 
X 
X 
X 
X 
X 
X14 
 
X10 
 
RADIOLOGIC STUDIES 
 
 
 
 
 
 
 
 
 
Radiographic staging5 
X 
 
 
 
 
X14 
 
X13 
X 
Bone scan6 
X 
 
 
 
 
X14 
 
 
X 
ECHO or MUGA  
X 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
Methotrexate 
 
X 
X 
X 
X 
 
 
 
 
Vinblastine 
 
X 
X 
X 
X 
 
 
 
 
Adriamycin 
 
X 
X 
X 
X 
 
 
 
 
Cisplatin 
 
X 
X 
X 
X 
 
 
 
 
Pegfilgrastim or filgrastim 
 
X 
X 
X 
X 
 
 
 
 
Nephroureterectomy (NU) 
 
 
 
 
 
 
X8 
 
 
Biospecimen Submissions12 
FFPE tumor tissue 
X 
 
 
 
 
 
X 
 
 
Serum, red top tube 
X 
 
 
 
 
X 
 
X 
 
Peripheral Blood, EDTA 
X 
 
 
 
 
X 
 
X 
 
Plasma, EDTA 
X 
 
 
 
 
X 
 
X 
 
Urine, Fresh Catch 
X 
 
 
 
 
X 
 
X 
 
Rev. 10/15 
Rev. 6/16 


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1. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done ≤ 2 
days prior to the treatment cycle. For cycle 1 day1, labs done < 5 days prior will be accepted. 
2. For women of childbearing potential. Must be done within 2 weeks prior to enrollment. 
3. Should include potassium, magnesium, phosphorus. Electrolyte levels should be monitored during the study and repleted per standard of care. 
Total bilirubin, AST and ALT should be included. Laboratory assessments must be done ≤ 2 days prior to the treatment cycle. For cycle 1 day 1, 
labs done < 5 days prior will be accepted. 
4. Standardized measures of renal function will be compared pre and post combined therapy. Thus all patients will have at least 2 assessments by 
24 hour urine for creatinine clearance. One measure will be in screening, and another following completion of chemotherapy and 
nephroureterectomy, and will be thus timed following NU. 
 
The creatinine clearance should be measured by 24-hour urine or calculated by Cocroft-Gault equation prior to each cycle. Patients must 
continue to meet creatinine clearance eligibility criteria in their arm to continue therapy; 24-hour urine assessment for creatinine clearance can 
be measured if needed. 
5. Radiographic imaging done at baseline should be continued throughout protocol if allowable. Assessments should include contrast enhanced CT 
chest/abdomen and pelvis, or MRI abdomen and pelvis with gadolinium with a non-contrast CT chest. Non-contrast CT chest/abdomen and 
pelvis are allowable if gadolinium is contraindicated. 
6. Nuclear medicine bone scan should be done for suspicion of bone lesions or elevated alkaline phosphatase. 
7. Post chemotherapy CBC with differential, comprehensive metabolic panel should be performed within 14 days prior to and up to one day before 
nephroureterectomy. 
8. Nephroureterectomy and lymph node dissection must be completed 21 to 60 days from completion of chemotherapy. 
9. Protocol completion visit 2-6 weeks from date of surgery. 
10. 24-hour urine creatinine clearance assessment post therapy +/- 10 days from completion visit. 
11. All patients, including those who discontinue protocol therapy early, will be followed according to standard institutional practices (see NCCN 
guidelines for guidance) until progression/systemic recurrence, even if non-protocol therapy is initiated, and for survival for 5 years from the date 
of registration. If patients develop a local recurrence (bladder or contralateral upper urinary tract), they must still be followed for response until 
development of a systemic recurrence. Patients will be followed by their urologists or medical oncologists according to standard institutional 
practices, but systemic recurrence-free survival, bladder cancer-free survival, cancer specific survival, and overall survival information will be 
collected every 3 months for 2 years, and every 6 months for 3-5 years. 
12. Refer to Section 10 – submission of biospecimens for research, for instructions. 
13. Scans must be obtained within 6 months of patient’s nephroureterectomy. 
14. Scans and labs must be done at least 1 week after the last dose of chemotherapy, but no later than 1 calendar day prior to surgery. 
 


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46 
7.2 
Arm B: GCa 
PHYSICAL 
Pre 
study 
C1D1 
C1D8 
C2D1 
C2D8 
C3D1 
C3D8 
C4D1 
C4D8 
Pre NU 
NU 
Post 
NU9 
Follow-
up11 
History and Physical Exam 
(Ht/WT included) 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
ECOG performance status 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Toxicity evalutation 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7,14 
 
X 
X 
Serum or Urine Pregnancy Test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive metabolic panel3 
X 
X 
 
X 
 
X 
 
X 
 
X7,14 
 
X 
X 
Creatinine clearance4 
X 
X 
 
X 
 
X 
 
X 
 
X14 
 
X10 
 
RADIOLOGIC STUDIES 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiographic staging5 
X 
 
 
 
 
 
 
 
 
X14 
 
X13 
X 
Bone scan6 
X 
 
 
 
 
 
 
 
 
X14 
 
 
X 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
Carboplatin 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Gemcitabine 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Nephroureterectomy (NU) 
 
 
 
 
 
 
 
 
 
 
X8 
 
 
Biospecimen Submissions 12 
FFPE tumor tissue 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Serum, red top tube 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Peripheral Blood, EDTA 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Plasma, EDTA 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Urine, Fresh Catch 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
1. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done ≤ 2 
days prior to the treatment cycle. For cycle 1 day1, labs done < 5 days prior will be accepted. 
2. For women of childbearing potential. Must be done within 2 weeks prior to enrollment. 
Rev. 6/16 


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3. Should include potassium, magnesium, phosphorus. Electrolyte levels should be monitored during the study and repleted per standard of care. 
Total bilirubin, AST and ALT should be included. Laboratory assessments must be done ≤ 2 days prior to the treatment cycle. For cycle 1 day1, 
labs done < 5 days prior will be accepted. 
4. Standardized measures of renal function will be compared pre and post combined therapy. Thus all patients will have at least 2 assessments by 
24 hour urine for creatinine clearance. One measure will be in screening, and another following completion of chemotherapy and 
nephroureterectomy, and will be thus timed following NU. 
 
The creatinine clearance should be measured by 24-hour urine or calculated by Cocroft-Gault equation prior to each cycle. Patients must 
continue to meet creatinine clearance eligibility criteria in their arm to continue therapy; 24-hour urine assessment for creatinine clearance can 
be measured if needed. 
5. Radiographic imaging done at baseline should be continued throughout protocol if allowable. Assessments should include contrast enhanced CT 
chest/abdomen and pelvis, or MRI abdomen and pelvis with gadolinium with a non-contrast CT chest. Non-contrast CT chest/abdomen and 
pelvis are allowable if gadolinium is contraindicated. 
6. Nuclear medicine bone scan should be done to for suspicion of bone lesions or elevated alkaline phosphatase. 
7. Post chemotherapy CBC with differential, comprehensive metabolic panel should be performed within 14 days prior to and up to one day before 
nephroureterectomy. 
8. Nephroureterectomy and lymph node dissection must be completed 21 to 60 days from completion of chemotherapy. 
9. Protocol completion visit 2-6 weeks from date of surgery. 
10. 24-hour urine creatinine clearance assessment post therapy +/- 10 days from completion visit. 
11. All patients, including those who discontinue protocol therapy early, will be followed according to standard institutional practices (see NCCN 
guidelines for guidance)for response until progression/systemic recurrence, even if non-protocol therapy is initiated, and for survival for 5 years 
from the date of registration. If patients develop a local recurrence (bladder or contralateral upper urinary tract), they must still be followed for 
response until development of a systemic recurrence. Patients will be followed by their urologists or medical oncologists according to standard 
institutional practices, but systemic recurrence-free survival, bladder recurrence-free survival and overall survival information will be collected 
every 3 months for 2 years, and every 6 months for 3-5 years. 
12. Refer to Section 10 – submission of biospecimens for research, for instructions. 
13. Scans must be obtained within 6 months of patient’s nephroureterectomy. 
14. Scans and labs must be done at least 1 week after the last dose of chemotherapy, but no later than 1 calendar day prior to surgery. 


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8. 
Drug Formulation and Procurement 
All agents in this protocol are commercially available and guideline endorsed treatment 
options for patients with invasive urothelial cancer. Drug will be obtained from 
institutional pharmacy supply. 
8.1 
Methotrexate 
8.1.1 
Other Names  
Folex, abitrexate, mexate 
8.1.2 
Classification  
antimetabolite and antifolate 
8.1.3 
Mode of Action  
Methotrexate is a folate antimetabolite that inhibits DNA synthesis, 
repair, and cellular replication. Methotrexate irreversibly binds to and 
inhibits dihydrofolate reductase, inhibiting the formation of reduced 
folates, and thymidylate synthetase, resulting in inhibition of purine 
and thymidylic acid synthesis, thus interfering with DNA synthesis, 
repair, and cellular replication. 
8.1.4 
Storage and Stability  
Store at room temperature 20° to 25°C (68° to 77°F). Protect from 
light. Opened vials are stable for 24 hours 
8.1.5 
Dose Specifics  
30 mg/m2 
8.1.6 
Preparation  
I.V.: Solution diluted in D5W or NS 
8.1.7 
Route of Administration  
IV push over 2-3 minutes 
8.1.8 
Incompatibilities  
Chlorpromazine, gemcitabine, idarubicin, ifosfamide, midazolam, 
nalbuphine, promethazine, propofol. 
8.1.9 
Availability  
8.1.10 
Side Effects  
Cardiovascular: Arterial thrombosis, cerebral thrombosis, chest pain, 
deep vein thrombosis, hypotension, pericardial effusion, pericarditis, 
plaque erosion (psoriasis), pulmonary embolism, retinal thrombosis, 
thrombophlebitis, vasculitis  
Central nervous system: Dizziness (≤3%), headache (pJIA 1%), 
abnormal cranial sensation, brain disease, chemical arachnoiditis 
(intrathecal; acute), chills, cognitive dysfunction (has been reported at 
low dosage), drowsiness, fatigue, leukoencephalopathy (intravenous 
administration after craniospinal irradiation or repeated high-dose 


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therapy; may be chronic), malaise, mood changes (has been reported 
at low dosage), neurological signs and symptoms (at high dosages; 
including confusion, hemiparesis, transient blindness, seizures, and 
coma), severe neurotoxicity (reported with unexpectedly increased 
frequency among pediatric patients with acute lymphoblastic leukemia 
who were treated with intermediate-dose intravenous methotrexate), 
speech disturbance 
Dermatologic: Alopecia (≤10%), burning sensation of skin (psoriasis 
3% to 10%), skin photosensitivity (3% to 10%), skin rash (≤3%), 
dermatitis (rheumatoid arthritis 1% to 3%), pruritus (rheumatoid 
arthritis 1% to 3%), acne vulgaris, dermal ulcer, diaphoresis, 
ecchymoses, erythema multiforme, erythematous rash, exfoliative 
dermatitis, furunculosis, hyperpigmentation, hypopigmentation, skin 
abnormalities related to radiation recall, skin necrosis, Stevens-
Johnson syndrome, telangiectasia, toxic epidermal necrolysis, 
urticaria 
Endocrine & metabolic: Decreased libido, decreased serum albumin, 
diabetes mellitus, gynecomastia, menstrual disease 
Gastrointestinal: Diarrhea (≤11%), nausea and vomiting (≤11%), 
stomatitis (2% to 10%), abdominal distress, anorexia, aphthous 
stomatitis, enteritis, gastrointestinal hemorrhage, gingivitis, 
hematemesis, intestinal perforation, melena 
Genitourinary: Azotemia, cystitis, defective oogenesis, defective 
spermatogenesis, dysuria, hematuria, impotence, infertility, 
oligospermia, pancreatitis, proteinuria, severe renal disease, vaginal 
discharge 
Hematologic & oncologic: Thrombocytopenia (rheumatoid arthritis 3% 
to 10%; platelet count <100,000/mm3), leukopenia (1% to 3%; WBC 
<3000/mm3), pancytopenia (rheumatoid arthritis 1% to 3%), 
agranulocytosis, anemia, aplastic anemia, bone marrow depression 
(nadir: 7-10 days), decreased hematocrit, eosinophilia, gastric ulcer, 
hypogammaglobulinemia, lymphadenopathy, lymphoma, 
lymphoproliferative disorder, neutropenia, non-Hodgkin’s lymphoma 
(in patients receiving low-dose oral methotrexate), tumor lysis 
syndrome 
Hepatic: Increased liver enzymes (14% to 15%), cirrhosis (chronic 
therapy), hepatic failure, hepatic fibrosis (chronic therapy), hepatitis 
(acute), hepatotoxicity 
Hypersensitivity: Anaphylactoid reaction 
Infection: Cryptococcosis, cytomegalovirus disease (including 
cytomegaloviral pneumonia, sepsis, nocardiosis), herpes simplex 
infection, herpes zoster, histoplasmosis, infection, pneumonia due to 
pneumocystis jiroveci, vaccinia (disseminated; following smallpox 
immunization) 


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Neuromuscular & skeletal: Arthralgia, myalgia, myelopathy 
(subacute), osteonecrosis (with radiotherapy), osteoporosis, stress 
fracture 
Ophthalmic: Blurred vision, conjunctivitis, eye pain, visual disturbance 
Otic: Tinnitus 
Renal: Renal failure 
Respiratory: Interstitial pneumonitis (rheumatoid arthritis 1%), chronic 
obstructive pulmonary disease, cough, epistaxis, pharyngitis, 
pneumonia, pulmonary alveolitis, pulmonary disease, pulmonary 
fibrosis, respiratory failure, upper respiratory tract infection 
Miscellaneous: Fever, nodule, tissue necrosis 
8.1.11 
Nursing/Patient Implications  
Use with caution in conditions such as renal impairment, peptic ulcer 
disease, ulcerative colitis, pericardial or pleural effusion, hepatic 
impairment, or bone marrow suppression. Vesicant. 
8.1.12 
References  
lexicomp 
8.2 
Drug Name - Vinblastine 
8.2.1 
Other Names  
vinblastine sulfate 
8.2.2 
Classification  
vinka alkaloid 
8.2.3 
Mode of Action  
Binds to tubulin and inhibits microtubule formation, therefore, arresting 
the cell at metaphase by disrupting the formation of the mitotic 
spindle; it is specific for the M and S phases. Vinblastine may also 
interfere with nucleic acid and protein synthesis by blocking glutamic 
acid utilization. 
8.2.4 
Storage and Stability 
Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). 
Protect from light. Solutions reconstituted in bacteriostatic NS are 
stable for 28 days under refrigeration. 
8.2.5 
Dose Specifics 
3 mg/m2 
8.2.6 
Preparation 
Hazardous agent; use appropriate precautions for handling and 
disposal (NIOSH, 2012). Reconstitute lyophilized powder to a 
concentration of 1 mg/mL with NS or bacteriostatic NS. For infusion, 
may dilute in 50 mL NS or D5W; dilution in larger volumes (≥100 mL) 
of I.V. fluids is not recommended. 


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8.2.7 
Route of Administration 
IV infusion 
8.2.8 
Incompatibilities 
Cefepime, furosemide. 
8.2.9 
Availability  
Commercial supply. 
8.2.10 
Side Effects  
Cardiovascular: Hypertension, Angina, cerebrovascular accident, 
coronary ischemia, ECG abnormalities, limb ischemia, MI, myocardial 
ischemia, Raynaud's phenomenon 
Central nervous system: Malaise, Depression, dizziness, headache, 
neurotoxicity (duration: >24 hours), seizure, vertigo  
Dermatologic: Alopecia, Dermatitis, photosensitivity (rare), rash, skin 
blistering 
Gastrointestinal: Constipation, Abdominal pain, anorexia, diarrhea, 
gastrointestinal bleeding, hemorrhagic enterocolitis, ileus, metallic 
taste, nausea (mild), paralytic ileus, rectal bleeding, stomatitis, toxic 
megacolon, vomiting (mild) 
Endocrine & metabolic: Aspermia, hyperuricemia, SIADH  
Genitourinary: Urinary retention, Hemolytic uremic syndrome 
Hematologic: Myelosuppression, leukopenia/granulocytopenia (nadir: 
5-10 days; recovery: 7-14 days; dose-limiting toxicity), Anemia, 
thrombocytopenia (recovery within a few days), thrombotic 
thrombocytopenic purpura  
Neuromuscular & skeletal: Bone pain, jaw pain, tumor pain, Deep 
tendon reflex loss, myalgia, paresthesia, peripheral neuritis, weakness 
Ocular: Nystagmus 
Otic: Auditory damage, deafness, vestibular damage 
Respiratory: Bronchospasm, dyspnea, pharyngitis 
8.2.11 
Nursing/Patient Implications 
Vesicant. intrathecal administration is contraindicated. 
8.2.12 
References 
lexicomp 
8.3 
Gemcitabine 
8.3.1 
Other Names 
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar 
8.3.2 
Classification 
Antimetabolite (nucleoside pyrimidine analogue) 
Rev. 10/15 


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8.3.3 
Mode of Action 
Gemcitabine exhibits cell phase specificity, primarily killing cells 
undergoing DNA synthesis (S phase) and also blocking the 
progression of cells through the G1/S phase boundary. Gemcitabine 
is metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The 
cytotoxic effect of gemcitabine is attributed to a combination of two 
actions of the diphosphate and the triphosphate nucleosides, which 
leads to inhibition of DNA synthesis. First, gemcitabine diphosphate 
inhibits ribonucleotide reductase, which is responsible for catalyzing 
the reactions that generate the deoxynucleoside triphosphates for 
DNA synthesis. Inhibition of this enzyme by the diphosphate 
nucleoside causes a reduction in the concentrations of 
deoxynucleotides, including dCTP. Second, gemcitabine triphosphate 
competes with dCTP for incorporation into DNA. The reduction in the 
intracellular concentration of dCTP (by the action of the diphosphate) 
enhances the incorporation of gemcitabine triphosphate into DNA 
(self-potentiation). After the gemcitabine nucleotide is incorporated 
into DNA, only one additional nucleotide is added to the growing DNA 
strands. After this addition, there is inhibition of further DNA synthesis. 
DNA polymerase epsilon is unable to remove the gemcitabine 
nucleotide and repair the growing DNA strands (masked chain 
termination). In CEM T lymphoblastoid cells, gemcitabine induces 
internucleosomal DNA fragmentation, one of the characteristics of 
programmed cell death. 
8.3.4 
Storage and Stability 
Unreconstituted drug vials are stored at controlled room temperature 
(15ºC to 30ºC, 59ºF to 86ºF). Reconstituted solution should be stored 
at controlled room temperature and used within 24 hours. Solutions of 
gemcitabine should not be refrigerated; as crystallization may occur. 
The unused portion should be discarded. 
8.3.5 
Dose Specifics 
1000 mg/m2 IV over 30-60 minutes on Days 1 and 8 of each cycle. A 
Cycle is 21 days. 
8.3.6 
Preparation 
Reconstitute the 200 mg vial with 5ml and the 1 gm vial with 25 ml 
preservative free normal saline to make a solution containing 38 
mg/ml. Shake to dissolve. Gemcitabine may be further diluted with NS 
as per institutional standards. 
8.3.7 
Route of Administration 
IV infusion. 
8.3.8 
Incompatibilities 
No information available. 


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8.3.9 
Availability 
Gemcitabine is commercially available in 200 mg and 1 gm vials. 
8.3.10 
Side Effects 
1. Hematologic: Neutropenia, anemia, thrombocytopenia, and 
leukopenia are reported. 
2. Dermatologic: A rash is seen in about 25% of patients and is 
associated with pruritus in about 10% of patients. The rash is 
usually mild, not dose-limiting, and responds to local therapy. 
Desquamation, vesiculation, and ulceration have been reported 
rarely. Alopecia is usually minimal. Injection-site reactions. 
3. Gastrointestinal: Nausea and vomiting are reported in about two-
thirds of patients and requires therapy in about 20% of patients. It 
is rarely dose limiting, and is easily manageable with standard 
antiemetics. Diarrhea, constipation, mucositis. 
4. Hepatic: Abnormalities of hepatic transaminase enzymes occur in 
two-thirds of patients, but they are usually mild, nonprogressive, 
and rarely necessitate stopping treatment. However, gemcitabine 
should be used with caution in patients with impaired hepatic 
function. 
5. Pulmonary: Bronchospasm and/or dyspnea within a few hours of 
infusion of the drug, cough, rhinitis, pneumonitis.  
6. Neurologic: Somnolence, insomnia, paresthesia, pain. 
7. Cardiovascular: A few cases of hypotension were reported. Some 
cases of myocardial infarction, congestive heart failure, and 
arrhythmias have been reported. Peripheral edema is reported in 
about 30% of patients. Some cases of facial edema have also 
been reported. Edema is usually mild to moderate, rarely dose-
limiting, sometimes painful, and reversible after stopping 
gemcitabine treatment. 
8. Other: Flu-like symptoms are reported for about 20% of patients. 
This includes fever, headache, back pain, chills, myalgia, 
asthenia, and anorexia. Malaise and sweating are reported. 
8.3.11 
Nursing/Patient Implications 
1. If the patient reports burning at the injection site, slow down rate to 
allow the dose to run in over 1 hour. 
2. Rash can be treated with topical therapy or the administration of 
diphenhydramine prior to administration. 
3. Flu-like symptoms can be treated with acetaminophen. 
8.4 
Doxorubicin 
8.4.1 
Other Names 
Adriamycin R, Rubex R, Adriamycin RDF R, Adriamycin PFS R, 
hydroxydaunorubicin, hydroxydaunomycin, ADR. 
8.4.2 
Classification 
Anthracycline antibiotic. 


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8.4.3 
Mode of Action 
Intercalation between adjoining nucleotide pairs in the DNA helix 
causes inhibition of DNA and DNA-dependent RNA synthesis. Free 
radical generation is responsible for cardiac toxicity. Doxorubicin also 
inhibits topoisomerase II. 
8.4.4 
Storage and Stability 
Rubex or Adriamycin RDF intact vials are stable protected from light 
at room temperature. Adriamycin PFS vials must be refrigerated. 
Reconstituted solutions are stable for 24 hours at room temperature 
and 48 hours under refrigeration. The Adriamycin RDF 150 mg 
multidose vial is stable after reconstitution for 7 days at room 
temperature or 15 days if refrigerated and protected from sunlight. 
8.4.5 
Dose Specifics 
The usual dose is 30 mg/m2day 1 slow IV push. 
8.4.6 
Preparation 
Add 5, 10, 25, 50, or 75 ml of preservative-free normal saline to the 
10, 20, 50, 100, or 150 mg vial to produce a solution containing 2 
mg/ml. 
8.4.7 
Administration 
Intravenously, either as a bolus injection or as a continuous infusion 
through a central venous line. 
8.4.8 
Incompatibilities 
Physically incompatible with heparin, fluorouracil, aminophylline, 
cephalothin, dexamethasone, diazepam, hydrocortisone, and 
furosemide. 
8.4.9 
Compatibilities 
Stable with vincristine in normal saline for five days at room 
temperature protected from light. Also compatible in solution with 
cyclophosphamide. 
8.4.10 
Availability 
Commercially available as powder for injection in 10, 20, 50, 100, 150 
mg vials, and as 2 mg/ml solution for injection in 10, 20, 50, and 200 
mg vials. 
8.4.11 
Side Effects 
1. Hematologic: Leukopenia (dose-limiting), also thrombocytopenia 
and anemia. Nadir 10-14 days, recovery in 21 days. 
2. Dermatologic: Alopecia, usually complete; hyperpigmentation of 
nailbeds and dermal creases; radiation recall. 
3. Gastrointestinal: Nausea and vomiting, sometimes severe; 
anorexia, diarrhea; mucositis, especially with daily x 3 schedule. 
4. Cardiovascular: Arrhythmias, ECG changes; rare sudden death. 
Congestive heart failure due to cardiomyopathy related to total 


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cumulative dose; risk is greater with total doses > 550 mg/m2, 
mediastinal irradiation pre-existing cardiac disease, advanced 
age; risk is reduced with weekly or continuous infusion regimens. 
5. Other: Red discoloration of urine; fever; anaphylactoid reaction; 
may enhance cyclophosphamide cystitis or mercaptopurine 
hepatotoxicity. 
6. Local effects: Vesicant if extravasated; flush along vein, facial 
8.4.12 
Nursing Implications 
1. Monitor CBC, platelet counts. 
2. Vesicant - do not extravasate. Refer to extravasation protocol if 
inadvertent infiltration occurs. 
3 
Advise patient of alopecia. Instruct on how to obtain wig, 
hairpiece, etc. Hair loss generally occurs 2-4 weeks after injection 
and is usually complete. 
4. Advise patient of red discoloration of urine for 24 hours after 
administration of the drug. 
5. Administer antiemetics as indicated. 
6. Assess for stomatitis and treat symptomatically. Generally occurs 
7-10 days after injection. 
7. Be aware of "Adria" flare - most common reaction consists of an 
erythematous streak up the vein. It is associated with urticaria and 
pruritus. Occasionally the use of corticosteroids and/or 
antihistamines has been useful. 
8. Monitor for signs and symptoms of cardiomyopathy. Calculate 
total cumulative dose with each administration. 
NOTE: 
Please refer to the commercially-available package 
labeling for more information. 
8.4.13 
References 
Speth PA. Clinical pharmacokinetics of doxorubicin. Clin 
Pharmacokinetics 15:51-31, 1988. 
Von Hoff DD, et al. Risk factors for doxorubicin-induced congestive 
heart failure. Ann Intern Med 91:710-17, 1979. 
Lum BL et al. Doxorubicin: Alteration of dose scheduling as a means 
of reducing cardiotoxicity. Drug Intell Clin Pharm 19:259-64, 1985. 
ECOG 2/91 
8.5 
Cisplatin 
8.5.1 
Other Names  
Cisdiaminedichloroplatinum, Cis-diaminedichloroplatinum (II), 
diaminedichloroplatinum, cis-platinum, platinum, Platinol, Platinol-AQ, 
DDP, CDDP, DACP, NSC 119875. 
8.5.2 
Classification  
Alkylating agent 


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8.5.3 
Mode of Action  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. 
Other possible mechanisms include chelation of DNA and binding to 
cell membranes thereby stimulating immune mechanisms. 
8.5.4 
Storage and Stability  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. 
Other possible mechanisms include chelation of DNA and binding to 
cell membranes thereby stimulating immune mechanisms. 
8.5.5 
Dose Specifics  
Cisplatin will be given by IV at a dose of 70 mg/m2 IV day 1 infusion 
over at least 2 hours of each cycle (each cycle to be repeated every 3 
weeks for a maximum of 4 cycles). At the discretion of the 
investigator, cisplatin dose can be divided and given 35 mg/m2 over 
day 1 and 2. 
8.5.5.1 
Suggested supportive care for all patients on the AMVAC 
treatment arm (Arm A) are: 
Aprepitant or fosaprepitant 
Aprepitant 125 mg po day 1 and 80 mg po 
days 2 and 3 or bioequivalent Fosaprepitant 
150 mg IV day 1 only 
Ondansetron  
Or 
Palonosetron  
Ondansetron 24 mg IV Day 1 
8 mg po q8 days 4-14 prn 
Palenosetron 0.25 mg IV day 1 with 
Ondansetron 8 mg po q8h prn days 3-14. 
Dexamethasone  
12 mg  IV Day 1 
4 mg PO BID Days 2 and 3 
Compazine 
10 mg every 6 hrs prn 
Salt and Soda Mouth rinse 
1 mouthful Swish and spit 
After every meal or snack, at least 5 times 
daily. 
Proton pump inhibitor  
PO Daily or BID for duration of chemotherapy 
Benzodiapine (Ativan) 
0.5 - 1 mg q 8 hrs prn 
Intravenous hydration 
Appropriate pre- and post hydration with total 
of 2 liters of fluid should be administered.  
Electrolyte support 
Pre-treatment and repletion with potassium 
and magnesium IV / po per institutional 
guidelines 
Diruesis 
Mannitol or furosemide diuresis 
recommended per institutional guidelines 
Myeloid growth factor 
support 
Neulasta 6 mg sq 24-48 hours following 
chemotherapy is a REQUIRED component 
of this regimen 
8.5.6 
Preparation  
The desired dose of cisplatin is diluted per institutional standards. 
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8.5.7 
Administration  
Cisplatin solution should be administered over at least 2 hours. 
8.5.8 
Incompatibilities  
Amsacrine, cefepime, gallium nitrate, mesna, piperacillin, sodium 
bicarbonate, thiotepa. Cisplatin may react with aluminum which is 
found in some syringe needles or IV sets, forming a black precipitate. 
8.5.9 
Compatibilities 
Admixture: Amphotericin-B, aztreonam, carmustine, cefazolin, 
cephalothin, droperidol, etoposide, floxuridine, hydroxyzine, 
ifosphamide, leucovorin, magnesium sulfate, mannitol, potassium 
chloride. Y-site: Allopurinol, bleomycin chlorpromazine, cimetidine, 
cyclophosphamide, dexamethasone, diphenhydramine, doxapram, 
doxorubicin, famotidine, filgrastim, fludarabine, fluorouracil, 
furosemide, ganciclovir, heparin, hydromorphone, lorazepam, 
melphalan, methotrexate, methylprednisolone, metoclopramide, 
mitomycin, morphine, ondansetron, paclitaxel, prochlorperazine, 
ranitidine, sargramostim, vinblastine, vincristine, vinorelbine. 
Consult your pharmacist regarding specific concentrations 
8.5.10 
Availability  
Commercially available as a mg/mL solution in 50 and 100 mg vials. 
8.5.11 
Side Effects  
Renal: A dose-related, cumulative renal tubular injury can occur; 
adequate hydration and diuresis usually minimize the risk.  Salt-
wasting nephropathy and/or orthostatic hypotension with 
hyporeninemic hypoaldosteronism can occur in up to 10% of patients. 
Neurologic: A dose-related ototoxicity, manifested by high-frequency 
hearing loss and tinnitus, occurs in about 30% of patients.  
Paresthesias, decreased vibratory, position, and touch sensations are 
less common; particularly at cumulative doses < 400 mg/m². 
Hematologic: Mild leukopenia and thrombocytopenia occur in 25-30% 
of patients, but are rarely dose-limiting; anemia is less common.  A 
potentially fatal hemolytic uremic syndrome has been reported. 
Gastrointestinal: Severe, dose-limiting nausea and vomiting occur in 
almost 100% of patients unless adequate antiemetic prophylaxis is 
given.  Even with successful prophylaxis of acute nausea a delayed 
(72-96 hour) reaction, requiring additional therapy may occur.  
Anorexia and taste changes may also occur. 
Hypersensitivity: Allergic reactions are reported in up to 20% of 
patients Symptoms include: rash, facial edema, wheezing, 
hypotension, and tachycardia.  Severe anaphylaxis is rare. 
Other: Electrolyte wasting (magnesium, potassium and sodium), 
papilledema, optic neuritis, retrobulbar neuritis, diarrhea, mouth sores, 
hair loss, dizziness, dehydration, nail changes, fatigue, fluid retention, 
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chills, lowered white blood cell counts, rash, muscle aches, joint pain, 
headache, confusion, loss of coordination, difficulty swallowing, 
indigestion, blood clotting in veins, fainting, seizures, difficulty 
urinating. 
8.5.12 
Nursing/Patient Implications  
1. Prior to administration, assess as per local standards: 
A. Labs: CBC, platelet count, BUN, creatinine. 
B. Urine output: 100-150 mL/hr for at least 4-6 hours. 
C. Signs of ototoxicity or neurotoxicity. 
2. Administer supportive medications: 
A. Antiemetics: 5HT3 antagonists and dexamethasone 
combinations can usually be given once daily. NOTE: 
Dexamethasone dose should be reduced by 50% when 
administered with aprepitant. 
B. Hydration. 
C. Diuretics - may be ordered. 
D. ESAs are allowed as per package guidelines. 
3. Observe for signs of allergic reaction. 
8.5.13 
References  
Alberts DS. Carboplatin versus cisplatin in ovarian cancer. Semin 
Oncol 1995;22 (5 Suppl 12):88-90. 
Bonomi P. Platinum/etoposide therapy in non-small cell lung cancer. 
Oncology 1992;49 (Suppl 1):43-50. 
Dabholkar M, Reed E. Cisplatin. Cancer Chemother Biol Response 
Modifiers 1993;14:86-97. 
Fram RJ. Cisplatin and platinum analogues: recent advances. Curr 
Opin Oncol 1992;4:1073-9. 
Garrow GC, Johnson, DH. Treatment of "good risk" metastatic 
testicular cancer. Semin Oncol 1992;19:159-65. 
Markman M. Current status of intraperitoneal therapy for ovarian 
cancer. Curr Opinion Obstet Gynecol 1993;5:99-104. 
Ozols RF, et al. Advanced ovarian cancer. Dose intensity. Ann Oncol 
1993; (4 Suppl 4):49-56. 
Saxman S. Salvage therapy in recurrent testicular cancer. Semin 
Oncol 1992;19:143-7. 
Wheeler RH, Spencer S. Cisplatin plus radiation therapy. J Infusional 
Chemother 1995;5:61-6. 
8.6 
Carboplatin 
8.6.1 
Chemical Name 
Carboplatin (carboplatin for injection or platinum diamine [1,1-
cyclobutane-decarbozxylate (2—0,0’)-,(SP-4-2)]) is a platinum 


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compound used as a chemotherapeutic agent.  It will be supplied 
commercially. 
8.6.2 
Formulation 
Carboplatin is available as a sterile lyophilized powder in single-dose 
vials containing 50 mg, 150 mg, or 450 mg of carboplatin.  Each vial 
contains equal parts by weight of carboplatin and mannitol.  
Commercial supplies of carboplatin will be used in this trial. 
8.6.3 
Storage and Stability 
Intact vials of carboplatin are stable for the period indicated on the 
package when stored at room temperature (15-30C or 59-86F) and 
protected from light. 
When prepared as described above, carboplatin solutions are stable 
for 8 hours at room temperature if protected from light.  The solution 
should be discarded after 8 hours since no antibacterial preservative 
is contained in the formulation. 
8.6.4 
Dose Specifics and Administration 
All patients on protocol treatment will receive Carboplatin at AUC 5 IV 
infusion over 30-60 minutes, every 21 days for a total of 4 cycles on 
Arm B. Carboplatin dosing is by the Calvert formula¹⁸:  
Total Dose (mg) = (target AUC) x (CrCl+ 25). See Section 5.1.2 for 
information on calculation of carboplatin dose. 
NOTE: 
When calculating dose, CrCl should not exceed 125 
mL/min. Thus, maximum carboplatin dose for this protocol 
is 5 x (125+25), or 750mg. 
8.6.5 
Preparation 
Immediately before use, the contents of a carboplatin vial must be 
reconstituted with either sterile water for injection, USP, 5% dextrose 
in water, or 0.9% sodium chloride injection, USP.  The following 
shows the proper diluent volumes to be used to obtain a carboplatin 
concentration of 10 mg/mL. Carboplatin solution can be further diluted 
to concentrations as low as 0.5 mg/mL with D5W or 0.9% normal 
saline. 
Vial size 
Diluent volume 
50 mg 
5 mL 
150 mg 
15 mL 
450 mg 
45 mL 
Carboplatin reacts with aluminum to form a precipitate and cause a 
loss of potency. Therefore, needles or intravenous sets containing 
aluminum parts that may come in contact with the drug must not be 
used for the preparation or administration of carboplatin. 
8.6.6 
Availability 
Carboplatin is commercially available 
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8.6.7 
Adverse Events Associated with Carboplatin 
Incidence rates of adverse events associated with carboplatin are 
provided in the product package insert. Some of the adverse events 
expected with Carboplatin treatment are listed below. 
Hematologic: 
Myelosuppression is the major dose-limiting 
toxicity. Thrombocytopenia, neutropenia, 
leukopenia, and anemia are common, but 
typically resolve by Day 28 when carboplatin is 
given as a single agent. 
Allergic Reactions: Hypersensitivity to carboplatin has been reported 
in 2% of patients receiving the drug. Symptoms 
include rash, urticaria, erythema, pruritus, and 
rarely bronchospasm and hypotension. The 
reactions can be successfully managed with 
standard epinephrine, corticosteroid, and 
antihistamine therapy. 
Neurologic: 
Peripheral neuropathies have been observed in 
4% of patients receiving carboplatin with mild 
paresthesia being the most common. 
Gastrointestinal: 
Nausea and vomiting are the most common GI 
events; both usually resolve within 24 hours and 
respond to antiemetics.  Other GI events include 
diarrhea, weight loss, constipation, and 
gastrointestinal pain. 
Hepatic Toxicity: 
Elevated alkaline phosphatase, total bilirubin, and 
SGOT have been observed. 
Other: 
Pain and asthenia are the most common 
miscellaneous adverse events.  Alopecia has 
been reported in 3% of the patients taking 
carboplatin. 
8.7 
Pegfilgrastim 
8.7.1 
Other Names  
Neulasta 
NOTE: 
Auto injector, Neulasta, is permitted for use on this trial 
8.7.2 
Classification  
Leukocyte Growth Factor 
8.7.3 
Mode of Action  
Pegfilgrastim (Neulasta™) is a covalent conjugate of recombinant 
methionyl human G-CSF (Filgrastim) and monomethoxypolyethylene 
glycol. Both pegfilgrastim and filgrastim are colony-stimulating factors 
that act on hematopoietic cells by binding to specific cell surface 
receptors, thereby stimulating proliferation, differentiation, 
commitment, and end cell functional activation. 
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8.7.4 
Storage and Stability  
Pegfilgrastim should be stored refrigerated at 2 to 8°C (36to 46°F); 
syringes should be kept in their carton to protect from light until time of 
use. Shaking should be avoided. Before injection, pegfilgrastim 
maybe allowed to reach room temperature for a maximum of 48 hours 
but should be protected from light. Pegfilgrastim left at room 
temperature for more than 48 hours should be discarded. Freezing 
should be avoided; however, if accidentally frozen, pegfilgrastim 
should be allowed to thaw in the refrigerator before administration. If 
frozen a second time, pegfilgrastim should be discarded. 
8.7.5 
Dose Specifics  
No preparation is required for administration of pegfilgrastim. Each 
subject will receive a fixed dose of 6 mg of pegfilgrastim. The entire 
contents of the 0.6 mL prefilled syringe should be administered 
subcutaneously irrespective of the subject’s actual weight. 
8.7.6 
Preparation  
No preparation is required for administration of pegfilgrastim. Each 
subject will receive a fixed dose of 6 mg of pegfilgrastim. The entire 
contents of the 0.6 mL prefilled syringe should be administered 
subcutaneously. 
8.7.7 
Route of Administration  
The entire contents of the 0.6 mL prefilled syringe should be 
administered subcutaneously. 
8.7.8 
Availability  
Pegfilgrastim is commercially available. 
8.8 
Neulasta 
8.8.1 
Generic Name 
Pegfilgrastim 
8.8.2 
Manufacturer 
Amgen 
8.8.3 
Class 
Colony Stimulating Factor, Hematopoietic Agent 
8.8.4 
Mechanism of Action 
Stimulate the production, maturation, and activation of neutrophils to 
increase both their migration and cytotoxicity. Has prolonged duration 
of effect relative to filgrastim, and a reduced renal clearance. 
8.8.5 
Pharmacokinetics 
 
Bioavailability: 85% - 90% 
 
Tmax: 24 – 72  
 
T1/2: 15-80 hours 
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8.8.6 
Dosage Forms 
 
Single-use prefilled syringe with needle guard 
 
Sterile on-body injector* 
8.8.7 
Available Preparations 
 
Syringe: 6mg/ 0.06mL 
 
On-body injector: 6mg/ 0.6mL 
8.8.8 
Storage/Stability 
Refrigerate at 36° to 46°F in the carton to protect from light. Avoid 
freezing; avoid shaking. 
Discard syringes stored at room temperature for more than 48 hours. 
8.8.9 
Dose specifics 
Per protocol 
8.8.10 
Route of Administration 
Subcutaneous Injection 
Administer by: 
 
Health care professional 
 
On-body injector* 
8.8.11 
Interchangeable 
No 
8.8.12 
Adverse Events 
 
MSK: bone pain (25% to 45%) 
 
Cardiovascular: capillary leak syndrome 
 
Hematologic: leukocytosis (<1%), sickle cell anemia with crisis 
 
Renal: glomerulonephritis  
 
Respiratory: acute respiratory distress syndrome 
 
Other: spleen rupture 
8.8.13 
Contraindications 
Serious allergic reactions to human G-CSFs, or any component of the 
product. 
8.8.14 
Interactions 
Lithium – greater than expected increase in white blood cell count. 
 


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9. 
Statistical Considerations 
9.1 
Study Design/Primary Endpoint 
The primary objective of this study is to evaluate the complete pathologic 
response (pCR = pT0pN0) rate attained by neoadjuvant chemotherapy followed 
by extirpative surgery in patients with high-grade upper tract urothelial 
carcinoma.  There are two treatment arms, and treatments will be assigned 
based on the measured creatinine clearance (mCrCl) at baseline.  Patients with 
mCrCl > 50 ml/min will receive AMVAC (accelerated methotrexate, vinblastine, 
doxorubicin and cisplatin) for 4 cycles followed by nephroureterectomy, while 
patients with 30 ml/min ≤ mCrCl ≤ 50 ml/min will receive GCa (gemcitabine and 
carboplatin) for 4 cycles followed by nephroureterectomy.  The primary analysis 
will be performed in eligible patients who start any part of protocol therapy.  A 
sensitivity analysis will be done in eligible patients who receive at least one dose 
of chemotherapy.  There will be no direct comparison between the two treatment 
arms. 
The primary endpoint of this study is pCR rates.  Based on prior studies, a pCR 
rate of 18% would be worthy of further study, while a pCR rate of 4% would not 
justify further utilization of the treatment. With 28 eligible patients per arm, a 
treatment will be deemed promising if at least 3 pCRs are observed in a given 
arm.  Using this design, there is a 10% probability of declaring a treatment worthy 
of further study if the true pCR rate is 4%, and a 90% probability of declaring a 
treatment worthy of further study if the true pCR rate is 18% by using a one-sided 
exact binomial test. 
Per protocol patients should complete protocol therapy with nephroureterectomy 
by 60 days following chemotherapy.  However, patients who are unable to 
complete protocol therapy in this timeframe will be evaluable for response if 
surgery is within 6 months of completion of chemotherapy. Patients who undergo 
nephroureterectomy beyond 6 months of completion of chemotherapy will be 
followed for recurrence and other endpoints but not evaluable for pathologic 
response.  
9.2 
Secondary Endpoints 
The secondary endpoints include recurrence-free survival (RFS), event-free 
survival (EFS), bladder cancer-free survival, cancer-specific survival and renal 
functional outcomes.   
RFS and bladder cancer-free survival will be evaluated in patients deemed 
disease free after surgery.  RFS is defined as the time from the date of surgery to 
disease recurrence or death from any cause.  Patients alive without documented 
recurrence will be censored at the date of last disease assessment.  Bladder 
cancer-free survival is defined as the time from the date of surgery to the earlier 
of a return of bladder cancer or death from any cause.  Patients alive without 
documented bladder cancer will be censored at the date of last disease 
assessment.  EFS is defined as the time from registration to the earlier of 
recurrence, disease progression, new invasive primary cancer, or death from any 
cause.  The method of Kaplan and Meier will be used to characterize RFS, EFS 
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Cancer-specific survival is defined as the time from registration to death due to 
cancer; deaths due to other causes will be counted as competing events.  
Cancer-specific survival will be analyzed using Gray’s method and cumulative 
incidence estimates will be reported.   
Renal function outcomes and safety are also important endpoints of this study.  
The proportion of patients with renal insufficiency (CrCl < 60 ml/min) post 
chemotherapy and post nephroureterectomy as well as the proportion of patients 
with renal function improvement (CrCl < 60 ml/min at baseline and CrCl ≥ 60 
ml/min on study) will be reported along with exact binomial confidence intervals.  
The distribution of changes in renal function post chemotherapy as well as post 
surgery from baseline will also be reported.  The analysis of renal function 
outcomes will be performed among patients who receive at least one dose of 
chemotherapy.  All patients who receive any part of the treatment will be 
monitored for toxicity, and the percent of patients with various toxicities will be 
tabulated. 
9.3 
Accrual 
We propose to accrue 28 eligible patients per arm for a total of 56 eligible 
patients in this study. With about 7% allowance for ineligibility, additional 4 
patients will be accrued for a total of 60 patients. We expect to accrue 2 patients 
per month. The total accrual will be completed in 2.5 years. 
9.4 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as described in Section 5.2. 
9.5 
Gender and Ethnicity  
Based on previous data from E1804 and E4802, the anticipated accrual in 
subgroups defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
3 
4 
Not Hispanic or Latino 
13 
43 
56 
Ethnic Category: Total of all subjects 
14 
46 
60 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
0 
1 
Black or African American 
1 
3 
4 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
12 
43 
55 
Racial Category: Total of all subjects 
14 
46 
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The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 


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10. 
Submission of Biospecimens for Research 
PATIENT CONSENT: Samples are to be submitted for research studies from patients 
who answer “Yes” to “My samples and related information may be kept in a Biobank for 
use in future health research.” 
LABELING: Specimens are to be labeled clearly with the ECOG-ACRIN protocol 
number “EA8141”, patient initials, date and time of collection, and sample type. All 
sample submissions are to be logged into the ECOG-ACRIN Sample Tracking System 
(STS).  An STS-generated shipping manifest is to accompany all submissions. 
Receiving Laboratory: Samples are to be shipped to the ECOG-ACRIN Central 
Biospecimen and Pathology Facility (CBPF) at MD Anderson. 
10.1 
Submissions to the CBPF  
If these criteria cannot be met, please contact the ECOG-ACRIN CBPF 
(eacbpf@mdanderson.org) to obtain alternative submission requirements. 
10.1.1 
Sample Preparation 
A. TUMOR TISSUE 
The submitting pathologist and clinical research associate should 
refer to Appendix I (Pathology Submission Guidelines) for 
guidelines and summary of submission requirements.  
Tumor tissue: One representative formalin-fixed paraffin-
embedded primary tumor block is requested from: 
 
Pre-trial diagnostic biopsy, should be submitted within four (4) 
weeks following registration 
 
Surgery, should be submitted within four (4) weeks following 
surgery 
NOTE: 
If there is no residual tumor found in the surgical 
specimen please go into the STS and click on ‘Can't 
Submit’ and write in the comment section ‘no residual 
tumor found in specimen.’ Please send the pathology 
report to the CBPF for documentation and note on the 
cover letter that no block is being submitted as there 
was no residual tumor. 
NOTE: 
If blocks are unavailable for submission, the following 
alternative submission is requested per availability: one 
(1) H&E, twenty (20) unstained slides 4µm thick and 
two (2) 4mm cores (if enough tissue is available). 
Forms and Reports (Submit with all pathology submissions): 
1. A copy of the surgical (if appropriate) and pathology reports. 
2. Immunologic studies, if available. 
3. Other Immunologic and cytologic reports. 
4. STS-generated shipping manifest. 
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B. BLOOD SUBMISSIONS  
Blood is to be collected at the following timepoints: 
 
After registration, prior to start of treatment 
 
End of chemotherapy, prior to surgery 
 
2-6 weeks post-surgery 
It is requested that samples be batched at > -70oC and shipped on 
dry ice on a quarterly basis. If samples must be stored at -20oC, 
ship on dry ice within one (1) week of draw. 
Draw the blood tubes in the following order: no anti-coagulant (red 
top or SST), potassium EDTA (EDTA, purple top). Note that 
vacutainer top colors are for BD vacutainers. Verify tube contents 
prior to the collection of any samples. 
1. Serum   
 
At each time point specified, draw one (1) 10mL vacutainer 
(no anti-coagulant)   
 
Allow to coagulate at room temperature for 20 minutes 
 
Separate by centrifugation at approximately 1200g x 20 
minutes 
 
Aliquot serum into four cryovials. Discard residual cells  
 
Freeze the serum, at > -70oC preferred 
2. Plasma, EDTA   
 
At each time point specified, draw  10mL plastic EDTA 
vacutainer 
 
Separate by centrifugation at approximately 1200g x 20 
minutes 
 
Aliquot plasma into four (4) cryovials. 
 
Replace the cap on the vacutainer  
 
Freeze the plasma and residual cells (WBC + RBC) at  
> -70oC preferred 
3. Whole Blood, EDTA   
 
At each time point specified, draw  10mL plastic EDTA 
vacutainer 
 
Freeze at > -70oC preferred 
C. URINE SUBMISSIONS  
Urine is to be collected at the following time points: 
 
After registration, prior to start of treatment 
 
End of chemotherapy, prior to surgery 
 
2-6 weeks post-surgery 
At each time point specified, collect 20-50mL of urine fresh catch 
 
It is requested that the urine be aliquoted into four cryovials. 
However, one large cryovial may be submitted. 
Ship Frozen   
Ship Frozen   
Ship Frozen   
Ship Frozen   
Ship Frozen   


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 
Freeze the urine, > -70oC preferred, and ship with the blood 
samples 
10.1.2 
Shipping Guidelines 
The requested initial diagnostic FFPE tumor tissue materials, reports 
and forms are to be submitted at ambient within four (4) weeks 
following patient registration. 
Frozen blood samples and frozen urine are to be shipped overnight 
on dry ice. 
The receiving laboratory is not available to receive shipments over 
holidays or weekends.  Therefore, samples are only to be shipped via 
overnight courier Sunday through Thursdays (excluding a day before 
a holiday). 
Ship using the CBPF's FedEx account using the FedEx on-line Ship 
Manager. 
Access to the shipping account for shipments to the CBPF can only 
be obtained by logging into fedex.com with an account issued by the 
CBPF. For security reasons, the account number will no longer be 
given out in protocols, over the phone, or via email. If your site needs 
to have an account created, please contact the CBPF by email at 
eacbpf@mdanderson.org. 
Shipping Address: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
Toll Free Phone: (844) 744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
10.2 
ECOG-ACRIN Sample Tracking System 
All specimens submitted must be entered and tracked using the ECOG-
ACRIN Sample Tracking System. 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important:  Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software.  A 
user manual and interactive demo are available by clicking this link: 
Rev. 6/16 
Rev. 6/16 


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http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu.  
Study Specific Notes 
If STS is unavailable at time of sample submissions, a completed Generic 
Specimen Submission Form (#2981) is to be submitted in lieu of the STS 
shipping manifest. Include site contact information on the form. Notify the 
laboratory of the shipment by faxing a copy of the completed form to the 
laboratory the day of shipping. Indicate the appropriate receiving laboratory on 
the submission form: 
 
ECOG-ACRIN CBPF 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.3 
Use of Specimens in Research 
Specimens submitted from patients who consented to allow their specimens to 
be used for future research studies will be retained in an NCI-affiliated central 
repository. Specimens submitted on this trial will be retained at the ECOG-
ACRIN Central Biospecimen and Pathology Facility at MD Anderson.  
Requests for the use of these specimens will require a correlative science 
proposal (or a protocol amendment) detailing the scientific hypothesis, research 
plan, assay methods for use of the biospecimens, and a complete statistical 
section (with adequate power justification and analysis plan) which would be 
submitted and reviewed by the cooperative group and CTEP in accordance with 
the NCI National Clinical Trials Network (NCTN) review process. 
Possible future studies include: 
 
Tumor RNA/DNA analysis  
 
Circulating free tumor RNA/DNA in plasma 
 
Circulating free tumor RNA/DNA in urine 
Specimens submitted will be processed to maximize their utility for research 
projects. Tissue processing may include, but not limited to, extraction of DNA and 
RNA and construction of tissue microarrays (TMAs). DNA, RNA, and plasma (if 
appropriate) will be isolated from the submitted peripheral blood samples. 
Tumor blocks will be available for purposes of individual patient management on 
specific written request.  
If future use is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. Tissue samples may be available 
for return upon written request and other samples may be destroyed per protocol 
of the given lab. Samples may also be anonymized (stripped of all identifiers) and 
used for instrument calibration or other quality control measures which are not 
published or linked to the clinical trial. 


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10.4 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory.  
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office – Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office – Boston.


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11. 
Electronic Data Capture 
Please refer to the EA8141 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
1. Adibi M, Youssef R, Shariat SF, et al: Oncological outcomes after radical 
nephroureterectomy for upper tract urothelial carcinoma: Comparison over the three 
decades. Int J Urol 19:1060-6, 2012 
2. Margulis V, Shariat SF, Matin SF, et al: Outcomes of radical nephroureterectomy: a 
series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 115:1224-
33, 2009 
3. 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 349:859-66, 2003 
4. Millikan R, Dinney C, Swanson D, et al: Integrated therapy for locally advanced 
bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC 
versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 
19:4005-13, 2001 
5. Matin SF, Margulis V, Kamat A, et al: Incidence of downstaging and complete 
remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell 
carcinoma. Cancer 116:3127-34, 2010 
6. Youssef RF, Shariat SF, Lotan Y, et al: Upper urinary tract urothelial carcinoma with 
loco-regional nodal metastases: insights from the Upper Tract Urothelial Carcinoma 
Collaboration. BJU Int 108:1286-91, 2011 
7. Kitamura H, Igarashi M, Tanaka T, et al: A Role for Preoperative Systemic 
Chemotherapy in Node-positive Upper Tract Urothelial Carcinoma Treated with 
Radical Nephroureterectomy. Jpn J Clin Oncol, 2012 
8. Siefker-Radtke AO, Kamat AM, Corn PG, et al: Neoadjuvant chemotherapy with DD-
MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at 
the University of Texas M. D. Anderson Cancer Center. ASCO Meeting Abstracts 
30:4523, 2012 
9. Huang WC, Levey AS, Serio AM, et al: Chronic kidney disease after nephrectomy in 
patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol 
7:735-40, 2006 
10. Lane BR, Smith AK, Larson BT, et al: Chronic kidney disease after 
nephroureterectomy for upper tract urothelial carcinoma and implications for the 
administration of perioperative chemotherapy. Cancer 116:2967-73, 2010 


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11. Margulis V, Youssef RF, Karakiewicz PI, et al: Preoperative multivariable prognostic 
model for prediction of nonorgan confined urothelial carcinoma of the upper urinary 
tract. J Urol 184:453-8, 2010 
12. Brien JC, Shariat SF, Herman MP, et al: Preoperative hydronephrosis, ureteroscopic 
biopsy grade and urinary cytology can improve prediction of advanced upper tract 
urothelial carcinoma. J Urol 184:69-73, 2010 
13. Brown GA, Matin SF, Busby JE, et al: Ability of clinical grade to predict final 
pathologic stage in upper urinary tract transitional cell carcinoma: implications for 
therapy. Urology 70:252-6, 2007 
14. Alva AS, Matin SF, Lerner SP, et al: Perioperative chemotherapy for upper tract 
urothelial cancer. Nat Rev Urol 9:266-73, 2012 
15. De Santis M, Bellmunt J, Mead G, et al: Randomized phase II/III trial assessing 
gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with 
advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results 
of EORTC study 30986. J Clin Oncol 27:5634-9, 2009 
16. Koie T, Ohyama C, Hashimoto Y, et al: Efficacies and safety of neoadjuvant 
gemcitabine plus carboplatin followed by immediate cystectomy in patients with 
muscle-invasive bladder cancer, including those unfit for cisplatin: a prospective 
single-arm study. Int J Clin Oncol 18:724-30, 2013 
17. Kondo T, Nakazawa H, Ito F, et al: Impact of the extent of regional 
lymphadenectomy on the survival of patients with urothelial carcinoma of the upper 
urinary tract. J Urol 178:1212-7; discussion 1217, 2007 
18. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective 
evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748-
1756. 


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A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by 
Extirpative Surgery for Patients with High Grade Upper Tract Urothelial Carcinoma 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
Rev. 6/16 


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Guidelines for Submission of Pathology Materials 
EA8141: A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy 
Followed by Extirpative Surgery for Patients with High Grade Urothelial Cancer of the 
Upper Urinary Tract 
A. The following materials are to be submitted: 
Provide adequate patient identifying information with the submitted pathology materials. 
At a minimum the following information must be provided with all pathology submissions: 
 
Patient name (last, first). Initials must be provided at a minimum 
 
Protocol number EA8141 and protocol-specific ECOG-ACRIN patient ID number 
 
Site’s pathology identification numbers 
 
Site information, including pathologist and site contact are to be provided on the 
Submission form and in STS 
Prior to Start of Treatment  
1. Institutional pathology report, including immunological reports if available 
2. STS-generated shipping manifest 
3. Tumor tissue block from the diagnostic ureteroscopic or percutaneous biopsy and/or 
cytology of the primary tumor. 
NOTE: 
If a block is unavailable for submission, submit the following: one (1) 
H&E, twenty (20) unstained slides 4µm thick and two (2) 4mm cores (if 
enough tissue is available). 
Surgery  
4. Institutional pathology report, including immunological reports if available (if enough 
tissue is available) 
5. Surgical Report 
6. STS-generated shipping manifest 
7. Tumor tissue block  
NOTE: 
If a block is unavailable for submission, submit the following: one (1) 
H&E, twenty (20) unstained slides 4µm thick and two (2) 4mm cores. 
B. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN 
Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biospecimen and Pathology 
Facility (CBPF) by telephone: (844) 744-2420, by fax: (713) 563-6506, or by email: 
eacbpf@mdanderson.org. 
Reminder: All biospecimen submissions must be logged and tracked in the ECOG-
ACRIN Sample Tracking System (STS). 


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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA8141: A Prospective Phase II 
Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative 
Surgery for Patients with High Grade Urothelial Cancer of the Upper 
Urinary Tract 
The patient named on the attached Generic Specimen Material Submission Form 
(#2981) has been entered onto an ECOG-ACRIN protocol by 
_____________________________ (ECOG-ACRIN Investigator). This protocol requires 
the submission of pathology materials for laboratory research studies. 
Please complete the Submission Form, keep a copy for your records and return the 
completed Submission Form, the surgical pathology report(s), the slides and/or blocks 
and any other required material (see List of Required Material) to the Clinical Research 
Associate (CRA). The CRA will forward all required pathology material to the ECOG-
ACRIN Central Biospecimen and Pathology Facility (CBPF) at MD Anderson. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN CBPF for 
future studies. Paraffin blocks will be returned upon written request for purposes of 
patient management. 
Please note: Since blocks are being used for research, in some cases the material may 
be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the CBPF at (844) 744-
2420 or Fax (713) 563-6506. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 


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A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by 
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Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 


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A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by 
Extirpative Surgery for Patients with High Grade Upper Tract Urothelial Carcinoma 
 
Appendix III 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 


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A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by 
Extirpative Surgery for Patients with High Grade Upper Tract Urothelial Carcinoma 
 
Appendix IV 
 
Lab Study EA8141LGS1 
Use of Next Generation Sequencing as a Urinary Biomarker Molecular Correlate 
for Pathologic Complete Response to Neoadjuvant Chemotherapy in Upper Tract 
Urothelial Carcinoma 
Study PI: Philip H. Abbosh, MD, PhD, Fox Chase Cancer Center 
Statistician: Eric Ross, PhD, Fox Chase Cancer Center 
Aim: 
To define genetic correlates of stage, grade, and pathologic complete response (pCR) 
after neoadjuvant platinum-based chemotherapy (NAC) in high grade UTUCC using next 
generation sequencing (NGS) of urinary DNA (uDNA). 
Background: 
The explosion in the identification of new drug targets in many cancers has been fueled 
in large part by NGS efforts. However, given the difficulty of access to preoperative 
tissue and the rarity of the disease, NGS studies of UTUCC has been absent with a few 
exceptions, thus contributing to the lack of improvements or new therapies in this 
disease. 
Although accurate clinical staging is difficult in bladder cancer, the problem is 
compounded in UTUCC because of difficulty in accessing and navigating the upper 
urinary tract. Often only small pieces of tissue from a heterogeneous tumor are 
available, making pathologic assignment of T-stage or histologic grade (and therefore 
therapy assignment) unreliable. Biopsy for the identification of high grade UTUCC is 
specific but not sensitive1-4. Urinary biomarkers which associate with grade or stage 
could lessen some of the diagnostic dilemmas surrounding UTUCC and provide 
predictive or prognostic biomarkers which are completely lacking in UTUCC as well as 
MIBC. For example, several genetic alterations are enriched only in non-muscle-invasive 
bladder cancer (NMIBC) or MIBC but not both5. These might be used to more effectively 
stage high grade T1 tumors if they genetically resemble muscle-invasive tumors. 
Enhanced clinical T-staging in UTUCC might thus more appropriately triage patients into 
endoscopic, extirpative, or multidisciplinary treatments. uDNA-based biomarkers would 
make for a facile, reproducible, and robust diagnostic medium in the management of 
UTUCC. 
In preliminary studies in MIBC, our group has shown that uDNA can be used to identify 
mutations in key bladder cancer genes, and quantitate their presence or clearance after 
NAC. Clearance of mutations from uDNA associates with pCR, while persistence of 
mutations correlates with persistence of disease. Our approach was recently funded by 
the NIH for further study in MIBC patients (R21CA218976). I now seek to apply the 
same approach in UTUCC patients treated in EA8141 as proposed in my recently-
funded Bladder Cancer Advocacy Network Young Investigator Award 2018. This 
approach in the future could be used to identify candidate UTUCC patients who achieve 
pCR after NAC and possibly steer them into organ preservation algorithms and avoid 


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radical nephroureterectomy. Enumeration of somatic variants in high grade/high stage 
UTUCCs such as those which are being recruited in EA8141 would also serve to help 
develop uDNA-based biomarkers to enhance clinical staging both at time of diagnosis 
(invasive vs noninvasive) and after NAC (pCR vs residual disease). Since several 
mutated genes in urothelial cancers are targetable with currently available drugs, uDNA 
might also one day be used for predictive biomarkers of response to these therapies. 
I propose to perform targeted NGS of uDNA isolated from urine specimens collected in 
the EA8141 study to define molecular correlates of T-stage and/or pCR after NAC. 
These molecular correlates might one day be used in conjunction with traditional clinical 
staging for precision medicine, precision surgery, or organ preservation approaches to 
treating UTUCC. 
Therefore, I propose to perform targeted exome sequencing of uDNA from patients 
treated in the EA8141 trial for the purpose of annotation of mutations before and after 
administration of NAC. Several biomarkers may be evaluable using this type of data 
including enhanced clinical T-staging, prospective biomarkers of cisplatin response (i.e. 
‘who will respond to NAC?’), as well as retrospective biomarkers (i.e. ‘who responded to 
chemotherapy?’). From a basic research standpoint, this endeavor will provide insight 
into upper tract biology and chemoresponse. From a clinical/translational standpoint, it 
will set the stage for personalized medicine algorithms which assign targeted therapies 
based on susceptibility-conferring mutations, and for personalized surgical algorithms 
possibly including surgical avoidance in patients who are complete responders at the 
molecular level. 
Rationale: 
Layering “genetic staging” onto clinical staging at the time of diagnosis of high grade 
UTUCC would deepen the clinicians understanding of each patient’s disease. In the 
future, if targeted therapies are to be applied to urothelial cancers, uDNA would be a 
natural source of companion biomarkers.  Additionally, if patients achieve pCR after 
NAC, then there will be no residual source of tumor to shed variant DNA into the urine. 
Pre-surgical identification of these complete responders might allow for nephron-
preserving approaches to UTUCC treatment. Additionally, follow up uDNA sampling 
might be used to identify subclinical recurrence and allow for early salvage 
nephroureterectomy. 
Preliminary Data 
Method: A panel of 50 
MIBC 
genes 
was 
selected for targeted 
NGS by virtue of being 
TCGA-nominated 
drivers6 or drivers in 
other cancers that are 
frequently mutated in 
MIBC7 (right). Mutation 
of at least one panel 
gene is present in 99% 
of TCGA MIBC tumors 
with a median of 4 
variants/tumor. 
HaloplexHS 
(Agilent) 


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was chosen for sequencing library preparation because it uses single molecule tags, 
which greatly enhances the sensitivity of variant detection, well below the Taq 
polymerase error rate8, 9. This allows for highly accurate variant calling by “stacking” 
PCR-duplicates to create consensus sequences.  Variants are only called if they are 
seen in all of the family members (true PCR duplicates) which comprise a consensus 
sequence because false calls arising from Taq errors will occur in <100% of the family 
members. Single molecule tags also allow for true depth-of-sequencing by counting the 
number of unique tags for each fragment or base. This makes variant detection highly 
accurate even at low variant allele fraction (VAF) which is expected after endoscopic 
debulking and/or NAC. 
Urine DNA (uDNA) was isolated from urine from 6 patients with upper tract urothelial cell 
carcinoma (UTUCC) before and after AMVAC treatment on Dr. Plimack’s trial 
(NCT01031420). 
 
Urine 
samples from this trial were 
centrifuged, and the pellets 
were used for other studies.  
The urine supernatants (4-8 mL 
of urine) were used to isolate 
uDNA.  This resulted in an 
average yield of 3.6 µg of DNA 
per sample (12 samples; range 
540 ng to 8.4 ug).  In addition, 
germline DNA was isolated 
from white blood cells. These 
three 
DNA 
sources 
were 
subjected to sequencing using 
the 50-gene panel.  Median 
depth of sequencing was 775x for pre-AMVAC samples (range 80 to 1307x), 456x for 
post-AMVAC samples (range 280-1352x), and 762x for germline (range 166 to 1023x). 
Pre-AMVAC variants in the uDNA were identified using SureCall.  These variants were 
compared against germline to filter SNPs, sequencing errors, and rare variants that may 
be associated with clonal. hematopoiesis of indeterminant potential10. Using this 
approach, 106 variants (hereafter called mutations) were identified (median 16.5, range 
3 to 38).  All six samples had evidence of branched evolutionary tumor growth as 
described by Gerlinger et al11, 12. This manifested as multiple distinct variants in the 
same gene (KMT2C, KMT2D, ARID1A, etc), often in multiple genes.   
Mutation 
persistence 
associates 
with 
tumor 
persistence. To determine if 
mutations 
persisted 
or 
cleared 
after 
neoadjuvant 
chemotherapy, post-AMVAC 
sequencing libraries were 
searched using the genomic 
coordinates 
of 
the 
pre-
AMVAC mutations.  Under 
the same calling conditions 
used 
for 
the 
previously 
described 
bladder 
cancer 
Figure 1: uDNA and germline DNA from 6 patients was subjected to 
targeted sequencing and mutation clearance/persistence status was 
assigned to each subject as described.  Subject-level mutation 
persistence was identified in 4 of 5 nonresponders.  Additionally, 
mutations associating with high-grade UTUCC are present in 5 of 6 
patients with high grade disease. 
Figure 2:  Mutation 
clearance 
status 
was correlated with 
responder status.  In 
analysis 
of 
the 
combined 
cohorts, 
the 
biomarker 
is 
strongly associated 
with 
responder 
status 
(p=0.0037, 
Fisher’s exact test). 


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preliminary data (at least 3 variant reads, at least 30 reads per site, Phred>30, mapping 
quality>30, strand bias<2:1), each pre-AMVAC mutation clearance or persistence status 
in the post-AMVAC urine sample was ascribed at the mutation level.   Subject-level 
mutation clearance was assigned only if all mutations demonstrated mutation clearance.  
Persistence of even one pre-AMVAC mutation in the post-AMVAC sample assigns 
subjects to mutation persistence status.  Mutation persistence was identified in 4 of 5 
nonresponders (Figure 1). Mutation clearance was identified in the single complete 
responder and one nonresponder.  This translates to an 80% sensitivity for identifying 
patients with residual disease, and 83.3% accuracy of the biomarker test.  In combined 
analysis of the UTUCC cohort described here and an additional 9 patients with MIBC, 
mutation persistence status translates to a 91% sensitivity for identifying patients with 
residual disease and 93% accuracy for the biomarker test. Combined cohort analysis 
shows that the biomarker strongly associates with responder status (p=0.0037, Fisher’s 
exact test; Figure 2).  Cautious optimism is being exercised because of the small cohort 
size, and additional patients with MIBC are being studied. 
Mutations associated with high grade disease are detectable in high grade disease. 
Additional analysis was performed to determine if mutations associated with grade. All 
UTUCC in the AMVAC trial were high grade.  Mutations in TP53, HRAS, ATM, CDKN1A, 
and deletion of CDKN2A are highly specific for high grade UTUCC, whereas FGFR3 
hotspot mutations are present in both high and low grade UTUCC13, 14.  FGFR3 
mutations, however, are much more common in low grade tumors (>90%) vs high grade 
tumors (10-15%).  Mutations in genes associated with high grade disease were identified 
in 5 of 6 AMVAC patients’ pre-AMVAC urine.  An FGFR3 hotspot mutation was identified 
in the lone patient without high-grade genetics.  This approach may therefore also be 
useful in assigning grade to disease using urine as a diagnostic medium. 
Mutations in tissue are represented in the urine.  Twelve MIBC cases where pre-AMVAC 
urine was available underwent whole exome sequencing of the tissue.  In the tissue, 64 
mutations in tissue (MT) were identified, and 39 of these 64 mutations (61%) were 
detected in the pre-AMVAC uDNA (MU). Additional MU were identified that were not 
called in the tissue.  Ten of the 64 MT were subclonal in the tissue; 5 of 10 subclonal MT 
were identified in uDNA. Two MT undetected in urine had <100x coverage in uDNA deep 
sequencing. Although no whole exome sequencing has been performed on UTUCC 
samples to similarly validate the approach, we expect to find a similar diagnostic overlap 
between MT and MU when we sequence a cohort of UTUCC patients in collaboration 
with Surena Matin, MD (MD Anderson Cancer Center, Houston).  In addition, most 
UTUCC patients had well-known hotspot mutations in either the TERT promoter, HRAS, 
TP53, or FGFR3, which suggests that some/most of the other identified variants are true 
variants.   
Experimental Plan: 
Specimens:  The following specimens from patients who consented on EA8141 to allow 
their specimens to be used for future research will be utilized for these assessments: 
 
Pre- and post-NAC urine, 4-8 mL 
 
Germline DNA isolated from EDTA whole blood or PBMCs isolated from whole 
blood. 
No samples are expected to be exhausted. 
Specimen Preparation: At the time of analysis, DNA will be isolated from 8mL (or 4mL if 
8mL is not available) of urine and from blood cells collected from each patient.  uDNA 


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quantity/quality will be measured OD260/280/230. dsDNA will be quantified using Qubit 
(Invitrogen).   
Sequencing: Germline DNA and pre- and post-chemotherapy uDNA sequencing libraries 
will be generated using the HaloPlexHS kit. Captured and pooled specimens will be 
subjected to targeted sequencing on the HiSeq 2500 (Illumina) which is housed within 
the Fox Chase Cancer Center Genomics Facility. 100 bp paired-end reads will be used 
to ensure complete coverage of fragments to a depth of 1000x. This depth of coverage 
was quite adequate to detect mutations in preliminary studies.   
Mutation Calling: Agilent provides variant calling software, SureCall, to detangle PCR 
duplicates which are identified using single molecule tags and call variants from 
HaloPlexHS sequencing output. Variants will be filtered out if they have <30 reads at the 
variant base, <3 variant reads, Phred <30, mapping quality <30, or strand bias >2:1 to 
maintain high quality of the called variants. Variants remaining after de-duplication, 
quality filters, and SNP removal will be considered true variants. Under these conditions, 
500x-coverage will reliably detect a 0.01 VAF allele 87.6% of the time based on Poisson 
statistics. Similarly, 1000x-coverage will reliably detect a 0.01 VAF allele 99.7% of the 
time.  For reference, the lowest VAF was 0.02 in the preliminary specimens excluding 
specimen #16pre, which missed two variants as the result of a technical error. Pre- and 
post-NAC sequences will be filtered against the germline to remove SNPs.   
Description of the High Grade UTUCC Genome: With this limited but relevant panel of 
genes, commonly mutated genes in high grade UTUCC will be identified. Some 
correlation to chemoresponse may be feasible for candidate DNA repair genes such as 
ERCC2 or ATM/FANCC/RB1.  
Evaluation of Mutation Clearance: Patients’ specimens will be analyzed to determine if 
mutation clearance or persistence occurred. Test negative and test positive cases will be 
separated into true responders and true non responders. Fisher’s exact test will be used 
to determine if mutation clearance/persistence identifies complete responders. Statistical 
analysis will be performed by ECOG/ACRIN statisticians supported by Dr. Abbosh.   
Sequence Validation: PCR products spanning NGS-identified variants will be amplified 
from uDNA using specific primer pairs and Sanger sequenced to confirm specificity of 
NGS findings for 10% of the variants. If variants are not identified, tumor tissue from 
nephroureterectomy specimens will be requested form EA8141 for confirmation of 
variants. Given that many variants identified in the preliminary data were found at low 
frequencies, amplicon-based NGS approaches may be necessary instead.   
Feasibility: The sequencing approach chosen to study urine samples from patients with 
urothelial cancer of the upper tract or bladder appears to be robust in pilot studies.  The 
main feasibility concern now becomes whether there will be adequate DNA isolated from 
the urine specimens to accomplish quality sequencing.  Several factors may impact DNA 
yield. In preliminary studies cellular debris was removed prior to freeze-thaw and NGS. 
In contrast, EA8141 bio-specimen processing and storage protocol does not involve 
separation of cells and debris from urine supernatant. One freeze-thaw cycle is 
anticipated to lyse intact cells (both malignant and benign), thus releasing more DNA. 
This may increase yield, but the impact on urine variant allele frequency (VAFU) may 
increase or decrease. For instance, if the intact cells are mostly normal urothelial cells or 
malignant cells, the VAFU may decrease or decrease, respectively.  Also, nephrostomy 
tubes placed to treat urinary obstruction may decrease the amount of shed uDNA if urine 
from the collecting system is diverted from the bladder (where it will be voided), whereas 
stents may increase DNA yield by promoting antegrade drainage. Lastly, uDNA used in 


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generation of preliminary data was previously isolated after ‘debulking’ by TURBT and 
still there was adequate template for sequencing.  Pre-chemotherapy UTUCC tumors 
probably retain a greater percentage of initial tumor bulk when compared to MIBC since 
endoscopic diagnostic or ablative procedures are probably less effective than TURBT. 
Sample size and statistical considerations: It is anticipated that 30 patients will have 
adequate specimens for study. pCR rates for NAC in UTUCC patients is historically 12-
33%15-18. Therefore, of the 30 patients, I anticipate 24 patients (80%) will have residual 
disease identified in their nephroureterctomy specimen (the EA8141 investigators 
expected 18% of patients to achieve pCR). Because a clinician would want to be very 
sure that a negative 
test (no residual 
mutations detected) is 
highly reassuring that 
there is no disease 
present, the statistical 
analysis is based on the true positive rate (TPR; ie sensitivity).  These 24 anticipated 
patients with residual disease will be used to estimate the TPR for the test (where the 
test positively identifies residual disease). The alternative hypothesis is 90% TPR, and 
there is a reasonably high power to detect a difference from the null hypothesis with a 
type I error of ≤0.1. In reality, the test is likely not clinically useful if sensitivity is <70%. 
Significance: 
The proposal outlined here will provide a genetic roadmap for high-grade UTUCC and its 
potential biomarkers, which are sorely needed for a disease where staging and grading 
is so difficult. It will also provide the basis for further studies into the nature of 
chemosensitivity and resistance in UTUCC. Prospective identification of chemosensitive 
tumors will lead to improvements in UTUCC patients in several respects: new 
opportunities might be identified to shuttle putative nonresponders to targeted therapies 
or immediate surgery; and nephron-sparing approaches might be within reach if 
chemotherapy reliably results in pCR as detected by mutation clearance; larger studies 
sequencing the whole exome through the urine could be undertaken to identify putative 
biomarkers of prospective response such as mutations in ERCC219 or other DNA repair 
genes20. 
Conclusion and Future Studies: 
Described here is a robust method to characterize the UTUCC genomes of patients 
undergoing neoadjuvant chemotherapy and perform correlative studies to determine if 
urine biomarkers enhance clinical staging before or after chemotherapy.  Correlations of 
mutations to long term outcomes and evaluation of predictive and prognostic alterations 
would be undertaken as follow up increases. Additionally, work will be ongoing in similar 
analyses on specimens from MIBC patients and might result in improvements to the 
technology and analysis pipeline prior to initiating studies on UTUCC specimens. Lastly, 
data will be made publically available after publication to serve as a resource for other 
scientists or clinicians.  Although the sample size is inadequate to establish a clinically 
useful test, this cohort will be combined with other cohorts which have been committed 
by collaborators to achieve stronger power.  If the accuracy of the test is confirmed, 
larger prospective studies will be sought to establish the test as an enhancement to 
clinical staging and potentially use chemotherapy for curative intent. 


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