Clinical trial NCT01524991
Conditions: Urothelial Carcinoma
Sponsor: Hoosier Cancer Research Network
Start date: 2012-01-01; Completion date: 2018-12-31
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Gemcitabine plus cisplatin is standard treatment for advanced urothelial cancer. Ipilimumab has shown intriguing activity as neoadjuvant therapy in patients with clinically localized bladder cancer undergoing radical cystectomy. The combination of gemcitabine, cisplatin, plus ipilimumab may build on the chemosensitivity of urothelial carcinoma to produce more durable responses and improved outcomes.

Detailed description:
OUTLINE: This is a multi-center study

Gemcitabine 1000 mg/m2 Days 1 \& 8 Cisplatin 70 mg/m2 Day 1 Ipilimumab 10 mg/kg Day 1 (start cycle 3)

Treatment during the induction phase will be administered in six 21-day cycles. During cycles 1 and 2, gemcitabine plus cisplatin will be administered WITHOUT ipilimumab. During cycles 3-6, combination therapy with gemcitabine, cisplatin, plus ipilimumab will be administered. Patients without evidence of disease progression (by irRC) after completion cycle 6 will continue single-agent ipilimumab maintenance every 3 months.

Karnofsky performance status (KPS) ≥ 80% within 14 days prior to registration for protocol therapy.

Life Expectancy: Not Specified

Hematopoietic:

* White blood cell count (WBC) ≥ 3.5K/mm3
* Hemoglobin (Hgb) ≥ 9 g/dL
* Platelets ≥ 100K/mm3
* Absolute neutrophil count (ANC) ≥ 1.5k/mm3

Hepatic:

* Bilirubin ≤ 1.5 times x Upper Limit of Normal (ULN) (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
* Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN. NOTE: If the patient has liver metastases present, then ≤ 5 x ULN

Renal:

* Calculated creatinine clearance of ≥ 55 cc/min using the Cockcroft-Gault formula

Cardiovascular: Not Specified

Arms: arm 1: Gemcitabine 1000 mg/m2 Days 1 \& 8 Cisplatin 70 mg/m2 Day 1 Ipilimumab 10 mg/kg Day 1 (start cycle 3)
Interventions: intervention 1: Gemcitabine intervention 2: Cisplatin intervention 3: Ipilimumab
Intervention descriptions: intervention 1: Gemcitabine 1000 mg/m2 Days 1 \& 8 (all cycles) intervention 2: Cisplatin 70 mg/m2 Day 1 (all cycles) intervention 3: Ipilimumab 10 mg/kg Day 1 (start cycle 3)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
Phase II Trial of Gemcitabine, Cisplatin, plus Ipilimumab as First-line 
Treatment for Patients with Metastatic Urothelial Carcinoma 
Hoosier Cancer Research Network GU10-148 
 
 
Sponsor Investigator 
Matthew D. Galsky, MD 
Mount Sinai School of Medicine/Tisch Cancer Institute 
                                      
Co-Investigators  
Noah Hahn, MD 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins  
Guru Sonpavde, MD 
The University of Alabama at Birmingham 
 
Statistician 
Ziyue Liu, PhD 
Indiana University, School of Medicine 
 
Trial Supported by Bristol-Myers Squibb 
 
 
Investigational New Drug (IND) Application #   
                                                                           IND Exempt  
 
 
 
Initial Protocol Version Date: 19JUL2011 
Amendment Version Date:   26APR2013  
Amendment Version Date: 22May2014   
 
 


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PROTOCOL SIGNATURE PAGE  
 
Protocol title: Phase II Trial of Gemcitabine, Cisplatin, plus Ipilimumab as First-line Treatment for 
Patients with Metastatic Urothelial Carcinoma 
 
 
VERSION DATE:  22MAY2014 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual. 
I will accept the monitor’s overseeing of the study. I will promptly submit the protocol to 
applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Investigator 
 
 
 
 
 
       Date 
 
 
____________________________________ 
 Investigator Name (print or type) 
 
 
____________________________________ 
 Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND EMAIL TO HOOSIER CANCER RESEARCH NETWORK 
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to Hoosier Cancer Research Network and keep a record 
for your files. 


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STUDY SYNOPSIS 
 
Hoosier Cancer Research Network Protocol: GU10-148 
TITLE 
 Protocol title: Phase II Trial of Gemcitabine, Cisplatin, plus Ipilimumab as First-line 
Treatment for Patients with Metastatic Urothelial Carcinoma 
 
STUDY PHASE  
Phase II 
OBJECTIVES 
Primary Objective: 
 To determine the 1-year overall survival of patients with advanced/metastatic 
urothelial carcinoma treated with gemcitabine, cisplatin, plus ipilimumab. 
 
Secondary Objective: 
 To determine the progression-free survival (using immune-related response 
criteria [irRC]) of patients with advanced/metastatic urothelial carcinoma treated 
with gemcitabine, cisplatin, and ipilimumab. 
 To determine the disease control rate (complete response + partial response + 
stable disease using irRC and Response Evaluation Criteria In Solid Tumors 
[RECIST] v1.0 [see Section 8.2]) to treatment with gemcitabine, cisplatin, plus 
ipilimumab. 
 To determine the safety of treatment with gemcitabine, cisplatin, plus 
ipilimumab. 
 
Exploratory Objectives: 
 To serially monitor the global composition immune cells in the blood by 
polychromatic flow cytometry and correlate changes with clinical outcome. 
 To determine the frequency of tumor-antigen specific CD8+ T cells by antigen-
specific multi-cytokine production (IFN-γ, TNF-α and IL-2) by intracellular 
cytokine staining. 
 
To perform transcriptional profiling of blood samples before and after treatment 
using microarray and correlate changes with clinical outcomes.  
STUDY DESIGN 
Treatment during the “induction” phase will be administered in six 21-day cycles. 
During cycles 1 and 2, gemcitabine plus cisplatin will be administered WITHOUT 
ipilimumab. During cycles 3-6, combination therapy with gemcitabine, cisplatin, plus 
ipilimumab will be administered. Patients without evidence of disease progression (by 
irRC) after completion of cycle 6 will continue single-agent ipilimumab “maintenance” 
every 3 months.  
 
Induction 
 
Patients will undergo a restaging CT scan after cycle 2 and after cycle 6. However, 
patients with evidence of disease progression (in the absence of significant 
functional/symptomatic deterioration) on the post-cycle 2 CT scan will not be required 
to come off study as they will have not yet started ipilimumab. Patients may elect to 
come off study at any time. 
 


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Furthermore, as durable disease stabilization and/or objective tumor response can be 
seen in other advanced solid tumors after early progression before 12 weeks of 
ipilimumab treatment, it is recommended that, in the absence of treatment-limiting 
toxicities (e.g., serious immune-related adverse events [irAEs]), all four doses of 
ipilimumab be administered over the initial 12 weeks even in the setting of apparent 
progression, providing the subject’s performance status remains stable. 
 
Based on clinical experience in ongoing and completed melanoma studies, the following 
recommendations apply for subject management in light of the post-cycle 6 or later 
tumor assessments: 
 
 The appearance of new lesions in subjects with other stable or shrinking baseline 
tumor burden may be experiencing clinical benefit and should continue in follow-up 
and/or maintenance therapy before alternative anti-cancer agents are considered. 
These subjects can be seen to have continued tumor shrinkage in follow-up scans. 
 As long as overall tumor burden is stable or decreasing, subjects should remain in 
follow-up and/or maintenance, even in the presence of new lesions. 
 Clinical progression warranting alternative anti-cancer treatment should be 
considered only in subjects whose overall tumor burden appears to be substantially 
increased and/or in subjects whose performance status is decreased. 
The irRC will be utilized which requires a confirmatory scan documenting progression 
22. The definition of confirmation of progression represents an increase in tumor burden 
≥ 25% compared with nadir at two consecutive time points at least 4 weeks apart. 
Therefore, patients with disease progression on the post-cycle 6 scan (in the absence of 
symptomatic/functional deterioration) should have a confirmatory CT scan at least 4 
weeks later. 
 
Maintenance 
 
As per the schedule of dosing in the ongoing and completed clinical studies using 
ipilimumab in subjects with pretreated advanced melanoma, maintenance therapy 
should be offered to all subjects who have not experienced unacceptable toxicity 
(refractory Grade > 3 irAEs) and are considered by the investigator to be obtaining 
clinical benefit, either because of apparent tumor stability or continued shrinkage and/or 
late response. 
 
A single dose of 10 mg/kg ipilimumab given intravenously over 90 minutes should be 
administered every 12 weeks, starting from approximately week 28 until the subject is 
no longer clinically benefiting from therapy, per the investigator, or until the occurrence 
of unacceptable or unmanageable toxicity. 
 
Subjects in maintenance should receive radiographic tumor assessments every 12 weeks 
before administration. Subjects who continue to experience clinical benefit, as defined 


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by the investigator, and who have not experienced unacceptable toxicity (refractory 
Grade > 3 irAEs), are eligible to receive continued maintenance. 
 
NUMBER OF 
PATIENTS 
36 
ELIGIBILITY 
 
 Written informed consent and HIPAA authorization for release of personal health 
information. 
 
NOTE: HIPAA authorization may be included in the informed consent or obtained 
separately. 
 
 Age ≥ 18 years at the time of consent. 
 
 Karnofsky performance status (KPS) ≥ 80% within 7 days prior to registration for 
protocol therapy. 
 
 Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for up to 26 weeks after 
the last dose of investigational product, in such a manner that the risk of pregnancy is 
minimized. 
 
WOCBP include any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as: 
Amenorrhea  12 consecutive months without another cause, or for women with 
irregular menstrual periods and taking hormone replacement therapy (HRT), a 
documented serum follicle-stimulating hormone (FSH) level  35 mIU/mL. 
 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal 
products, skin patches, or implanted or injectable products), or mechanical products 
such as an intrauterine device or barrier methods (diaphragm, condoms, 
spermicides) to prevent pregnancy, or are practicing abstinence or where their 
partner is sterile (e.g., vasectomy) should be considered to be of childbearing 
potential. 
 
 WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab. 
 
 Men of fathering potential must be using an adequate method of contraception to 
avoid conception throughout the study [and for up to 26 weeks after the last dose of 
investigational product] in such a manner that the risk of pregnancy is minimized. 
 
 Females must not be pregnant or breastfeeding. 
 
 Histological or cytological proof of urothelial carcinoma of the urethra, bladder, 


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ureters, or renal pelvis. 
 
 Advanced (clinical stage T4b, unresectable) or metastatic disease.  
 
 No active CNS metastases. Subjects with neurological symptoms must undergo a 
head CT scan or brain MRI to exclude brain metastasis within 28 days of 
registration. 
 
NOTE: A subject with prior brain metastasis may be considered if they have 
completed their treatment for brain metastasis, no longer require corticosteroids, and 
are asymptomatic 
 
 No prior malignancy is allowed except for cancers that have been definitively treated 
with a risk of recurrence of < 30% based on the treating oncologist’s assessment.  
 
 Patients may not have received prior systemic chemotherapy for metastatic/advanced 
urothelial carcinoma.  
 
NOTE: Prior neoadjuvant/adjuvant therapy is permitted if completed ≥ 12 months 
prior to registration for protocol therapy. Prior intravesical therapy is permitted. 
 
 No treatment with any investigational agent within 30 days prior to registration for 
protocol therapy.  
 
 Prior radiation therapy is allowed to < 25% of the bone marrow [see bone marrow 
radiation chart in the study procedure manual (SPM)].  
 
NOTE: No radiation therapy within 30 days prior to registration for protocol 
therapy.  
 
 Prior Autoimmune disease: Patients with a history of inflammatory bowel disease, 
including ulcerative colitis and Crohn’s Disease, are excluded from this study, as are 
patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic 
progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune 
vasculitis [e.g., Wegener’s granulomatosis]); motor neuropathy considered of 
autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis).  
 
NOTE: Patients with other immune disorders should not be enrolled without 
discussion with the principal investigator. 
 
 No underlying medical or psychiatric condition, which in the opinion of the 
investigator will make the administration of ipilimumab hazardous or obscure the 
interpretation of adverse events (AEs), such as a condition associated with frequent 
diarrhea. 
 
 No non-oncology vaccine therapy used for prevention of infectious diseases (for up 


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to 1 month before or after any dose of ipilimumab). 
 
 No history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 
inhibitor or agonist (See SPM for list of drugs). 
 
 No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C. 
 
 No clinically significant infections as judged by the treating investigator. 
 
 No chronic systemic corticosteroids (defined as the equivalent of prednisone ≥ 20 
mg PO daily for > 6 months during the past year) 
 
NOTE: Laboratory values must be obtained within 7 days prior to registration for 
protocol therapy.  
 
 White blood cell count (WBC) ≥ 3.5K/mm3  
 
 Hemoglobin (Hgb) ≥ 9 g/dL 
 
 Platelets ≥ 100K/mm3 
 
 Absolute neutrophil count (ANC) ≥ 1.5k/mm3 
 
 Actual or Calculated creatinine clearance of ≥ 55 cc/min using the Cockcroft-Gault 
formula: 
 
Males: (140 – Age in years) × Actual Body Weight in kg 
72 × Serum Creatinine (mg/dL) 
 
Females: Estimated creatinine clearance for males × 0.85 
 
 Bilirubin ≤ 1.5 times () Upper Limit of Normal (ULN) (except patients with 
Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL) 
 
 
Aspartate aminotransferase (AST) ≤ 2.5  ULN. NOTE: If the patient has liver 
metastases present, then ≤ 5  ULN 
 
 
Alanine aminotransferase (ALT) ≤ 2.5  ULN. NOTE: If the patient has liver 
metastases present, then ≤ 5  ULN 
 
 
Patient must consent to mandatory correlative sample collection. 
 


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STATISTICAL 
CONSIDERATIONS 
 
hough not a standard endpoint for a phase II trial, the current study will utilize 1 year 
overall survival as the primary endpoint. Given that late responses (and variable 
response patterns such as responses after documented progression) have occurred in 
patients with other solid tumors treated with ipilimumab, and given that the use of the 
irRC and timing of the scans in our study will bias progression-free survival endpoints, 
overall survival will provide the most definitive endpoint to consider the activity of the 
current regimen in the context of historical controls. The 1 year overall survival of 
patients treated with cisplatin and gemcitabine alone is 60% 3.  
 
The primary objective is to estimate the 1 year overall survival (OS) rates for 
gemcitabine, cisplatin, plus ipilimumab. The sample size is calculated for a power level 
of 0.80, based on 90% one-sided confidence intervals (CI) calculated at the target rate of 
80% for 1 year OS. We will recommend the regimen if lower bound of the resulting CI 
exceeds 60%. This is equivalent to testing the following hypothesis at Type I error level 
0.10: H0: 1-year overall survival rate ≤ 60%, vs. Ha: 1-year overall survival rate > 60%. 
For this purpose, we will enroll 36 subjects (inflating the sample size of 33 by 10% to 
account for potential missing data due to various reasons), assuming fewer than 20% of 
subjects will be off study before 1 year for various reasons (and thus with unknown 
survival status at 1 year). The sample size is determined from an upper bound for the 
Greenwood formula for the variance of Kaplan-Meier estimate at 1 year. All patients 
will be followed for at least 1 year from the enrollment. We expect an accrual rate of 
approximately 1-2 per month. This leads to approximately 17-34 months for accrual. 
With at least one year follow-up for the last subject, we expect the study to finish within 
approximately 2.5-3 years. 
 
The confidence interval of 1 year overall survival (OS) rates will be constructed based 
on Kaplan-Meier estimate. Response rates will be analyzed using statistical methods for 
binary outcomes. Progression-free survival and overall survival will be analyzed using 
log-rank test and Cox regression model. Association between immune-related adverse 
events and overall response rate will be tested using Fisher’s exact test and Chi-square 
test. 
 
Potential biomarkers will be assessed by repeating the analysis of each clinical outcome 
with the level of each individual marker included as factor or covariate as appropriate. 
We will correlate outcomes with changes in the frequency of circulating immune cells, 
tumor antigen-specific CD8+ T cells, and whole blood transcriptional profiling before 
and after treatment. Significance of this association will be evaluated using the Chi-
square test for binary outcomes and log-rank tests for time-to-event outcomes. 
 
The analysis population will be the group who receives at least one cycle of protocol 
therapy. Therefore, subjects who experience clinical deterioration and are removed from 
the study prior to cycle 3 (the first cycle with ipilimumab) will still be included in the 
analysis; however, based on prior studies of first-line therapy in patients with metastatic 
urothelial cancer, we expect this population to be very small. {Hahn, 2011 #1449} The 
starting point for survival analysis is the treatment (Gem+Cis) initiation date.  
 
An early stopping rule will be employed. If we are confident that more than 20% of 


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patients have experienced a nondermatologic immune-related adverse event of grade 3 
or higher attributable to ipilimumab, that cannot be alleviated or controlled by 
appropriate care or corticosteroid therapy within 14 days after the initiation of 
supportive care or corticosteroid therapy, the study will close to further enrollment. We 
will therefore monitor the study when 5, 10, 20, and 30 patients have completed 6 
cycles of treatment. We will continue enrollment while the toxicity evaluation is taking 
place (we will not halt enrollment for the analysis). The study regimen will be 
considered excessively toxic if we observe 3 or more out of 5, 4 or more out of 10, 6 or 
more out of 20, and 9 or more out of 30 patients. We will then stop the trial. These 
boundaries are determined from the lower bound of 80% exact binomial confidence 
intervals. See Section 12, Table 10 for the probabilities of stopping the trial due to this 
toxicity monitoring rule. 


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Phase II Trial of Gemcitabine, Cisplatin, plus Ipilimumab as First-line Treatment for 
Patients with Metastatic Urothelial Carcinoma 
Hoosier Cancer Research Network GU10-148 
 
 
 
INDEX  
 
SECTION                                                                                                               
PAGE 
 
 
 
SCHEMA ........................................................................................................................................ 11 
1.0 
BACKGROUND & RATIONALE .................................................................................... 12 
2.0 
OBJECTIVES ..................................................................................................................... 23 
3.0 
ELIGIBILITY CRITERIA ................................................................................................ 24 
4.0 
PATIENT REGISTRATION ............................................................................................. 26 
5.0 
TREATMENT PLAN ......................................................................................................... 25 
6.0 
DOSE MODIFICATIONS ................................................................................................. 30 
7.0 
STUDY CALENDAR & EVALUATIONS ....................................................................... 38 
8.0 
CRITERIA FOR DISEASE EVALUATION ................................................................... 46 
9.0 
BIOLOGICAL CORRELATIVES ................................................................................... 52 
10.0 CTM INFORMATION & ADVERSE EVENTS MANAGEMENT .............................. 52 
11.0 REPORTING ADVERSE EVENTS & SERIOUS ADVERSE EVENTS  .................... 63 
12.0 STATISTICAL CONSIDERATIONS .............................................................................. 66 
13.0 TRIAL MANAGEMENT ................................................................................................... 68 
14.0 REFERENCES .................................................................................................................... 84 
 
 
 
 
 
 


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SCHEMA 
 
Phase II Trial of Gemcitabine, Cisplatin, plus Ipilimumab as First-line Treatment for 
Patients with Metastatic Urothelial Carcinoma 
Hoosier Cancer Research Network GU10-148 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent and HIPAA 
Evaluation of Eligibility Criteria 
Registration 
36 Eligible Patients  
2 Cycles of 
Gemcitabine + 
Cisplatin 
Off Treatment 
4 Cycles of Gemcitabine 
+ Cisplatin+ Ipilimumab 
Single agent Ipilimumab 
maintenance every 3 
months until progression 
Clinical 
deterioration 
Stable or responding disease OR 
progression in the absence of clinical 
deterioration  
PD (confirmed as per irRC) 
Off Treatment 
 
Stable or 
responding disease 
Gemcitabine 1000 mg/m2 Days 1 & 8 
Cisplatin 70 mg/m2 Day 1 
Ipilimumab 10 mg/kg Day 1 (start cycle 3) 
Cycle length = 21 days 
Survival 
Follow up 
Survival 
Follow up 
Survival 
Follow up 
Off Treatment 


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1.0 
BACKGROUND & RATIONALE 
 
 
Urothelial carcinoma of the urinary bladder is the second most common genitourinary malignancy. 
Each year in the United States, more than 60,000 patients will develop urothelial carcinoma and 
over 12,000 will die of their disease. While urothelial carcinoma is a chemosensitive neoplasm, 
current therapeutic approaches are inadequate. Response durations are short and the median 
survival of patients with metastatic disease is slightly over 1 year. These findings highlight the 
need for novel approaches to the treatment of metastatic urothelial carcinoma. 
 
Chemotherapy is standard treatment for advanced bladder cancer. Cisplatin is among the 
most active agents in urothelial carcinoma and cisplatin-based combinations have long been the 
standards of care. The M-VAC (methotrexate, vinblastine, Adriamycin, and cisplatin) regimen, 
developed in the early 1980’s, became a treatment standard based on data from two large 
randomized trials demonstrating improved survival with MVAC compared with single agent 
cisplatin or CISCA (cisplatin, Adriamycin, and cyclophosphamide), respectively 1-2. However, few 
patients achieved long-term survival with this regimen and severe treatment-related side effects 
were common.  
 
In an attempt to improve the efficacy and tolerability of therapy for advanced urothelial 
carcinoma, various combinations of cisplatin with newer drugs have been explored. In a 
multicenter randomized phase III trial comparing gemcitabine and cisplatin (GC) with M-VAC in 
patients with advanced/metastatic urothelial carcinoma, 405 patients were enrolled 3. Both arms 
yielded similar response rates and overall survival (13.8 months with GC and 14.8 months with 
MVAC; HR 1.04; 95% CI, .82 – 1.32; p=.75). However, GC was associated with a better safety 
profile and improved tolerability. Given the results of this trial, GC has become a standard 
regimen for patients with metastatic urothelial carcinoma.  
 
While the tolerability of treatment has improved over the past 20 years, efficacy has not. Novel 
approaches are clearly needed. 
 
Bladder cancer is an immunogenic malignancy. Immunotherapy has played a major role in the 
treatment of superficial bladder cancer since the introduction of intravesical bacillus Calmette-
Guérin (BCG); randomized trials have demonstrated treatment with intravesical BCG results in 
lower recurrence rates and significantly superior survival rates. 4 While the mechanism of action 
of BCG remains poorly defined, studies support an immunological mechanism including the role 
of BCG in the maturation of dendritic cells by signaling through Toll-like receptors, and secretion 
of inflammatory cytokines such as IL- 12, IFN-γ, and TNF-α. 5 Increasing evidence reveals more 
advanced stages of bladder cancer are particularly immunogenic. Multiple studies have shown that 
bladder cancer specimens harbor tumor infiltrating lymphocytes 6-7; immunohistochemical 
staining for intratumoral CD8 T cells in tissue samples from 69 patients with bladder cancer (pT2, 
pT3, or pT4) demonstrated that patients with higher numbers of CD8 tumor infiltrating 
lymphocytes within the tumor (8 or more) had better disease-free survival (P < 0.001) and overall 
survival (P = 0.018) than did patients with similar-staged bladder cancer and fewer intratumoral 
CD8 tumor infiltrating lymphocytes. 7 
 
Despite the immunogenicity of bladder cancer, patients with bladder cancer also exhibit 
tumor-associated immunologic suppression. Patients with bladder cancer exhibit a tumor-


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associated immunologic suppression, particularly evident as an impaired T-cell response, which 
may worsen with advanced tumor stage. 8-10 Bladder cancer specimens have been shown to be 
infiltrated by T regulatory cells, and to express high levels of inhibitory cytokines. 9 In addition, 
aberrant expression of T-cell coregulatory molecules, known to inhibit the immune response, have 
been demonstrated on bladder cancer cells and tumor infiltrating lymphocytes and have correlated 
with clinical outcomes. 11 
 
These findings suggest that the balance between CD8+ cytotoxic T cells and negative immune 
regulatory elements in the tumor microenvironment may be critical in determining the host’s 
overall immune response and ultimate clinical outcome.  
 
Blocking Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) may break immune tolerance in 
bladder cancer. Engagement of the T cell antigen receptor by itself is insufficient for full T cell 
activation; a second co-stimulatory signal is required. The primary source of this co-stimulation is 
through engagement of CD28 on the T cell surface by members of the B7 family on antigen-
presenting cells. However, upon activation, T cells transiently express CTLA-4, which binds to 
member of the B7 family with much higher affinity than CD28, and down regulates T cell 
responses. Blockade of CTLA-4 has been shown to enhance T cell activation in animal models 
and results in an increased ratio of effector to regulatory T cells, which correlates with tumor 
regression. 12-14 In a study of MB49 bladder cancer murine xenografts, combined antibody 
blockade of CTLA-4 plus local toll-like receptor stimulation with CpG resulted in a complete 
response rate of 86%, an increase in numbers of circulating tumor-specific CD107a expressing 
CD8+ T cells, and a decrease in the numbers of local T regulatory cells. 15 
 
The anti-CTLA4 antibody ipilimumab has shown safety and efficacy in patients with 
metastatic solid tumors and intriguing activity in localized bladder cancer. Ipilimumab is a 
human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody (mAb). A recent 
randomized phase III trial of ipilimumab plus gp100 vaccine versus ipilimumab alone versus 
gp100 alone demonstrated a significant improvement in survival among patients receiving 
ipilimumab; grade 3-4 immune-related adverse events occurred in 10-15% of patients. 16 
Ipilimumab has been explored pre-cystectomy in a pilot trial of patients with clinically localized 
bladder cancer. In this trial, 12 patients were treated with two doses of ipilimumab (6 with 3 
mg/kg and 6 with 10 mg/kg). 17 Most drug-related adverse events were grade 1 or 2, all patients 
demonstrated an increase in CD4+ ICOShi T cells in tumor tissue and systemic circulation, and 
8/12 patients had downstaging of their disease on final pathology review. Notably, a retrospective 
analysis of peripheral blood samples from patients with metastatic melanoma who were treated 
with ipilimumab revealed that a sustained increase in peripheral blood CD4+ ICOShi T cells at 12 
weeks correlated with improved overall survival. 
 
Several lines of evidence suggest that the immune system can be activated by chemotherapy. 
Mechanisms by which chemotherapy may enhance tumor immunity include: a) eliciting cellular 
responses that render tumor cell death immunogenic, b) transient lymphodepletion, and c) direct or 
indirect stimulatory effects on immune effectors. Specifically, gemcitabine has been shown to 
induce apoptosis of established tumor cells in vivo, thereby increasing tumor antigen cross-
presentation leading to priming of tumor-specific CD8+ T cells. 18 Gemcitabine has also been 
shown to have selective detrimental effects on B lymphocytes inhibiting tumor-specific antibody 
production, which may skew antitumor immunity towards therapeutic T cell responses. 19 In a 


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tolerogenic tumor model in mice, gemcitabine combined with immunotherapeutic approaches 
resulted in potent therapeutic antitumor immunity and was shown to eliminate myeloid-derived 
suppressor cells. 20  
 
Taken together, these data support approaches combining gemcitabine plus cisplatin with 
ipilimumab for the treatment of advanced bladder cancer 
 
CTLA-4 and Ipilimumab. Advances in the understanding of the mechanisms that regulate T cell 
activation have allowed the rational design of new strategies for immunotherapy of tumors, 
including melanoma. It has been known for some time that engagement of the T cell antigen 
receptor by itself is not sufficient for full T cell activation; a second co-stimulatory signal is 
required for induction of IL-2 production, proliferation and differentiation to effector function of 
naive T cells. Abundant data now indicate that the primary source of this co-stimulation is 
mediated by engagement of CD28 on the T cell surface by members of the B7 family on the 
antigen-presenting cell (APC). 
 
Expression of B7 has been shown to be limited to “professional” antigen presenting cells; that is, 
specialized cells of the hematopoietic lineage, including dendritic cells, activated macrophages, 
and activated B cells. It has been suggested that this sharply defined restriction of B7 expression is 
a fail-safe mechanism for maintenance of peripheral T cell tolerance, insuring that T cell 
activation can only be stimulated by appropriate APCs. The fact that tumor cells do not express B7 
contributes to their poor capacity to elicit immune responses. 
 
The demonstration that induction of expression of B7 on many tumor cells by transfection, 
transduction, or other mechanisms can heighten tumor immunogenicity led to great interest in 
pursuing this as an approach to tumor immunotherapy. As demonstrated in vivo in murine tumor 
models, the utility of B7 expression as a vaccination approach is limited by the following factors: 
(1) B7-expressing tumor cell vaccines are only effective when the tumor cells have a high degree 
of inherent immunogenicity; (2) while B7-expressing vaccines have been shown in many cases to 
be effective in inducing protective immune responses, they have demonstrated only limited utility 
in inducing responses to established tumors; and (3) inactivation of tumor cells by radiation has 
been shown to destroy the immuno-enhancing activity of the B7 gene product. 
 
In the past few years, it has become apparent that co-stimulation is even more complex than 
originally thought. After activation, T cells express CTLA-4, a close homologue to CD28. CTLA-
4 binds members of the B7 family with a much higher affinity than CD28. Although there was 
initially some controversy as to the role of CTLA-4 in regulating T cell activation, it has become 
clear that CTLA-4 down-regulates T cell responses. This was initially suggested by the following 
in vitro observations: (1) blockade of CTLA-4/B7 interactions with antibody enhanced T cell 
responses; (2) cross-linking of CTLA-4 with CD3 and CD28 inhibited T cell responses; and 
(3) administration of antibodies to CTLA-4 in vivo enhanced the immune response to peptide 
antigens or superantigens in mice. Blocking CTLA-4-B7 interaction while preserving signaling 
via CD28 resulted in enhanced T cell responses in vitro. 
 
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-4 came from 
examination of mice with a null mutation. CTLA-4 knockout mice appear to have spontaneously 
activated T cells evident at approximately 1 week after birth, followed by rampant 


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lymphoproliferation and lymphadenopathy. These mice die at approximately 3 weeks of age, 
either as a result of polyclonal T cell expansion and tissue destruction or as a result of toxic shock 
resulting from lymphokine production by the T cells. Since thymocyte differentiation and 
selection proceed normally in CTLA-4-deficient mice, the rampant T cell expansion that occurs in 
the mice indicates that CTLA-4 plays a critical role in down-regulating T cell responses in the 
periphery. 
 
Pharmacology of Ipilimumab 
 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody (mAb). In 
vitro studies were performed with ipilimumab to demonstrate that it is specific for CTLA-4, 
actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any cross-reactivity with 
human B7.1, B7.2 negative cell lines, and stains the appropriate cells without non-specific cross-
reactivity in normal human tissues, as demonstrated by immunohistochemistry. Ipilimumab does 
cross-react with CTLA-4 in non-human primates including cynomolgus monkeys. 
 
Ipilimumab was originally produced and purified from a hybridoma clone. Subsequently, a 
transfectoma (CHO cell) has been generated that is capable of producing more ipilimumab on a 
per cell basis than the hybridoma. Material from the transfectoma will be utilized in this and future 
ipilimumab clinical studies. Biochemical, immunologic and in vivo preclinical primate 
assessments demonstrated similarity between hybridoma and transfectoma-derived ipilimumab. 
 
Pre-Clinical Toxicology of Ipilimumab 
 
Complete information on the pre-clinical toxicology studies can be found in the Ipilimumab 
Investigator Brochure (IB). Non-clinical toxicity assessments included in vitro evaluation for the 
potential of ipilimumab to mediate complement-dependent cellular cytotoxicity (CDCC) or 
antibody-dependent cellular cytotoxicity (ADCC), and toxicology assessments in cynomolgus 
monkeys alone and in the presence of vaccines. 
 
The in vitro studies demonstrated that ipilimumab did not mediate CDCC of PHA- or (CD)3-
activated human T cells. However, low to moderate ADCC activity was noted at concentrations up 
to 50 ug/mL. These data are consistent with the requirement of high levels of antigen expression 
on the surface of target cells for efficient ADCC or CDCC. Since ipilimumab is a human IgG1, an 
isotype generally capable of mediating CDCC and ADCC, the lack of these activities is likely due 
to a very low expression of CTLA-4 on activated T cells. Therefore, these data suggest that 
ipilimumab treatment would not result in depletion of activated T cells in- vivo. Indeed, no 
depletion of T cells or T cell subsets were noted in toxicology studies in cynomolgus monkeys. 
No mortality or signs of toxicity were observed in three independent 14-day intravenous 
toxicology studies in cynomolgus monkeys at multiple doses up to 30 mg/kg/dose. Furthermore, 
ipilimumab was evaluated in sub chronic and chronic toxicology studies in cynomolgus monkeys 
with and without Hepatitis B (HepB) Vaccine and Melanoma Vaccine. Ipilimumab was well 
tolerated alone or in combination in all studies. There were no significant changes in clinical signs, 
body weight values, clinical pathology values or T cell activation markers. In addition, there were 
no significant histopathology changes in the stomach or colon. 
 
Human Pharmacokinetics of Ipilimumab 


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Pharmacokinetic (PK) profiles for ipilimumab have been analyzed. The primary objective of 
Protocol MDX010-015 was to determine the safety and PK profile of single and multiple doses of 
ipilimumab derived from a transfectoma or hybridoma cell line. Mean plasma concentrations of 
ipilimumab administered at doses of 3 mg/kg (hybridoma-derived drug product); 2.8 mg/kg, 
5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, and 20 mg/kg (transfectoma-derived drug product) 
demonstrated approximate dose proportionality. Equimolar doses of hybridoma-derived and 
transfectoma-derived drug product had comparable PK profiles. The range of mean volume of 
distribution at steady state (Vss) across cohorts 2.8, 3, 5, 7.5, 10, 15, and 20 mg/kg, was 57.3 to 
82.6 mL/kg, indicating drug distribution was mostly limited to the intravascular space. The 
clearance was low (range 0.11 to 0.29 mL/h/kg) and reflective of the half-life (range 297 to 414 h), 
which is consistent with the long terminal disposition phase of ipilimumab. There was moderate 
variability in the PK parameters among subjects, with CV of 11% to 48% in AUC(0-21d), 20% to 
59% in CL, and 17% to 46% in Vss. 
 
Clinical Safety with Ipilimumab 
 
Ipilimumab has been administered to more than 13,800 subjects with different cancers in 
completed and ongoing clinical trials as well as a compassion use program as of 10-Mar-2014 
with a dose range between 0.3 mg/kg and 20 mg/kg and in various combinations. 
 
In general, the safety profile of ipilimumab administered as single doses of up to 20-mg/kg and 
multiple doses of up to 10 mg/kg every 3 weeks was characterized by adverse reactions that were 
mostly immune in nature. Drug-related serious adverse events (SAEs) were reported in studies of 
ipilimumab administered as monotherapy, as well as in combination with vaccines, cytokines, 
chemotherapy, or radiation therapy. 
 
The overall summary of safety for 2901 patients treated with ipilimumab in completed or ongoing 
clinical trials and a subset of 658 patients treated at the 10 mg/kg dose level is presented in Table 
1.  
 
 


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Table 1: Ipilimumab - Overall Summary of Safety 
 
Number of Subjects (%) 
 
Ipilimumab 0.3 - 20 
mg/kg 
N = 2901 
Ipilimumab 10 mg/kg 
N = 658 
Any Drug-related AE 
2357 (81.2) 
561 (85.3) 
 
Grade 1  
699 (24.1) 
158 (24.0) 
 
Grade 2  
889 (30.6) 
198 (30.1) 
 
Grade 3  
617 (21.3) 
163 (24.8) 
 
Grade 4 
127 (4.4) 
38 (5.8) 
 
Grade 5 
20 (0.7) 
4 (0.6) 
Any Serious Adverse Events 
1258 (43.4) 
310 (47.1) 
 
Grade 3 - 4 
806 (27.8) 
179 (27.2) 
Any Drug-related Serious Adverse 
Events 
595 (20.5) 
179 (27.2) 
 
Grade 3 - 4 
469 (16.2) 
140 (21.3) 
 
Details of Drug-Related Adverse Events 
 
Treatment-emergent adverse events (AEs) considered by the investigator to be related to study 
drug were reported for 81.2% of all treated subjects and 85.3% of subjects treated with ipilimumab 
at 10 mg/kg. Among all treated subjects, the most frequently reported treatment-related AEs of 
any grade included fatigue (27.8%), diarrhea (27.5%), nausea (23.4%), rash (21.8%), pruritus 
(19.9%), pyrexia (11.9%), and vomiting (11.7%). Similarly, among subjects treated with 
ipilimumab at 10 mg/kg, the most frequently reported treatment-related AEs of any grade included 
diarrhea (38.1%), fatigue (30.5%), rash (34.5%), pruritus (29.8%), nausea (17.6%), pyrexia 
(12.3%), vomiting (10.9%). and colitis (10.2%). 
 
Details of Drug-Related Serious Adverse Events 
 
Among 2901 treated subjects, SAEs considered possibly, probably, or definitely related to study 
drug were reported for 20.5% of subjects. Drug-related SAEs reported in at least 1% of the 2901 
subjects included diarrhea (5.8%), colitis (4.7%), ALT increased (2.3%), AST increased (2.2%), 
pyrexia (1.6%), and vomiting (1.3%). Among 658 subjects who received ipilimumab at 10 mg/kg, 
SAEs considered possibly, probably, or definitely related to study drug were reported for 27.2% of 
subjects. Drug-related SAEs reported in at least 1% of the 658 subjects treated at 10 mg/kg 
included diarrhea (8.5%), colitis (7.0%), vomiting (2.1%), AST increased (2.1%), ALT increased 
(2.0%), autoimmune hepatitis (2.0%), pyrexia (1.8%), hypopituitarism (1.7%), dehydration 
(1.7%), nausea (1.2%), and abdominal pain (1.1%). 
 
Immune-Related Adverse Events (irAEs) with Ipilimumab 
 
Many of the adverse events considered related to ipilimumab may be immune in nature and 
presumably a consequence of the intrinsic biological activity of ipilimumab. An irAE is defined as 
any adverse event associated with drug exposure and consistent with an immune-mediated event. 
Disease progression, infections and other etiologic causes are ruled out or deemed unlikely as 
contributing to the event. Supportive data, such as autoimmune serology tests or biopsies, are 


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helpful but not necessary to deem an event an irAE. Events of unclear etiology, which were 
plausibly “immune-mediated,” have been conservatively categorized as irAEs even if serologic or 
histopathology data are absent. These irAEs likely reflect a loss of tolerance to some self-antigens 
or an unchecked immune response to gut or skin flora. Some breakthrough of immunity may be 
inseparably linked to the clinical antitumor activity of ipilimumab. 
 
Immune-related AEs predominately involve the GI tract, endocrine glands, liver or skin. Among 
2901 treated subjects, 59.6% (1729/2901) of subjects reported any irAE and 15.2% (441/2901) of 
subjects reported serious irAEs. Among subjects who received ipilimumab at 10 mg/kg, 21.9% 
(144/658) of subjects reported serious irAEs.  
 
Table 2 summarizes the incidence of serious irAEs among all treated subjects and subjects who 
received ipilimumab 10 mg/kg. 
 
Table 2: Serious Immune-related Adverse Events Reported for at Least 2% of 
Subjects in any Event Category 
 
 
Number of Subjects (%) 
 
 
Ipilimumab 0.3 - 20 
mg/kg 
Ipilimumab 10 mg/kg 
 
 
N = 2901 
N = 658 
 
irAEsa 
 
 
 
 
Any 
441 (15.2) 
144 (21.9) 
 
 
Grade 3 
298 (10.3) 
87 (13.2) 
 
 
Grade 4 
59 (2.0) 
25 (3.8) 
 
GI irAEa 
 
 
 
 
Any 
236 (8.1) 
85 (12.9) 
 
 
Grade 3 
166 (5.7) 
58 (8.8) 
 
 
Grade 4 
17 (0.6) 
10 (1.5) 
 
Liver irAEa 
 
 
 
 
Any 
109 (3.8) 
33 (5.0) 
 
 
Grade 3 
72 (2.5) 
18 (2.7) 
 
 
Grade 4 
32 (1.1) 
13 (2.0) 
 
Endocrine irAEa 
 
 
 
 
Any 
61 (2.1) 
21 (3.2) 
 
 
Grade 3 
44 (1.5) 
12 (1.8) 
 
 
Grade 4 
3 (0.1) 
1 (0.2) 
aBased on treatment-related adverse events retrieved from the clinical database using pre-defined MedDRA terms that 
were considered potential irAEs. 
 
With few exceptions, irAEs were clinically manageable and reversible with supportive care or 
corticosteroids.  
 
Corticosteroid treatment did not adversely affect antitumor responses in those subjects who had 
both an irAE requiring steroid therapy and an objective tumor response. Systemic corticosteroids 
do not appear adversely associated with ipilimumab-induced clinical response when used to 
manage irAEs in patients with advanced melanoma. Similar results were observed regardless of 
whether modified World Health Organization (mWHO) or the novel irRC criteria were used. 


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Steroids can be used promptly to manage severe irAEs and minimize the risk for serious 
complications. In the setting where subjects were enrolled to receive ipilimumab every 3 weeks 
dosing until progression, irAEs could be reported at any time, with colitis and rash reported most 
often during the early doses and hypophysitis reported with later doses. 
 
Gastrointestinal irAEs 
 
The most common Grade 3 or greater irAE involved the lower GI tract and clinically manifested 
as diarrhea or hematochezia. Diarrhea resulting from treatment with ipilimumab ranged from mild 
to severe and was life threatening in some cases. Some cases of diarrhea began as mild and 
became very severe. Among subjects who received ipilimumab at 10 mg/kg, GI irAEs of any 
grade were reported for 40.0% (263/658) of subjects, and Grade 3 - 4 GI irAEs were reported for 
12.6% (83/658) of subjects. Serious GI irAEs, mostly involving diarrhea or colitis, were reported 
in 12.9% (85/658) of subjects treated with ipilimumab at 10 mg/kg.  
 
Inflammatory Hepatotoxicity 
 
Immune-related hepatic dysfunction, including hepatitis or abnormal liver function tests (LFT) 
attributed to ipilimumab therapy, has been reported. Subjects may develop elevations in LFTs in 
the absence of clinical symptoms. Inflammatory hepatotoxicity includes non-infectious hepatitis 
(e.g., autoimmune hepatitis). Among subjects who received ipilimumab at 10 mg/kg, 
inflammatory hepatotoxicity of any grade was reported for 9.0% (59/658) of subjects, and Grade 3 
- 4 inflammatory hepatotoxicity was reported for 6.4% (42/658). Serious inflammatory 
hepatotoxicity has been reported in 5.0% (33/658) of subjects who received ipilimumab at 10 
mg/kg. Inflammatory hepatotoxicity is usually reversible when immediately treated with high-
dose steroids, if applicable, with or without additional immunosuppressants as recommended in 
the hepatotoxicity management algorithm. 
 
Hypophysitis/Hypopituitarism and Other Endocrine Conditions 
 
Hypophysitis/hypopituitarism, clinically manifested by fatigue, has been reported. Most subjects 
with hypopituitarism presented with nonspecific complaints such as fatigue, confusion, visual 
disturbance, or impotence. Some had headache as the predominant presentation. The majority of 
subjects with hypopituitarism demonstrated enlarged pituitary glands based on brain magnetic 
resonance imaging (MRI). Low adrenocorticotropic hormone (ACTH) and cortisol were the most 
common biochemical abnormality reported; low thyroid-stimulating hormone (TSH), testosterone, 
or prolactin was also reported in some subjects. 
 
Hypophysitis/hypopituitarism was controlled with appropriate hormone-replacement therapy and 
may be dose related. Among subjects who received ipilimumab at 10 mg/kg, endocrinopathy of 
any grade was reported for 7.6% (50/658) of subjects, and Grade 3-4 endocrinopathy was reported 
for 
2.4% 
(16/658) 
of 
subjects. 
Serious 
drug-related 
endocrinopathy, 
such 
as 
hypophysitis/hypopituitarism, was reported in 3.2% (21/658) of subjects who received ipilimumab 
at 10 mg/kg. 


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The first onset of endocrine irAEs typically occurred between weeks 6 and 12 of treatment. 
Endocrine events were generally manageable with hormone-replacement therapy, and the majority 
of subjects were not weaned from steroids. 
 
Rash and Other Skin Conditions 
 
Rash was one of the most common irAEs, and most cases were Grade 1 or 2 in intensity; pruritus 
has also been reported. When biopsied, pleomorphic infiltrates were noted in the skin. Among 
subject who received ipilimumab at 10 mg/kg, skin irAEs of any grade were reported for 52.9% 
(348/658) of subjects, and Grade 3 - 4 skin irAEs were reported for 2.9% (19/658) of subjects. 
Serious skin irAEs were reported in < 1% (4/658) of subjects who received ipilimumab at 10 
mg/kg. Skin irAEs were generally reversible.  
 
Other presumed irAEs reported include, but were not limited to, arthritis/arthralgias, pneumonitis, 
pancreatitis, autoimmune (aseptic) meningitis, autoimmune nephritis, pure red cell aplasia, non-
infective myocarditis, ocular inflammation, Guillain-Barre syndrome (GBS), myasthenia gravis, 
and neuropathy (e.g., motor neuropathy, neuritis), of which were individually reported for < 1% of 
subjects.  
 
Other reported irAEs 
 
Ocular inflammation, manifested as Grade 2 or Grade 3 episcleritis or uveitis, was associated with 
concomitant diarrhea in a few subjects and occasionally occurred in the absence of clinically 
apparent GI symptomsi. Serious ocular inflammation was reported in 1 of 658 (0.2%) subjects 
who received ipilimumab at 10 mg/kg (8 [0.3%] of 2901 subjects program-wide reported serious 
ocular inflammation). Preliminary analysis (based on the manual extraction of the SAE data from 
the internal safety database) indicated that the median time to event onset was approximately 61 
days (range: 14 - 114 days). Based on the available data with known outcome, most of the subjects 
recovered or improved with or without corticosteroid therapy with a median duration of 
approximately 6 days (range: 5 - 23 days). 
 
Drug-Related Deaths 
 
Based on reports from the safety database as of June 30, 2009, there have been reports of death 
(approximately 1% [35/3800]), deemed by the investigator as possibly related to the 
administration of study drug. The most common cause of drug related deaths was GI perforation. 
Other causes included multi-organ failure, sepsis, hypotension, acidosis, and adult respiratory 
distress syndrome. For details on all drug-related deaths, refer to the current version of the 
Ipilimumab Investigator Brochure. 
 
Safety of 10 mg/kg Multiple Doses 
 
Based on a review of the program-wide SAE data as previously reported, evidence had suggested 
that ipilimumab-associated irAEs were dose dependent in frequency, and higher irAE rates had 
been observed at 10 mg/kg than at lower doses of ipilimumab. Subsequently, this dose-dependent 
effect was further demonstrated in CA184-022 in which three dose levels of ipilimumab were 


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studied, including 0.3 vs 3 vs 10 mg/kg. Table 3 summarizes the overall irAE frequencies by dose 
from CA184-022 based on safety data from the locked clinical database. 
 
Qualitatively, the safety profile of ipilimumab at 10 mg/kg remains consistent with the low-dose 
safety profile in that most of the drug-related SAEs are characteristic of immune-related toxicity, 
and most of the irAEs are reported in the GI, hepatic, and endocrine systems. However, the data 
presented in Table 3 suggest that the frequency of irAEs in association with 10 mg/kg of 
ipilimumab at multiple doses is higher compared with the irAE frequency reported for lower 
doses.  
 
Table 3: Summary of Immune-Related Adverse Events (irAEs) by Treatment 
Groups - Treated Subjects (CA184-022) 
 
Number of Subjects (%) 
 
Ipilimumab 
 
0.3 mg/kg 
(N=72) 
3 mg/kg 
(N=71) 
10 mg/kg 
(N=71) 
Overall irAEs 
 
Grade 3-4 
26.4 
0 
64.8 
7.0 
70.4 
25.4 
GI irAEs 
 
Grade 3-4 
16.7 
0 
32.4 
2.8 
39.4 
15.5 
Hepatic irAEs 
 
Grade 3-4 
0 
0 
0 
0 
2.8 
2.8 
Endocrine irAEs 
 
Grade 3-4 
0 
0 
5.6 
2.8 
4.2 
1.4 
Skin irAEs 
 
Grade 3-4 
12.5 
0 
45.1 
1.4 
46.5 
4.2 
 
Neuropathies 
 
Isolated cases of motor neuropathy of an autoimmune origin have been reported among patients 
treated with ipilimumab. Three cases have been diagnosed as Guillain-Barre syndrome (GBS), two 
of which were considered study related. In both cases, the GBS was atypical in nature and more 
clinically resembled polyneuritis. As of 30 June 2009, 27 cases of neuropathy SAEs have been 
reported. Of these, 22 were assessed as unrelated to study therapy because alternative etiologies, 
including brain metastases, spinal cord compression, arterial thrombosis, or platinum-base 
chemotherapy were identified in almost every case. 
 
Clinical Efficacy of Ipilimumab 
 
Treatment with ipilimumab has demonstrated clinically important and durable tumor responses in 
several malignancies including melanoma, prostate cancer, and renal cell carcinoma. The most 
extensively studied tumor type has been malignant melanoma and the principal demonstration of 
the efficacy of ipilimumab comes from a phase III trial of ipilimumab versus placebo as second 
line therapy in patients with metastatic melanoma. In this trial, patients were randomized to 
ipilimumab plus the gp100 vaccine, ipilimumab alone, or gp100 alone. The median overall 
survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 


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months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median 
overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison 
with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the 
ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). 16 Notably, several 
analyses have suggested an association between the development of irAEs and response to 
therapy.  
 
Rationale for a Phase II Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Urothelial 
Carcinoma 
 
A study exploring the combination of gemcitabine, cisplatin, and ipilimumab in advanced 
urothelial carcinoma is supported by the following: 
 
1. Gemcitabine plus cisplatin is standard treatment for advanced urothelial cancer; while the 
majority of patients respond to treatment, response durations are short with a median 
survival of 14 months.  
2. Immunotherapy (with BCG) has played a major role in the treatment of non-muscle 
invasive urothelial carcinoma. However, immunotherapeutic approaches for advanced 
disease have been largely unsuccessful. 
3. CTLA4 blockade with ipilimumab is a novel approach to immunotherapy involving 
augmentation of cell mediated immunity by interrupting T-cell pathways responsible for 
immune down-regulation or tolerance. Ipilimumab has shown activity in a range of 
advanced solid tumors and has resulted in improved survival in patients with melanoma. 
4. Ipilimumab has shown intriguing activity as neoadjuvant therapy in patients with clinically 
localized bladder cancer undergoing radical cystectomy. 
5. Several preclinical and clinical studies support additive/synergistic effects of combination 
chemotherapeutic and immunotherapeutic approaches. Ipilimumab has been administered 
in combination with chemotherapy in several clinical trials and has demonstrated safety 
and intriguing antitumor activity. In a phase II study, patients with chemotherapy-naive, 
recurrent or stage IIIB/IV non-small cell lung cancer were randomized 1:1:1 to receive 
either: ipilimumab (10 mg/kg IV q3wks) + concurrent paclitaxel/carboplatin, ipilimumab + 
sequential paclitaxel + carboplatin, or paclitaxel plus carboplatin alone. 21 There were 
generally manageable and reversible immune related adverse events and rare and 
comparable drug related deaths across all study arms. There was an improvement in 
progression-free survival with the addition of ipilimumab. 
6. Combination gemcitabine, cisplatin, plus ipilimumab may build on the chemosensitivity of 
urothelial carcinoma to produce more durable responses and improved outcomes.  
 
Rationale for using immune-related Tumor Assessment Criteria (irRC) 
 
Ipilimumab is an immune-stimulating antibody with evidence of anti-cancer activity (durable 
objective response and stable disease) across various solid tumors. Observations of clinical 
activity defined by tumor response endpoints defined by conventional criteria (e.g., mWHO) may 
be inadequate to realize the kinetics and magnitude of clinical benefit achieved with ipilimumab. 
Histopathological evidence has demonstrated ipilimumab can produce an influx or expansion of 
tumor infiltrating lymphocytes. Therefore, early increases in lesion size detected radiologically or 


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upon gross examination could be misinterpreted as progressive tumor growth and precede 
objective tumor shrinkage. In addition the appearance of new lesions may have categorized a 
subject to have progressive disease using conventional tumor assessment criteria despite the 
concurrent observation of objective tumor responses in preexisting lesions and a net reduction in 
global tumor burden that includes the new lesions. 
 
Hence, the appearance of new lesions in and of themselves may not necessarily constitute 
progressive disease. The immune-related response criteria (irRC) were developed as a tool to 
gauge tumor response using the changes in global tumor burden22. In addition, the irRC may be 
useful to inform a physician’s decision to continue dosing in subjects who may receive benefit 
from additional ipilimumab therapy. The ir-response assessment is based solely on objective 
measurements (sum of the product of the 2 largest perpendicular diameters, SPD) of index and 
new lesions. Non-index lesions are not considered. The irRC identified 9.7% of subjects (22/227 
treated subjects) from CA184022 and CA184008 at 10 mg/kg who demonstrated disease control in 
the form of stable or reduced measurable tumor burden, including new lesions, at or after disease 
progression by mWHO. 
 
For the current trial, response will be assessed both by irRC and RECIST v1.0 providing 
additional data for comparisons of these systems of response assessment in patients receiving 
combination immune plus cytotoxic therapy. 
 
2.0 
OBJECTIVES 
 
 
2.1 
Primary Objective: 
 
 To determine the 1-year overall survival of patients with advanced/metastatic urothelial 
carcinoma treated with gemcitabine, cisplatin, plus ipilimumab. 
 
2.2 
Secondary Objectives: 
 
 To 
determine 
the 
progression-free 
survival 
(using 
irRC) 
of 
patients 
with 
advanced/metastatic urothelial carcinoma treated with gemcitabine, cisplatin, and 
ipilimumab. 
 To determine the disease control rate (complete response + partial response + stable 
disease using irRC and RECIST v1.0 [see Section 8.2]) to treatment with gemcitabine, 
cisplatin, plus ipilimumab. 
 To determine the safety of treatment with gemcitabine, cisplatin, plus ipilimumab. 
 
2.3 
Exploratory Objectives: 
 
 To serially monitor the global composition immune cells in the blood by polychromatic 
flow cytometry and correlate changes with clinical outcome. 
 To determine the frequency of tumor-antigen specific CD8+ T cells by antigen-specific 
multi-cytokine production (IFN-γ, TNF-α and IL-2) by intracellular cytokine staining. 
 To perform transcriptional profiling of blood samples before and after treatment using 
microarray and correlate changes with clinical outcomes.  


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3.0 
ELIGIBILITY CRITERIA 
 
3.1 
Written informed consent and HIPAA authorization for release of personal health 
information. 
 
NOTE: HIPAA authorization may be included in the informed consent or obtained 
separately. 
 
3.2 
Age ≥ 18 years at the time of consent. 
 
3.3 
Karnofsky performance status (KPS) ≥ 80% within 7 days prior to registration for 
protocol therapy. 
 
3.4 
Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for up to 26 weeks after 
the last dose of investigational product, in such a manner that the risk of pregnancy 
is minimized. 
 
WOCBP include any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined 
as: Amenorrhea  12 consecutive months without another cause, or for women with 
irregular menstrual periods and taking hormone replacement therapy (HRT), a 
documented serum follicle-stimulating hormone (FSH) level  35 mIU/mL. 
 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal 
products, skin patches, or implanted or injectable products), or mechanical products 
such as an intrauterine device or barrier methods (diaphragm, condoms, 
spermicides) to prevent pregnancy, or are practicing abstinence or where their 
partner is sterile (e.g., vasectomy) should be considered to be of childbearing 
potential. 
 
3.5 
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 72 hours before the start of 
ipilimumab. 
 
3.6 
Men of fathering potential must be using an adequate method of contraception to 
avoid conception throughout the study [and for up to 26 weeks after the last dose of 
investigational product] in such a manner that the risk of pregnancy is minimized. 
 
3.7 
Females must not be pregnant or breastfeeding. 
 
3.8 
Histological or cytological proof of urothelial carcinoma of the urethra, bladder, 
ureters, or renal pelvis. 
 
3.9 
Advanced (clinical stage T4b, unresectable) or metastatic disease.  


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3.10 
No active CNS metastases. Subjects with neurological symptoms must undergo a 
head CT scan or brain MRI to exclude brain metastasis within 28 days of 
registration. 
 
NOTE: A subject with prior brain metastasis may be considered if they have 
completed their treatment for brain metastasis, no longer require corticosteroids, 
and are asymptomatic. 
 
3.11 
No prior malignancy is allowed except for cancers that have been definitively 
treated with a risk of recurrence of < 30% based on the treating oncologist’s 
assessment.  
 
3.12 
Patients may not have received prior systemic chemotherapy for 
metastatic/advanced urothelial carcinoma. 
 
NOTE: Prior neoadjuvant/adjuvant therapy is permitted if completed ≥ 12 months 
prior to registration for protocol therapy. Prior intravesical therapy is permitted. 
 
3.13 
No treatment with any investigational agent within 30 days prior to registration for 
protocol therapy.  
 
3.14 
Prior radiation therapy is allowed to < 25% of the bone marrow [see bone marrow 
radiation chart in the study procedure manual (SPM)].  
 
NOTE: No radiation therapy within 30 days prior to registration for protocol 
therapy.  
 
3.15 
Prior Autoimmune disease: Patients with a history of inflammatory bowel disease, 
including ulcerative colitis and Crohn’s Disease, are excluded from this study, as 
are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [e.g., Wegener’s granulomatosis]); motor neuropathy 
considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia 
Gravis).  
 
NOTE: Patients with other immune disorders should not be enrolled without 
discussion with the principal investigator. 
 
3.16 
No underlying medical or psychiatric condition, which in the opinion of the 
investigator will make the administration of ipilimumab hazardous or obscure the 
interpretation of AEs, such as a condition associated with frequent diarrhea. 
 
3.17 
No non-oncology vaccine therapy used for prevention of infectious diseases (for up 
to 1 month before or after any dose of ipilimumab). 
 


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3.18 
No history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 
inhibitor or agonist. 
 
3.19 
No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C. 
 
3.20 
No clinically significant infections as judged by the treating investigator. 
 
3.21 
No chronic systemic corticosteroids (defined as the equivalent of prednisone ≥ 20 
mg PO daily for > 6 months during the past year) 
 
NOTE: Laboratory values must be obtained within 7 days prior to registration for protocol 
therapy.  
 
3.22 
White blood cell count (WBC) ≥ 3.5K/mm3  
 
3.23 
Hemoglobin (Hgb) ≥ 9 g/dL 
 
3.24 
Platelets ≥ 100K/mm3 
 
3.25 
Absolute neutrophil count (ANC) ≥ 1.5K/mm3 
 
3.26 
Actual or Calculated creatinine clearance of ≥ 55 cc/min using the Cockcroft-Gault 
formula: 
 
 
Males: (140 – Age in years) × Actual Body Weight in kg 
 72 × Serum Creatinine (mg/dL) 
 
Females: Estimated creatinine clearance for males × 0.85 
 
3.27 
Bilirubin ≤ 1.5 times () Upper Limit of Normal (ULN) (except patients with 
Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL) 
 
3.28 
Aspartate aminotransferase (AST) ≤ 2.5  ULN. NOTE: If the patient has liver 
metastases present, then ≤ 5  ULN 
 
3.29 
Alanine aminotransferase (ALT) ≤ 2.5  ULN. NOTE: If the patient has liver 
metastases present, then ≤ 5  ULN 
 
3.30 
Patient must consent to mandatory correlative sample collection. 
 
4.0 
PATIENT REGISTRATION  
 
All patients must be registered through the Hoosier Cancer Research Network electronic 
data capture (EDC) system. 
  
Detailed guidelines for patient registration and electronic case report form (eCRF) 
completion can be found in the Study Procedures Manual (SPM).  


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Patients must be registered prior to starting protocol therapy and begin therapy within 5 
working days of registration.  
 
 
Blinding 
 
 
The study treatment is not blinded to the patient or the investigator. 
 
5.0 TREATMENT PLAN  
 
Treatment during the “induction” phase will be administered in six 21-day cycles. During cycles 1 
and 2, gemcitabine plus cisplatin will be administered WITHOUT ipilimumab. During cycles 3-6, 
combination therapy with gemcitabine, cisplatin, plus ipilimumab will be administered. Patients 
without evidence of disease progression (by irRC) after completion cycle 6 will continue single-
agent ipilimumab “maintenance” every 3 months.  
 
5.1 
Induction: 
 
Patients will undergo a restaging CT scan after cycle 2 and after cycle 6. However, patients with 
evidence of disease progression (in the absence of significant functional/symptomatic 
deterioration) on the post-cycle 2 CT scan will not be required to come off study as they will have 
not yet started ipilimumab. Patients may elect to come off study at any time. 
 
Furthermore, as durable disease stabilization and/or objective tumor response can be seen in other 
advanced solid tumors after early progression before 12 weeks of ipilimumab treatment, it is 
recommended that, in the absence of treatment-limiting toxicities (e.g., serious irAEs), all four 
doses of ipilimumab be administered over the initial 12 weeks even in the setting of apparent 
progression, providing the subject’s performance status remains stable. 
 
Based on clinical experience in ongoing and completed melanoma studies, the following 
recommendations apply for subject management in light of the post-cycle 6 or later tumor 
assessments: 
 The appearance of new lesions in subjects with other stable or shrinking baseline tumor 
burden may be experiencing clinical benefit and should continue in follow-up and/or 
maintenance therapy before alternative anti-cancer agents are considered. These subjects can 
be seen to have continued tumor shrinkage in follow-up scans. 
 As long as overall tumor burden is stable or decreasing, subjects should remain in follow-up 
and/or maintenance, even in the presence of new lesions. 
 Clinical progression warranting alternative anti-cancer treatment should be considered only in 
subjects whose overall tumor burden appears to be substantially increased and/or in subjects 
whose performance status is decreased. 
 
The irRC will be utilized which requires a confirmatory scan documenting progression 22. The 
definition of confirmation of progression represents an increase in tumor burden ≥ 25% compared 
with nadir at two consecutive time points at least 4 weeks apart. Therefore, patients with disease 


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progression on the post-cycle 6 scan (in the absence of symptomatic/functional deterioration) 
should have a confirmatory CT scan at least 4 weeks later. 
 
5.2 
Maintenance: 
 
As per the schedule of dosing in the ongoing and completed clinical studies using ipilimumab in 
subjects with pretreated advanced melanoma, maintenance therapy should be offered to all 
subjects who have not experienced unacceptable toxicity (refractory Grade > 3 irAEs) and are 
considered by the investigator to be obtaining clinical benefit, either because of apparent tumor 
stability or continued shrinkage and/or late response. 
 
A single dose of 10 mg/kg ipilimumab given intravenously over 90 minutes should be 
administered every 12 weeks, starting from approximately week 28 until the subject is no longer 
clinically benefiting from therapy, per the investigator, or until the occurrence of unacceptable or 
unmanageable toxicity. 
 
Subjects in maintenance should receive radiographic tumor assessments every 12 weeks before 
administration. Subjects who continue to experience clinical benefit, as defined by the investigator, 
and who have not experienced unacceptable toxicity (refractory Grade > 3 irAEs), are eligible to 
receive continued maintenance. 
 
5.3 
Pre-medication:  
 
Gemcitabine 
 
There are no required/recommended premedications for the administration of gemcitabine. 
Antiemetics may be administered per institutional guidelines. 
 
Cisplatin 
 
The antiemetic regimen is at the discretion of the treating physician and according to institutional 
standards.  
 
Ipilimumab 
 
There are no required premedications for the administration of ipilimumab. 
 


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5.4 
Drug Administration: 
Cycles 1 and 2: Gemcitabine plus cisplatin 
Agent 
Route Dose 
Administration 
Frequency 
* 
(± 3 days) 
Cycle 
Length 
# 
Cycles 
Gemcitabine IV 
1000 
mg/m2 
Over 30 minutes 
according to 
institutional 
guidelines 
Day 1, 8 
21 days 1-2 
Cisplatin 
IV 
70 
mg/m2 
As per institutional 
guidelines 
Day 1 
 
Cycles 3-6: Gemcitabine, Cisplatin, plus Ipilimumab 
Agent 
Route Dose 
Administration 
Frequency 
* 
(± 3 days) 
Cycle 
Length 
# 
Cycles 
Ipilimumab 
IV 
10 
mg/kg 
Over 90 minutes 
Day 1 
21 days 3-6 
Gemcitabine IV 
1000 
mg/m2 
Over 30 minutes 
according to 
institutional 
guidelines 
Day 1, 8 
Cisplatin 
IV 
70 
mg/m2 
As per institutional 
guidelines 
Day 1 
 
Maintenance Single Agent Ipilimumab (starting ~ week 28) 
Agent 
Route Dose 
Administration 
Frequency 
* 
(± 3 days) 
Cycle 
Length 
# Cycles 
Ipilimumab IV 
10 
mg/kg 
Over 90 minutes 
Day 1 
3 
months 
Until 
progression 
 
Note: * Infusions may be given ±3 days for reasons such as observed holidays, inclement weather, 
scheduling conflicts, etc. It should be clearly documented in patient’s chart and case report forms. 
 
Only if patient’s weight changes by > 10% during the course of the study, the body surface area 
and chemotherapy drug dose should be recalculated. Ipilimumab dosing should be calculated at 
each visit using patient’s current weight (obtained within 3 days of the dosing visit, and prior to 
the infusion). 
 


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5.5 
Supportive Care: 
 
The use of supportive care will be permitted as clinically indicated and according to institutional 
guidelines. The use of white blood cell and red blood cell growth factors should be consistent with 
American Society of Clinical Oncology (ASCO) guidelines. 
 
5.6 
Concomitant Medications: 
 
Patients in this study may not use vaccines for the treatment of cancer or prevention of disease 
unless indicated as a component of the protocol regimen (including those for common medical 
conditions) for up to one month pre and post dosing with ipilimumab.  
 
Concomitant systemic or local anti-cancer medications or treatments are prohibited in this study 
while receiving ipilimumab treatments unless as otherwise specified in this protocol. 
 
Patients may not use any of the following therapies during the study: 
 Any non-study anti-cancer agent (investigational or non-investigational) 
 Any other investigational agents 
 Any other (non-CA184024 related) CTLA-4 inhibitors or agonists 
 CD137 agonists 
 Immunosuppressive agents 
 Chronic systemic corticosteroids (defined as the equivalent of prednisone ≥ 20 mg daily) 
 Any non-oncology vaccine therapies used for the prevention of infectious diseases (for up 
to 30 days prior to or after any dose of study drug). 
 
6.0 
DOSE MODIFICATIONS  
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be used to 
grade adverse events. 
  
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study as specified in Section 7.0 
 
Patients will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation at each study visit for the duration of 
their participation in the study.  
 
Patients discontinued from the treatment phase of the study for any reason will be evaluated at 
least 30 days after the last dose of study drug. 
 
Dose modifications will be based on blood counts within 3 days prior to Day 1 or Day 8 of each 
cycle.  
 
Each treatment cycle will begin only when:  
 ANC ≥ 1.5K/mm3 
 Platelets ≥ 100K/mm3 


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 Resolution of non-hematologic toxicities to ≤ Grade 1 or baseline 
 For treatment cycles involving ipilimumab, LFT results must be reviewed by the 
treating physician to meet dosing criteria specifications:  2.5 x ULN for AST, 
ALT and  1.5 x ULN for T. bilirubin unless liver metastases are present in which 
case LFT  5 x ULN for AST, ALT and T. bilirubin  3.0 x ULN) prior to dosing. 
 
Patients requiring treatment to be held for toxicity > 21 days will be removed from study 
treatment. 
 
6.1 
Treatment Limiting Adverse Event: 
 
 
 A treatment-limiting adverse event is any adverse event related to protocol therapy 
experienced during the study resulting in treatment termination.  
 
 
6.2 
Dose Modifications for Treatment Related Hematological Toxicity: 
 
Dose modifications for Day 1 Treatment (Cycle 2 through Cycle 6) 
The following dose modifications will be based on blood counts within 3 days prior to Day 
1 of each cycle of therapy. 
ANC 
 
Platelets 
Cisplatin dose 
Lowest 
gemcitabine 
dose in prior 
cycle 
Day 1 dose 
of 
gemcitabine 
≥1.5K/
mm3 
And ≥ 100 
K/mm3 
Continue dose of 
cisplatin from prior 
cycle (e.g., if no prior 
dose reductions, 
continue at 70 
mg/m2) 
1000 mg/m2 
1000 mg/m2 
≥ 
1.5K/m
m3 
And ≥ 100 
K/mm3 
800 mg/m2 
800 mg/m2 
≥ 
1.5K/m
m3 
And ≥ 100 
K/mm3 
600 mg/m2 
600 mg/m2 
<1.5K/
mm3 
Or 
<100 
K/mm3 
*Hold and recheck in 
1 week 
Any 
*Hold and 
recheck 
in 1 week 
*Once ANC ≥ 1500 and platelets ≥ 100,000, resume therapy with gemcitabine 
reduced by 1 dose level. If gemcitabine has already been reduced by 1 dose level, 
discuss dose reduction with principal investigator. Granulocyte colony stimulating 
factors may be used at the discretion of the treating physician; however, growth 
factors should be not used during cycle #1 or in lieu of recommended dose reductions. 
Treatment with ipilimumab will also be HELD until patients meet criteria to resume 
dosing with gemcitabine and cisplatin.  
Dose modifications for Day 8 Treatment (any cycle) 
 
The following dose modifications of gemcitabine will be based on blood counts within 3 
days prior to day 8 of each cycle of therapy. 
 


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ANC 
 
Platelets 
if Day 1 dose 
level of 
gemcitabine 
was: 
then Day 8 dose 
level of 
gemcitabine will 
be: 
≥ 
1.5K/mm3 
And 
≥ 100 K/mm3 
1000 mg/m2 
1000 mg/m2 
≥1.5K/mm3 And 
≥ 100,000 
800 mg/m2 
800 mg/m2 
≥ 
1.5K/mm3 
And 
≥ 100 K/mm3 
600 mg/m2 
600 mg/m2 
1.0K/mm3-
1.4 K/mm3 
And 
≥ 100 K/mm3 
1000 mg/m2 
800 mg/m2 
<1.0 
K/mm3 
Or 
<100,000 K/mm3 Any 
Hold and recheck 
in 1 week* 
*Treatment held on Day 8 should not be made up at a later date; resume next cycle as 
scheduled with gemcitabine reduced by 1 dose level.  
 
There should be no dose re-escalation after a dose reduction.  
 
Febrile neutropenia 
 
If febrile neutropenia develops in a given cycle, hold gemcitabine, cisplatin, and 
ipilimumab during febrile neutropenia.  
 
NOTE: Doses missed on Days 8 of therapy will not be made up.  
 
Resume gemcitabine and cisplatin at one dose lower than the dose administered in the 
last cycle. This dose should be used for all subsequent cycles. The dose of ipilimumab 
will be unchanged. Granulocyte colony stimulating factors may be used at the discretion 
of the treating physician. 
 
6.3 
Dose Modifications for Other Treatment Related Non-Hematological Toxicity 
Secondary to Gemcitabine or Cisplatin: 
 
Dose reductions for nonhematologic toxicities attributable to gemcitabine or cisplatin (with 
the exception of alopecia or nausea/vomiting not optimally managed with antiemetics) are 
outlined in the table below. Only the drugs felt to be contributing to the toxicity per the 
Treating Physician should be dose reduced. Patients with treatment-related nausea that is 
grade ≥ 2 despite optimal use of antiemetics will be dose reduced by 1 level.  
 
If nonhematologic toxicity occurs mid-cycle, and is attributed to gemcitabine, the Day 8 
gemcitabine dose should be held and resumed with the subsequent cycle as scheduled. 
 
Dose reductions for nonhematologic toxicities 
Nonhematologic toxicity 
Gemcitabine/Cisplatin 
Grade 0-2 
No change 
Grade 3 
Hold until Grade ≤1 and 


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resume treatment reduced by 1 
dose level 
Grade 4 
Hold until Grade ≤1 and 
resume treatment reduced by 1 
dose level 
 
Dose modifications for gemcitabine and cisplatin 
Dose level 
Gemcitabine 
Cisplatin 
Dose level -1 
800 mg/m2 
60 mg/m2 
Dose level -2 
600 mg/m2 
50 mg/m2 
 
Dose re-escalation after a dose reduction for nonhematologic toxicity should not occur 
without discussion with the Study Investigator. 
 
If toxicity is specifically attributable to cisplatin and warrants discontinuation of 
cisplatin, patients may be considered for continuation on treatment with gemcitabine and 
ipilimumab but this must be discussed with the Study Investigator. 
 
6.4 
Dose Modifications for Ipilimumab: 
 
Dose de-escalation of ipilimumab from 10 mg/kg is not allowed. 
 
Ipilimumab Dose Skipping Rule 
 
Decisions to skip an ipilimumab dose must be made on specified safety criteria. Treatment 
with ipilimumab will be skipped or discontinued if the subject experiences at least one 
adverse event, specified below, considered by the investigator to be “possibly”, probably” 
or “certainly” related to ipilimumab treatment.  
 
The following criteria will be used to determine dose skipping, restarting doses, or 
discontinuing ipilimumab. 
 
It may be necessary to skip study drug dosing for the following related adverse event(s) at 
investigator’s discretion: 
 Any ≥ Grade 2 non-skin related adverse event (including irAEs), except for 
laboratory abnormalities 
 Any ≥ Grade 3 laboratory abnormality 
 Any adverse event, laboratory abnormality or intercurrent illness that, in the 
judgment of the investigator, presents a substantial clinical risk to the subject with 
continued dosing. 
 
It is necessary to skip study drug dosing for the following adverse events: 
 Any ≥ Grade 3 skin related adverse event regardless of causality. 
 Any toxicities resulting in chemotherapy being held (unless otherwise approved by 
the principal investigator). 
 


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Restart ipilimumab dosing if/when the adverse event(s) resolve(s) to ≤ Grade 1 severity or 
returns to baseline within 2 weeks of initial dose administration: 
 If the adverse event has resolved, restart ipilimumab dosing at the next scheduled 
time point per protocol.  
 If the adverse event has not resolved in the protocol-specified dosing window (3 
weeks, the next scheduled dose will be skipped and dosing will be resumed at the 
subsequently scheduled dose. 
 If > 1 dose is expected to be skipped, the dosing schedule modifications must be 
discussed with the principal investigator prior to implementation.  
 
The following treatment related non-neurological adverse events require permanent 
discontinuation of ipilimumab: 
 Any ≥ Grade 2 eye pain or reduction of visual acuity that does not respond to 
topical therapy and does not improve to ≤ Grade 1 severity within 2 weeks of 
starting therapy, OR, requires systemic treatment. 
 Any ≥ Grade 3 bronchospasm or other hypersensitivity reaction. 
 Any other ≥ Grade 3 non-skin related adverse event with the exception of events 
listed under “No Discontinuation” (below). 
 Any ≥ Grade 4 laboratory abnormalities, except AST, ALT, or Total Bilirubin 
 AST or ALT > 8 x ULN 
 Total Bilirubin > 5 x ULN 
 Any other ≥ Grade 4 adverse event 
 Any adverse event, laboratory abnormality or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the patient with 
continued dosing.  
 
The following neurological adverse event requires permanent discontinuation of 
ipilimumab and defines unacceptable neurotoxicity: 
 Any motor neurologic toxicity >/= Grade 3 regardless of causality 
 Any ≥ Grade 3 treatment related sensory neurologic toxicity 
 
Exceptions to Permanent Discontinuation 
 Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor 
reaction and a potential therapeutic response. This includes inflammatory reactions 
at sites of tumor resections or in draining lymph nodes, or at sites suspicious for, 
but not diagnostic of metastasis. 
 Hospitalization for ≤ Grade 2 adverse events where the primary reason for 
hospitalization is to expedite the clinical work-up. 
 Patients with the following conditions where in the investigator’s opinion 
continuing study drug administration is justified: 
o Ocular toxicity that has responded to topical therapy. 
o Endocrinopathies where clinical symptoms are controlled with appropriate 
hormone replacement therapy. Note: Ipilimumab may not be restarted while 
the patient is being treated with systemic corticosteroids except for patients 
on stable doses of hormone replacement therapy such as hydrocortisone. 
 


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6.5 
Immune-Related Adverse Events (irAEs): Definition, Monitoring, and Treatment: 
 
Blocking CTLA-4 function may permit the emergence of auto-reactive T cells and 
resultant clinical autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis, 
and hypopituitarism were drug-related, presumptive autoimmune events, now termed 
irAEs, noted in previous ipilimumab studies. 
 
For the purposes of this study, an irAE is defined as an AE of unknown etiology associated 
with drug exposure and consistent with an immune phenomenon. Efforts should be made 
to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling 
an AE an irAE. Serological, immunological, and histological (biopsy) data should be used 
to support the diagnosis of an immune-mediated toxicity. Suspected irAEs must be 
documented on an AE or SAE form.  
 
Patients should be informed of and carefully monitored for evidence of clinically 
significant systemic irAE (e.g., systemic lupus erythematosus-like diseases) or 
organ-specific irAE (e.g., rash, colitis, uveitis, hepatitis or thyroid disease). If an irAE is 
noted, appropriate work-up (including biopsy if possible) should be performed, and steroid 
therapy may be considered if clinically necessary. .  
 
It is unknown if systemic corticosteroid therapy has an attenuating effect on ipilimumab 
activity. However, clinical anti-tumor responses have been maintained in patients treated 
with corticosteroids and discontinued from ipilimumab. If utilized, corticosteroid therapy 
should be individualized for each patient. Prior experience suggests that colitis manifested 
as ≥ Grade 3 diarrhea requires corticosteroid treatment. 
 
Specific treatment algorithms for immune-related adverse events are included in Appendix 
A. 
 
6.6 
Treatment of Infusions Reactions and Fever Associated with Ipilimumab: 
 
Treatment of Infusion Reactions Associated with Ipilimumab 
 
Since ipilimumab contains only human protein sequences, it is less likely that any allergic 
reaction will be seen in patients. However, it is possible that infusion of ipilimumab will 
induce a cytokine release syndrome that could be evidenced by fever, chills, rigors, rash, 
pruritus, hypotension, hypertension, bronchospasm, or other symptoms. No prophylactic 
pre-medication will be given unless indicated by previous experience in an individual 
patient. Reactions should be treated based upon the following recommendations. 
 
For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, flushing, 
rash): 
 Decrease the rate of infusion until recovery from symptoms, remain at bedside and 
monitor patient. 
 Complete the ipilimumab infusion at the initial planned rate. 
 Diphenhydramine 50 mg IV may be administered at the discretion of the treating 
physician and patients may receive additional doses with close monitoring. 


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 Premedication with diphenhydramine may be given at the discretion of the investigator 
for subsequent doses of ipilimumab. 
 
For moderate symptoms (any symptom not listed above [mild symptoms] or below [severe 
symptoms] such as generalized pruritus, flushing, rash, dyspnea, hypotension with systolic 
BP >80 mmHg):  
 Interrupt ipilimumab. 
 Administer diphenhydramine 50 mg IV. 
 Monitor patient closely until resolution of symptoms. 
 Corticosteroids may abrogate any beneficial immunologic effect, but may be 
administered at the discretion of the treating physician. 
 Resume ipilimumab infusion after recovery of symptoms. 
 At the discretion of the treating physician, ipilimumab infusion may be resumed at one 
half the initial infusion rate, then increased incrementally to the initial infusion rate. 
 If symptoms develop after resumption of the infusion, the infusion should be 
discontinued and no additional ipilimumab should be administered that day. 
 The next dose of ipilimumab will be administered at its next scheduled time and may 
be given with pre-medication (diphenhydramine and acetaminophen) and careful 
monitoring, following the same treatment guidelines outlined above. 
 At the discretion of the treating physician additional oral or IV antihistamine may be 
administered prior to dosing with ipilimumab. 
 
For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticaria, 
systolic blood pressure 80 mm Hg, or angioedema): 
 Immediately discontinue infusion of ipilimumab, and disconnect infusion tubing from 
the subject. 
 Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or 
diphenhydramine 50 mg IV, with Solu-Medrol 100 mg IV, as needed. 
 Patients should be monitored until the investigator is comfortable that the symptoms 
will not recur. 
 No further ipilimumab will be administered. 
 
In case of late-occurring hypersensitivity symptoms (e.g., appearance within one week 
after treatment of a localized or generalized pruritus), symptomatic treatment may be given 
(e.g., oral antihistamine, or corticosteroids). 
 
Treatment of Ipilimumab-Related Isolated Drug Fever 
 
In the event of isolated drug fever, the investigator must use clinical judgment to determine 
if the fever is related to the ipilimumab or to an infectious etiology. If a patient experiences 
isolated drug fever, for the next dose, pre-treatment with acetaminophen or non-steroidal 
anti-inflammatory agent (investigator discretion) should be instituted and a repeated 
antipyretic dose at 6 and 12 hours after ipilimumab infusion should be administered. The 
infusion rate will remain unchanged for future doses. If a patient experiences recurrent 
isolated drug fever following premedication and post dosing with an appropriate 
antipyretic, the infusion rate for subsequent dosing should be decreased to 50% of the 


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previous rate. If fever recurs following infusion rate change, the investigator should assess 
the patient’s level of discomfort with the event and use clinical judgment to determine if 
the patient should receive further ipilimumab. 


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7.0 
STUDY CALENDAR & SCHEDULE OF EVALUATIONS  
                                                                                 Induction  
 
 
     Maintenance Ipilimumab 
 
Pre-study 
Cycle 1-21 
(cycle = 21 days) 
Cycles 3-61 
(cycle = 21 days) 
 
Cycle Length = 3 months 
End of 
Treatment 
Follow-up 
-28 days 
-7 days 
Day 1 
Day 8 
Day 1 
Day 8 
 
Day 1 
 
Day 30 
± 7 
 
Day 
60 ± 
7 
 
(30 ± 7 days 
post last 
treatment) 
Follow-up10 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & smoking history 
 
X 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
X 
X2 
X 
X2 
 
X 
X 
X 
X 
 
Blood pressure 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Weight [Kg] 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
KPS 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
CMP3 
 
X 
X 
 
X4 
 
 
X4 
X 
X 
X 
 
TSH 5 
 
 
 
 
X 
 
 
X 
 
 
 
 
Calculated creatinine clearance 
 
X 
 
 
 
 
 
 
 
 
 
 
CBC (including platelets, ANC & Hgb) 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Urine pregnancy 
 
X 
 
 
X6 
 
 
 
 
 
 
 
Adverse event and concomitant medication 
assessment 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
 
 
 
 
 
CT chest , abdomen, pelvis7 
X 
 
Disease evaluations will be performed after 
cycle 2 and after cycle 6 
 
Disease evaluations will 
be performed prior to 
each maintenance cycle 
X9 
X 
Bone Scan (if clinically indicated)8 
X 
 
 
X9 
X 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine 
 
X 
X 
X 
X 
 
 
 
 
 
 
Cisplatin 
 
X 
 
X 
 
 
 
 
 
 
 
Ipilimumab 
 
 
 
X 
 
 
X 
 
 
 
 
CORRELATIVE STUDIES 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory blood draws. See Section 7, 
Table 4 
 
 
 
 
 
 
 
 
 
 
 
 
Unstained tissue slides11  
 
 
X 
 
 
 
 
 
 
 
 
 
FOLLOW-UP 
 
 
 
 
 
 
 
 
 
 
 
 
Disease progression and survival 
 
 
 
 
 
 
 
 
 
 
 
X 
Calendar Footnotes on next page.


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1. There will be a window of ± 3 days for the start of each cycle, and a window of ± 3 day for each Day 8 visit. 
2. Abbreviated physical examination targeted to signs and symptoms 
3.Complete metabolic profile (CMP) will include: serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, 
total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium).  
4. Liver function tests (AST, ALT, T. bilirubin) will be evaluated for every subject prior to administration of ipilimumab. Blood samples must be collected and analyzed 
within 3 days prior to dosing. LFT results must be reviewed by the treating physician to meet dosing criteria specifications:  2.5 x ULN for AST, ALT and  1.5 x ULN 
for T. bilirubin unless liver metastases are present in which case LFT  5 x ULN for AST, ALT and T. bilirubin  3.0 x ULN) prior to dosing. 
If, during the course of treatment abnormal LFT values are detected, the subject must be managed using the hepatotoxicity algorithm, which is included as an Appendix. 
5. Results are needed prior to Ipilimumab dosing.  
6. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab. 
7. Patients will continue therapy, in the absence of prohibitive toxicities, until disease progression. Patients discontinuing treatment for reasons other than progression will 
be followed for disease progression and survival every 3 months (±7 days) for 2 years, every 6 months (±7 days) for years 3 - 5, and annually thereafter.  
8. Bone scan only if clinically indicated (elevated alkaline phosphatase, bone pain) 
9. A repeat CT scan is not required at end of treatment if performed within the 28 days. 
10. All patients who receive study drug will be followed for disease progression and survival every 3 months (±7 days) for 2 years from completion of protocol therapy, 
every 6 months (±7 days) for years 3 - 5, and annually thereafter.  
11. Unstained slides from the patients previously collected tumor tissue are to be submitted. Please refer to the Study Procedures Manual for collection and shipping 
instructions. 


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Figure and Table 4: Schedule for correlative blood sample collections (refer to study procedure manual for specimen processing and 
shipping instruction) 
 
 
 
 
Ipi
Ipi
-2     1    2    3    4    5    6    7    8     9   10    11    12    13    14    15    16    17    18    19    20
Screen
Scan
Scan
GC1
GC2
GC3
GC4
GC5
GC6
Ipi
Ipi
• Patients with stable or 
responding disease continue 
Ipilimumab maintenance every 
3 months (starting ~week 28)
• Scan every 3 months until 
progression
Scan
GC: Gemcitabine + Cisplatin
Gemcitabine 1000 mg/m2  days 1 + 8
Cisplatin 70 mg/m2 day 1
Cycle length = 21 days
Ipi: Ipilimumab 10 mg/kg on day 1 every 21 days with 
CYCLES 3-6. 
1 ACD tube (8.5 ml) for global T cell analysis (flow)
2 Tempus tubes (6 ml) for microarray
10 ACD tubes (85 ml) for cancer antigen specific CD8+ cells


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Table 4: Schedule for correlative blood sample collections 
 
 
 
 
 
 
 
 
 
 
7.1 
BASELINE/SCREENING 
  
7.1.1 Within 28 days prior to registration for protocol therapy: 
 
 
Radiological assessment (CT chest, abdomen, and pelvis) with tumor measurements; and 
 
Bone Scan if clinically indicated (e.g., elevated alkaline phosphatase, bone pain) 
 
7.1.2 Within 7 days of registration for protocol therapy: 
 
 
Eligibility evaluation (review of inclusion criteria) 
 
Medical & smoking history 
 
Height 
 
Blood pressure 
 
Weight [kg] 
 
Concomitant medications 
 
Physical examination 
 
Karnofsky Performance Status (KPS) 
 
12-lead electrocardiogram (ECG) 
 
Complete metabolic profile (CMP) will include: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline 
phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes 
(total calcium, chloride, potassium, sodium)  
 
Calculated creatinine clearance 
 
Complete blood count (CBC), including platelets, ANC & HGB 
 
Serum or urine pregnancy test for female patients of childbearing potential 
 
Documentation of commitment to abstinence for female patients of childbearing potential OR use of 
appropriate contraception 
Time point 
Correlative blood samples 
Cycle 1 Day 1 
1 ACD tube (8.5 ml total) 
2 Tempus tubes (6 ml total) 
10 ACD tubes (85 ml total) 
Cycle 3 Day 1 
1 ACD tube (8.5 ml total) 
2 Tempus tubes (6 ml total) 
10 ACD tubes (85 ml total) 
Cycle 6 Day 1 
1 ACD tube (8.5 ml total) 
2 Tempus tubes (6 ml total) 
10 ACD tubes (85 ml total) 
Maintenance Cycle 1 Day 1 
1 ACD tube (8.5 ml total) 
2 Tempus tubes (6 ml total) 
Time of progression 
1 ACD tube (8.5 ml total) 
2 Tempus tubes (6 ml total) 


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 
Documentation of commitment to abstinence from heterosexual intercourse for male patients OR 
commitment to use latex condoms with heterosexual intercourse with females of childbearing 
potential 
 
7.2 
ON TREATMENT 
 
7.2.1 Cycles 1-2 
 
On Day 1 of each treatment cycle, the following assessments/treatment administrations will occur: (For 
Cycle 1 Day 1 only, required tests do not need to be repeated if done within 7 days prior.) 
 
Blood pressure 
 
 Weight [kg] 
 
Physical examination 
 
Karnofsky Performance Status (KPS) 
 
Complete metabolic profile (CMP) will include: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline 
phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes 
(total calcium, chloride, potassium, sodium)  
 
CBC (including platelets, ANC & HGB) 
 
Blood collection for correlative studies (Cycle 1) 
 
Concomitant medications 
 
Collection of AEs 
 
Gemcitabine administration  
 
Cisplatin administration following appropriate hydration.  
 
Correlative studies: Submission of unstained slides from archived tumor sample (Cycle 1 Day 1 
only) 
 
On Day 8 of each treatment cycle, the following assessments/treatment administrations will occur: 
 
Blood pressure 
 
Weight [Kg] 
 
Abbreviated physical examination targeted to signs and symptoms 
 
Karnofsky Performance Status (KPS) 
 
CBC (including platelets, ANC & HGB) 
 
Concomitant medications 
 
Collection of AEs  
 
Gemcitabine administration  
 
7.2.2 Cycles 3-6 
 
On Day 1 of each treatment cycle, the following assessments/treatment administrations will occur:  
 
Blood pressure 
 
Weight [Kg] 
 
Physical examination 
 
Karnofsky Performance Status (KPS) 
 
Complete metabolic profile (CMP) will include: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline 


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phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes 
(total calcium, chloride, potassium, sodium)  
 
 Liver function tests (AST, ALT, T. bilirubin) will be evaluated for every subject prior to 
administration of ipilimumab. Blood samples must be collected and analyzed within 3 days prior to 
dosing. 
 
TSH 
 
CBC (including platelets, ANC & HGB) 
 
Blood collection for correlative studies. (Cycles 3 and 6) 
 
Concomitant medications 
 
Collection of AEs 
 
Serum or urine pregnancy test within 72 hours of first dose of ipilimumab 
 
Gemcitabine administration 
 
Cisplatin administration following appropriate hydration 
 
Ipilimumab administration 
 
On Day 8 of each treatment cycle, the following assessments/treatment administrations will occur: 
 
Blood pressure 
 
Weight [Kg] 
 
Karnofsky Performance Status (KPS) 
 
Abbreviated physical examination targeted to signs and symptoms 
 
CBC (including platelets, ANC & HGB) 
 
Concomitant medications 
 
Collection of AEs  
 
Gemcitabine administration for all patients. 
 
7.2.3 Restaging Radiographic Examinations 
 
A CT scan of the chest, abdomen, and pelvis (and bone scan if clinically indicated) will be performed after 
cycle 2 and after cycle 6. During the maintenance phase with single-agent ipilimumab, patients will 
undergo restaging CT scans (and bone scans if clinically indicated) every 3 months, until the time of 
progression. 
 
7.2.4 Maintenance Phase 
 
Day 1 of each cycle 
 
Patients achieving at least stable disease after 6 cycles of “induction therapy” will proceed with single-
agent ipilimumab maintenance given once every 3 months. The following assessments will occur on Day 1 
of each maintenance cycle:  
 
Blood pressure 
 
Weight [Kg] 
 
Physical examination 
 
Karnofsky Performance Status (KPS) 
 
Complete metabolic profile (CMP) will include: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline 
phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes 
(total calcium, chloride, potassium, sodium)  


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 
 Liver function tests (AST, ALT, T. bilirubin) will be evaluated for every subject prior to 
administration of ipilimumab. Blood samples must be collected and analyzed within 3 days prior to 
dosing. 
 
TSH 
 
CBC (including platelets, ANC & HGB) 
 
Blood collection for correlative studies (Maintenance Cycle 1 Day 1 Only) 
 
Concomitant medications 
 
Collection of AEs 
 
Review of restaging CT of the chest, abdomen, and pelvis (performed prior to initiation of each 
subsequent cycle) 
 
Ipilimumab administration. 
 
Day 30 ±7 days 
 
 
Blood pressure 
 
Weight [kg] 
 
Physical examination 
 
Karnofsky Performance Status (KPS) 
 
Complete metabolic profile (CMP) will include: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline 
phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes 
(total calcium, chloride, potassium, sodium)  
 
CBC (including platelets, ANC & HGB) 
 
Concomitant medications 
 
Collection of AEs 
 
Day 60 ± 7 days 
 
 
Blood pressure 
 
Weight [kg] 
 
Physical examination 
 
Karnofsky Performance Status (KPS) 
 
Complete metabolic profile (CMP) will include: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline 
phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes 
(total calcium, chloride, potassium, sodium)  
 
CBC (including platelets, ANC & HGB) 
 
Concomitant medications 
 
Collection of AEs 
 
7.3 
TREATMENT DISCONTINUATION 
 
A patient will be discontinued from the treatment under the following circumstances: 
 
If there is evidence of progressive disease (See Section 8.0).  
 
If the attending physician thinks a change of therapy would be in the best interest of the 
patient. 
 
If the drug(s) exhibit(s) unacceptable adverse event. 


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 
If a patient becomes pregnant. 
 
Treatment interruption for greater than 21 days due to treatment related adverse event.  
 
Patients can stop participating at any time. However, if they decide to stop participating in the 
study, patients will continue to be followed for disease progression and survival. 
 
7.4 
END OF TREATMENT EVALUATIONS: ~30 days (±7 days) post last therapy  
 
At the end of treatment or if the patient withdraws from the study, the following assessments/treatment 
administrations will occur: 
 
Blood pressure 
 
Weight [Kg] 
 
Physical examination  
 
Karnofsky Performance Status (KPS) 
 
Complete metabolic profile (CMP) will include: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline 
phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes 
(total calcium, chloride, potassium, sodium)  
 
CBC (including platelets, ANC & HGB) 
 
Blood collection for correlative studies (At the time the patient progresses) 
 
Concomitant medications 
 
Collection of AEs 
 
Radiological assessments if >28 days since last assessment. 
 
Patients will continue to be followed until resolution or stabilization of any treatment-related 
toxicities.  
 
7.5 
FOLLOW-UP: 
 
Patients proceeding with single-agent maintenance ipilimumab will be followed as described for 
progression. Patients discontinuing treatment for reasons other than tumor progression will also be 
followed for progression.  
 
The Investigator or designees will make every possible attempt every 3 months (±7 days), for 2 years from 
completion of protocol therapy, every 6 months (±7 days) for years 3 - 5, and annually thereafter, to contact 
the patient or family to obtain the survival information of the patient and start date of additional anticancer 
treatment. 
 
7.6 
END OF STUDY: 
 
Patients will be considered off study if any of the following occur: 
1. Termination of the study 
2. Withdrawal of consent (patient will not be contacted and no further information will be collected). If 
the patient withdraws consent, then no additional data will be collected without his/her explicit consent; 
all data collected prior to withdrawal of consent may be used in the data analysis. The collection of date 
of death and cause of death (if available) will be collected in the study since survival is an endpoint.  
3. Lost to follow-up; 3 attempts should be documented in the patient’s source document before the site 
considers the patient as lost to follow-up. 
4. Death 


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8.0 
CRITERIA FOR DISEASE EVALUATION 
 
 
For the current study, response assessments will be made both using the Immune Related Response 
Criteria, and using RECIST v1.0, allowing additional comparisons among these criteria for disease 
response assessment. The same measurable and non-measurable lesions will be followed by both RECIST 
& irRC. 
 
8.1 
Immune Related Response Criteria: 
 
This study will utilize the Immune Related Response Criteria (irRC). These response criteria were 
developed to overcome the variable and unusual patterns of response to immunotherapeutic agents, in 
particular, ipilimumab 22. The development of the guidelines were prompted by observations, mostly in 
patients with metastatic melanoma, of initial disease progression followed by later response, late responses, 
and mixed responses with an overall decrease in tumor burden.  
 
8.1.1 
Antitumor response based on total measurable tumor burden 
 
For the irRC, only index and measurable new lesions are taken into account (in contrast to conventional 
WHO criteria, which do not require the measurement of new lesions, nor do they include new lesion 
measurements in the characterization of evolving tumor burden). At the baseline tumor assessment, the sum 
of the products of the two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, 
up to 10 visceral lesions) is calculated. At each subsequent tumor assessment, the SPD of the index lesions 
and of new, measurable lesions (up to 5 new lesions per organ; 10 visceral lesions) are added together to 
provide the total tumor burden:
 
 
Table 5: Comparison of WHO and irRC criteria 
 
WHO 
irRC 
New, measurable 
lesions  
Always represent PD 
Incorporated into tumor burden 
New, 
nonmeasurable 
lesions  
Always represent PD 
Do not define progression (but preclude irCR) 
Non-index lesions Changes contribute to defining BOR of CR, PR, SD, and PD 
Contribute to defining irCR (complete 
disappearance required) 
CR 
Disappearance of all lesions in two consecutive observations 
not less than 4 wk apart 
Disappearance of all lesions in two consecutive 
observations not less than 4 wk apart 
PR 
≥50% decrease in SPD of all index lesions compared with 
baseline in two observations at least 4 wk apart, in absence of 
new lesions or unequivocal progression of non-index lesions  
≥50% decrease in tumor burden compared with 
baseline in two observations at least 4 wk apart 
SD 
50% decrease in SPD compared with baseline cannot be 
established nor 25% increase compared with nadir, in absence 
of new lesions or unequivocal progression of non-index lesions  
50% decrease in tumor burden compared with 
baseline cannot be established nor 25% increase 
compared with nadir 
PD 
At least 25% increase in SPD compared with nadir and/or 
unequivocal progression of non-index lesions and/or 
appearance of new lesions (at any single time point)  
At least 25% increase in tumor burden compared 
with nadir (at any single time point) in two 
consecutive observations at least 4 wk apart  


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8.1.2 
Time-point response assessment using irRC 
 
Percentage changes in tumor burden per assessment time point describe the size and growth kinetics of 
both conventional and new, measurable lesions as they appear. At each tumor assessment, the response in 
index and new, measurable lesions is defined based on the change in tumor burden (after ruling out 
immune-related progressive disease [irPD]). Decreases in tumor burden must be assessed relative to 
baseline measurements (i.e., the SPD of all index lesions at screening). The irRC were derived from WHO 
criteria and, therefore, the thresholds of response remain the same. However, the irRC response categories 
have been modified from those of WHO criteria as detailed in Section 8, Tables 5 and 6.  
 
8.1.3 Overall response using the irRC 
 
The sum of the products of diameters at tumor assessment using the immune-related response criteria 
(irRC) for progressive disease incorporates the contribution of new measurable lesions. Each net 
Percentage Change in Tumor Burden per assessment using irRC criteria accounts for the size and growth 
kinetics of both old and new lesions as they appear. 
Definition of Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the products 
of the two largest perpendicular diameters of all index and all new measurable lesions (i.e., Percentage 
Change in Tumor Burden). Note: the appearance of new measurable lesions is factored into the overall 
tumor burden, but does not automatically qualify as progressive disease until the SPD increases by 
≥25% when compared to SPD at nadir. 
 irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive disease. 
 irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden (i.e., taking 
sum of the products of all index lesions and any new lesions) when compared to SPD at nadir. 
Definition of Non-Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all non-index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not considered in the 
definition of PR, these terms do not apply. 
 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does not constitute 
progressive disease unless/until the Percentage Change in Tumor Burden increases by 25% (i.e., the 
SPD at nadir of the index lesions increases by the required amount). 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However, their contribution to 
total tumor burden is included in the SPD, which in turn feeds into the irRC criteria for tumor response. 
Therefore, new non-measurable lesions will not discontinue any subject from the study. 


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Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria (see Section 8, Table 6): 
 Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions (index 
and non-index together with no new measurable/unmeasurable lesions) for at least 4 weeks from the 
date of documentation of complete response.  
 Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular 
diameters of all index lesions is measured and captured as the SPD baseline. At each subsequent tumor 
assessment, the sum of the products of the two largest perpendicular diameters of all index lesions and 
of new measurable lesions are added together to provide the Immune Response Sum of Product 
Diameters (irSPD). A decrease, relative to baseline of the irSPD compared to the previous SPD 
baseline, of 50% or greater is considered an immune Partial Response (irPR).  
 Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for immune 
complete response or immune partial response, in the absence of progressive disease.  
 Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to confirm PD by 
serial imaging. Any of the following will constitute progressive disease: 
 At least 25% increase in the sum of the products of all index lesions over nadir SPD calculated for 
the index lesions. 
 At least a 25% increase in the sum of the products of all index lesions and new measurable lesions 
(irSPD) over the baseline SPD calculated for the index lesions. 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between the date of 
first dose until the last tumor assessment before subsequent therapy (except for local palliative radiotherapy 
for painful bone lesions) for the individual subject in the study. For the assessment of irBOR, all available 
assessments per subject are considered. 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks after the 
criteria for response are first met. 


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Table 6: Derivation of irRC overall responses 
 
Measurable response 
Nonmeasurable response 
Overall response 
Index and new, measurable lesions (tumor burden),*%
Non-index lesions 
New, nonmeasurable lesions
Using irRC 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal progression
Any 
irPR† 
↓≥50 
Absent/Stable 
Any 
irPR† 
↓≥50 
Unequivocal progression
Any 
irPR† 
↓<50 to <25↑ 
Absent/Stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal progression
Any 
irSD 
≥25 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), including measurable lesions only  
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 wk apart.  
8.1.4 
Progression criteria for the current study 
 
Ipilimumab is expected to trigger immune-mediated responses, which require activation of the immune 
system prior to the observation of clinical responses. Such immune activation may take weeks to months to 
be evident. Some patients may have objective volume increase of tumor lesions or other disease parameters 
(based on study indication, i.e., hematologic malignancies) within 12 weeks following start of ipilimumab 
dosing. Such patients may not have had sufficient time to develop the required immune activation or, in 
some patients, tumor volume or other disease parameter increases may represent infiltration of 
lymphocytes into the original tumor or blood. In conventional studies, such tumor volume or relevant 
laboratory parameter increases during the first 12 weeks of the study would constitute progressive disease 
(PD) and lead to discontinuation of imaging to detect response, thus disregarding the potential for 
subsequent immune-mediated clinical response.  
 
Therefore, patients with tumor volume increase detected or lack of laboratory parameter response 
documentation prior to week 12 but without rapid clinical deterioration should continue to be treated with 
ipilimumab and clinically observed with a stringent imaging schedule to allow detection of a subsequent 
tumor response. This will improve the overall assessment of the clinical activity or ipilimumab and more 
likely capture its true potential to induce clinical responses. 
 
On the current study, patients will undergo a restaging CT scan after cycle 2 and after cycle 6. However, 
patients with evidence of disease progression (in the absence of rapid clinical deterioration) on the post-
cycle 2 CT scan will not be taken off study, as they will have not yet started ipilimumab.  
 
Furthermore, as durable disease stabilization and/or objective tumor response can be seen in other 
advanced solid tumors after early progression before 12 weeks of ipilimumab treatment, it is recommended 
that, in the absence of treatment-limiting toxicities (e.g., serious irAEs), symptomatic progression, or 
deterioration in functional status, all four doses of ipilimumab be administered (cycles 3-6). 
 
Based on clinical experience in ongoing and completed ipilimumab studies, the following 
recommendations apply for subject management in light of the post-cycle 6 or later tumor assessments: 


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 The appearance of new lesions in subjects with other stable or shrinking baseline tumor burden may be 
experiencing clinical benefit and should continue in follow-up and/or maintenance therapy before 
alternative anti-cancer agents are considered. These subjects can be seen to have continued tumor 
shrinkage in follow-up scans. 
 As long as overall tumor burden is stable or decreasing, subjects should remain in follow-up and/or 
maintenance, even in the presence of new lesions. 
 Clinical progression warranting alternative anti-cancer treatment should be considered only in subjects 
whose overall tumor burden appears to be substantially increased (e.g., meets criteria for irPD) and/or 
in subjects whose performance status is decreased. 
 
Patients with disease progression on the post-cycle 6 scan (in the absence of symptomatic/functional 
deterioration) should have a confirmatory CT scan at least 4 weeks later as per the irRC. 
 
8.1.5 Definition of Measurable and Non-Measurable Lesions 
 
Measurable Lesions are lesions that can be accurately measured in two perpendicular diameters, with at 
least one diameter ≥ 20 mm and the other dimension ≥ 10 mm (10 mm x 10 mm for spiral CT). The area 
will be defined as the product of the largest diameter with its perpendicular. Skin lesions can be considered 
measurable. 
 
Non-Measurable (evaluable) Lesions are all other lesions, including unidimensionally measurable disease 
and small lesions (lesions without at least one diameter ≥ 20 mm), and any of the following: 
 Lesions occurring in a previously irradiated area (unless they are documented as new lesions since 
the completion of radiation therapy), bone lesions, leptomeningeal disease, ascites, pleural or 
pericardial 
effusion, 
lymphangitis 
cutis/pulmonis, 
abdominal 
masses 
that 
are 
not 
pathologically/cytologically confirmed and followed by imaging techniques and cystic lesions. 
 All measurable and non-measurable lesions should be measured at screening and at the defined 
tumor assessment time points (see Section 7, Study Calendar & Evaluations). Extra assessments 
may be performed, as clinically indicated, if there is a suspicion of progression. 
 
8.2 
Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST v1.0):  
 
8.2.1 
Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
 
8.2.2 
Measurable lesions - lesions that can be accurately measured in at least one dimension 
with longest diameter (LD) >20 mm using conventional techniques or >10 mm with spiral 
CT scan. 
 
8.2.3 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 
mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques. 


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8.2.4 
Baseline documentation of “Target” and “Non-Target” lesions - all measurable lesions up 
to a maximum of five lesions per organ and 10 lesions in total, representative of all 
involved organs should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their LD. The baseline sum LD 
will be used as reference by which to characterize the objective tumor. All other lesions 
(or sites of disease) should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.  
 
8.2.5 
Response Criteria 
 
Table 7: Response Criteria for Target Lesions 
 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more 
new lesions 
 
Table 8: Response Criteria for Non-Target Lesions 
 
Response 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of 
tumor marker level 
Incomplete Response/  
Stable Disease (SD) 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions(1) 
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be confirmed later 
on by the review panel (or the Sponsor Investigator). 
 
8.2.6 Evaluation of best overall response 
 
The objective response rate is the proportion of all patients with confirmed PR or CR according to 
RECIST v1.0, from the start of treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the start of treatment). 
 


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The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 
Table 9: Evaluation of best overall response 
Target Lesions 
Non-Target lesion 
New Lesion 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete Response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the Definitions Associated with Response 
Evaluation Criteria in Solid Tumors (RECIST v1.0) 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
 
9.0 
BIOLOGICAL CORRELATIVES 
 
See Correlative Science Plan (Attachment) 
 
10.0 
CLINICAL TRIAL MATERIALS (CTM) INFORMATION & ADVERSE EVENTS 
MANAGEMENT 
 
10.1  
Ipilimumab: 
 
The investigational product is defined as a pharmaceutical form of an active ingredient being tested as a 
reference in the study, whether blinded or unblinded. In this study, the investigational product is 
ipilimumab. 
Other medications used in the study as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, are considered 
noninvestigational products. In this protocol, noninvestigational product(s) is/are: gemcitabine, cisplatin. 
Identification 
Ipilimumab is available in concentrations of 5 mg/mL (50 mg/10 mL and 200 mg/40 mL). The sterile 
solution in the vial is clear and colorless. Ipilimumab is administered via intravenous infusion only. 


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Packaging and Labeling 
BMS will provide ipilimumab at no cost for this study. Ipilimumab will be provided in open-label 
containers. The labels will contain the protocol prefix, batch number, content, storage conditions, and 
dispensing instructions along with the Investigational New Drug (IND) caution statement. 
Storage, Handling, and Dispensing 
Storage 
Ipilimumab must be stored in a secure area according to local regulations. The investigator must ensure 
that it is stored at a temperature ³ 2°C and £ 8°C. 
Handling and Disposal 
As with all injectable drugs, care should be taken when handling and preparing ipilimumab. Whenever 
possible, ipilimumab should be prepared in a laminar flow hood or safety cabinet using standard 
precautions for the safe handling of intravenous agents applying aseptic technique. Latex gloves are 
required. If ipilimumab concentrate or solution comes in contact with skin or mucosa, immediately and 
thoroughly wash with soap and water. After final drug reconciliation, unused ipilimumab solution 
should be disposed at the site following procedures for the disposal of anticancer drugs. 
Dispensing 
It is the responsibility of the investigator to ensure that ipilimumab is only dispensed to study subjects. 
The ipilimumab must be dispensed only from official study sites by authorized personnel according to 
local regulations. 
Drug Ordering and Accountability 
Orders, See SPM for instruction on drug ordering.  
Ipilimumab Accountability 
It is the responsibility of the investigator to ensure that a current record of ipilimumab disposition is 
maintained at each study site where ipilimumab is inventoried and disposed. Records or logs must comply 
with applicable regulations and guidelines, and should include: 
 Amount received and placed in storage area. 
 Amount currently in storage area. 
 Label ID number or batch number and use date or expiry date. 
 Dates and initials of person responsible for each ipilimumab inventory entry/movement. 
 Amount dispensed to and returned by each subject, including unique subject identifiers. 
 Amount transferred to another area/site for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 Amount destroyed at study site. 


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Ipilimumab Destruction 
If ipilimumab is to be destroyed on site, it is the investigator’s responsibility to ensure that arrangements 
have been made for disposal and that procedures for proper disposal have been established according to 
applicable regulations, guidelines, and institutional procedures. Appropriate records of the disposal must be 
maintained. 
Preparation and Administration 
 
Refer to the package insert for YERVOY® (ipilimumab) for detailed preparation and administration 
guidelines. 
 
The supplies needed for ipilimumab preparation and administration include calibrated syringes and infusion 
containers. Ipilimumab is to be administered as an IV infusion using a volumetric pump through a 0.2 or 
1.2 micrometer in-line filter (supplied by site) at the 10 mg/kg dose. See the current Investigator Brochure 
for additional information on allowable filter types.  
 
Ensure that the ipilimumab solution is clear colorless, essentially free from particulate matter on visual 
inspection. If multiple vials are needed for a subject, it is important to use a separate sterile syringe and 
needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated friction of 
plunger against syringe barrel wall, etc. 
 
Preparation of Solution 
As ipilimumab is stored at refrigerated temperatures (2-8ºC), allow the appropriate number of vials of 
ipilimumab to stand at room temperature for approximately five minutes. 
 
 
Aseptically withdraw the required volume of ipilimumab solution and transfer to an intravenous bag. Do 
not draw into each vial more than once. 
 
Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted 
solution with a final concentration ranging from 1 mg/mL to 2 mg/ML.  
  
 
 
Mix by GENTLY inverting several times. DO NOT shake. 
 
 
Visually inspect the final solution. If the initial diluted solution or final dilution for infusion is not clear or 
contents appear to contain precipitate, the solution should be discarded. 
 
Store diluted solution for no more than 24 hours under refrigeration (2-8ºC) or at room temperature (20-25 
ºC). Any partial vials should be safely discarded and should not be stored for reuse. 
 
 
Administration Instructions  
Ipilimumab should be administered under the supervision of a physician experienced in the use of 
intravenous (IV) agents. Ipilimumab is administered as an IV infusion only. 
 
The infusion must be completed in 90 minutes with a 10 ml normal saline flush at the end. The ratio and 
rate will be specified in the pharmacy manual. The total dose must be calculated using the most recent 
subject weight (obtained within 3 days of the dosing visit, and prior to the infusion). 


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Side Effects:  
Among all treated subjects, the most frequently reported treatment-related AEs of any grade included 
fatigue (27.8%), diarrhea (27.5%), nausea (23.4%), rash (21.8%), pruritus (19.9%), pyrexia (11.9%), and 
vomiting (11.7%).  
Similarly, among subjects treated with ipilimumab at 10 mg/kg, the most frequently reported treatment-
related AEs of any grade included diarrhea (38.1%), fatigue (30.5%), rash (34.5%), pruritus (29.8%), 
nausea (17.6%), pyrexia (12.3%), vomiting (10.9%). and colitis (10.2%). 
Among all 2901 treated subjects, SAEs considered possibly, probably, or definitely related to study drug 
were reported for 20.5% of subjects. Drug-related SAEs reported in at least 1% of the 2901 subjects 
included diarrhea (5.8%), colitis (4.7%), ALT increased (2.3%), AST increased (2.2%), pyrexia (1.6%), 
and vomiting (1.3%). Among the 658 subjects who received ipilimumab at 10 mg/kg, SAEs considered 
possibly, probably, or definitely related to study drug were reported for 27.2% of subjects. Drug-related 
SAEs reported in at least 1% of the 658 subjects treated at 10 mg/kg included diarrhea (8.5%), colitis 
(7.0%), vomiting (2.1%), AST increased (2.1%), ALT increased (2.0%), autoimmune hepatitis (2.0%), 
pyrexia (1.8%), hypopituitarism (1.7%), dehydration (1.7%), nausea (1.2%), abdominal pain (1.1%), and 
GI perforation (.17%). 
 
10.2 
Cisplatin: 
 
Drug Name: 
Cisplatin 
Other: Platinol; Cis-diamminedichloroplatinum 
 
 
Classification: 
Alkylating agent 
 
 
Action: 
Cisplatin forms covalent bonds with nucleophilic sites on guanine present in 
all DNA. As cisplatin is a bifunctional agent, it is able to bind to 2 sites in a 
DNA strand. This results in the formation of inter- and intra-chain cross-
linkings, which interferes with cellular transcription and replication. 
Regulatory mechanisms detect the abnormal DNA and so activate a chain of 
responses to try and correct it. This, ultimately, causes cell death (apoptosis). 
 
 
Availability: 
Cisplatin is commercially available. 
 
 
 
Storage: 
Cisplatin Injection is a sterile, multi-dose vial without preservatives. Store at 
15° to 25°C (59° to 77°F). Note: Do not refrigerate. Protect unopened 
container from light. The cisplatin remaining in the amber vial following 
initial entry is stable for 28 days protected from light or for 7 days under 
fluorescent room light. 
 
 
Reconstitution: 
The aqueous solution should be used intravenously only and should be 
administered by IV. Cisplatin is a cytotoxic chemotherapeutic agent. 


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Appropriate precautions for hazardous drug handling should be taken during 
handling, preparation, administration and disposal of this agent. As with other 
potentially toxic compounds, caution should be exercised in handling the 
aqueous solution. Skin reactions associated with accidental exposure to 
cisplatin may occur. The use of gloves is recommended. If cisplatin contacts 
the skin or mucosa, immediately and thoroughly wash the skin with soap and 
water and flush the mucosa with water. 
 
 
Administration: 
Cisplatin will be administered IV according to institutional guidelines. 
 
Hydration 
Hydration for cisplatin can be administered at the discretion of the treating 
physician and according to institutional standards.  
 
Side Effects: 
Nephrotoxicity: Dose related and cumulative renal insufficiency is the major dose-
limiting toxicity. Renal toxicity has been noted in 28-36% of patients treated with a 
single dose of 50 mg/m2. It is first noted during the second week after a dose and is 
manifested by elevations in BUN and creatinine, serum uric acid, and/or a decrease 
in creatinine clearance. 
Note: Renal toxicity becomes more prolonged and severe with repeated courses of 
the drug. Renal function must return to normal before another dose of cisplatin can 
be given. 
 
Ototoxicity: Ototoxicity has been observed in up to 31% of patients treated with a 
single dose of cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss 
in the high frequency range (4,000 to 8,000 Hz). Decreased ability to hear normal 
conversational tones may occur occasionally. Deafness after the initial dose of 
cisplatin has been reported rarely. Ototoxic effects may be more severe in children 
receiving cisplatin. Hearing loss can be unilateral or bilateral and tends to become 
more frequent and severe with repeated doses. Ototoxicity may be enhanced with 
prior or simultaneous cranial irradiation. It is unclear whether cisplatin-induced 
ototoxicity is reversible. Ototoxic effects may be related to the peak plasma 
concentration of cisplatin. Vestibular toxicity has also been reported. Ototoxicity 
may become more severe in patients being treated with other drugs with 
nephrotoxic potential. Patients should be questioned regarding any history of 
hearing deficit. 
 
Hematologic: Myelosuppression occurs in 25% to 30% of patients treated with 
cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 
to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). 
Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 
mg/m2). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the 
same frequency and with the same timing as leukopenia and thrombocytopenia. 
Fever and infections have also been reported in patients with neutropenia. 
In addition to anemia secondary to myelosuppression, a Coombs’ positive 
hemolytic anemia has been reported. In the presence of cisplatin hemolytic anemia, 


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a further course of treatment may be accompanied by increased hemolysis, and this 
risk should be weighed by the Treating Physician. 
 
The development of acute leukemia coincident with the use of cisplatin has rarely 
been reported in humans. In these reports, cisplatin was generally given in 
combination with other leukemogenic agents. 
 
Gastrointestinal: Marked nausea and vomiting occur in almost all patients treated 
with cisplatin, and are occasionally so severe that the drug must be discontinued. 
Nausea and vomiting usually begin within 1 to 4 hours after treatment and last for 
24 hours. Various degrees of vomiting, nausea and/or anorexia may persist for up 
to 1 week after treatment. Delayed nausea and vomiting (begins or persists 24 
hours or more after chemotherapy) has occurred in patients attaining complete 
emetic control on the day of cisplatin therapy. Diarrhea has also been reported. 
 
Other Toxicities: Vascular toxicities coincident with the use of cisplatin in 
combination with other antineoplastic agents have been reported rarely. The events 
are 
clinically 
heterogeneous 
and 
may 
include 
myocardial 
infarction, 
cerebrovascular accident, thrombotic microangiopathy (HUS), or cerebral arteritis. 
Various mechanisms have been proposed for these vascular complications. There 
are also reports of Raynaud’s phenomenon occurring in patients treated with the 
combination of bleomycin, vinblastine with or without cisplatin. It has been 
suggested that hypomagnesemia developing coincident with the use of cisplatin 
may be an added, although not essential, factor associated with this event. 
However, it is currently unknown if the cause of Raynaud’s phenomenon in these 
cases is the disease, underlying vascular compromise, bleomycin, vinblastine, 
hypomagnesemia, or a combination of any of these factors. 
Serum Electrolyte Disturbances: Hypomagnesemia, hypocalcemia, hyponatremia, 
hypokalemia, and hypophosphatemia have been reported to occur in patients 
treated with cisplatin and are probably related to renal tubular damage. Tetany has 
occasionally 
been 
reported 
in 
those 
patients 
with 
hypocalcemia 
and 
hypomagnesemia. 
Generally, 
administering 
supplemental 
electrolytes and 
discontinuing cisplatin restore normal serum electrolyte levels. Inappropriate 
antidiuretic hormone syndrome has also been reported. 
 
Hyperuricemia: Hyperuricemia has been reported to occur at approximately the 
same frequency as the increases in BUN and serum creatinine. It is more 
pronounced after doses greater than 50 mg/m2, and peak levels of uric acid 
generally occur between 3 to 5 days after the dose. Allopurinol therapy for 
hyperuricemia effectively reduces uric acid levels. 
 
Neurotoxicity: Neurotoxicity, usually characterized by peripheral neuropathies, has 
been reported. The neuropathies usually occur after prolonged therapy (4 to 7 
months); however, neurologic symptoms have been reported to occur after a single 
dose. Although symptoms and signs of cisplatin neuropathy usually develop during 
treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of 
cisplatin, although this is rare. Cisplatin therapy should be discontinued when the 


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symptoms are first observed. The neuropathy, however, may progress further even 
after stopping treatment. Preliminary evidence suggests peripheral neuropathy may 
be irreversible in some patients. Lhermitte’s sign, dorsal column myelopathy, and 
autonomic neuropathy have also been reported. Loss of taste and seizures have also 
been reported. 
Muscle cramps, defined as localized, painful, involuntary skeletal muscle 
contractions of sudden onset and short duration, have been reported, and were 
usually associated in patients receiving a relatively high cumulative dose of 
cisplatin and with a relatively advanced symptomatic stage of peripheral 
neuropathy. 
 
Ocular Toxicity: Optic neuritis, papilledema, and cerebral blindness have been 
reported infrequently in patients receiving standard recommended doses of 
cisplatin. Improvement and/or total recovery usually occurs after discontinuing 
cisplatin. Steroids with or without mannitol have been used; however, efficacy has 
not been established. 
 
Blurred vision and altered color perception have been reported after the use of 
regimens with higher doses of cisplatin or greater dose frequencies than those 
recommended in the package insert. The altered color perception manifests as a 
loss of color discrimination, particularly in the blue-yellow axis. The only finding 
on funduscopic exam is irregular retinal pigmentation of the macular area. 
 
Anaphylactic-like Reactions: Anaphylactic-like reactions have been occasionally 
reported in patients previously exposed to cisplatin. The reactions consist of facial 
edema, wheezing, tachycardia, and hypotension within a few minutes of drug 
administration. Reactions may be controlled by IV epinephrine with corticosteroids 
and/or antihistamines as indicated. Patients receiving cisplatin should be observed 
carefully for possible anaphylactic- like reactions and supportive equipment and 
medication should be available to treat such a complication. 
 
Hepatotoxicity: Transient elevations of liver enzymes, especially SGOT, as well as 
bilirubin, have been reported to be associated with cisplatin administration at the 
recommended doses. 
 
Other Events: Other toxicities reported to occur infrequently are cardiac 
abnormalities, hiccups, elevated serum amylase, and rash. Alopecia, malaise, and 
asthenia have been reported as part of post-marketing surveillance. 
 
Local soft tissue toxicity has rarely been reported following extravasation of 
cisplatin. Severity of the local tissue toxicity appears to be related to the 
concentration of the cisplatin solution. Infusion of solutions with a cisplatin 
concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, and 
necrosis. 
 
Pregnancy. Cisplatin can cause fetal harm when administered to a pregnant woman. 
Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal 


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cells in tissue culture. In mice, cisplatin is teratogenic and embryotoxic. If this drug 
is used during pregnancy or if the patient becomes pregnant while taking this drug, 
the patient should be apprised of the potential hazard to the fetus. Patients should 
be advised to avoid becoming pregnant. 
 
Nursing mothers. Cisplatin has been reported to be found in human milk, patients 
receiving cisplatin should not breastfeed. 
 
10.3  
Gemcitabine: 
 
Drug Name: 
Gemcitabine 
Other: 2’-deoxy-2’,2’-difluorocytidine monohydrochloride, Gemzar 
 
 
Classification: 
Nucleoside analogue 
 
 
Action: 
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 2 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 1 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). 
 
 
Availability: 
Commercially available and FDA approved for pancreatic cancer. Also, 
recently approved for locally unresectable or metastatic non-small cell lung 
cancer in combination with cisplatin. 
 
 
 
Storage: 
Unopened vials of Gemzar are stable until the expiration date indicated on the 
package when stored at controlled room temperature 20° to 25°C (68° to 
77°F). When prepared as directed, Gemzar solutions are stable for 24 hours at 
controlled room temperature 20° to 25°C (68° to 77°F). Discard unused 
portion. Solutions of reconstituted Gemzar should not be refrigerated, as 
crystallization may occur. 
 
 
Reconstitution: 
The recommended diluent for reconstitution of Gemzar is 0.9% Sodium 
Chloride Injection without preservatives. Due to solubility considerations, the 
maximum concentration for Gemzar upon reconstitution is 40 mg/mL. 


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Reconstitution at concentrations greater than 40 mg/mL may result in 
incomplete dissolution, and should be avoided.  
To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200-mg 
vial or 25 mL of 0.9% Sodium Chloride Injection to the 1-g vial. Shake to 
dissolve. These dilutions each yield a gemcitabine concentration of 
38 mg/mL, which includes accounting for the displacement volume of the 
lyophilized powder (0.26 mL for the 200-mg vial or 1.3 mL for the 1-g vial). 
The total volume upon reconstitution will be 5.26 mL or 26.3 mL, 
respectively. Complete withdrawal of the vial contents will provide 200 mg or 
1 g of gemcitabine, respectively. The appropriate amount of drug may be 
administered as prepared or further diluted with 0.9% Sodium Chloride 
Injection to concentrations as low as 0.1 mg/mL.  
Reconstituted Gemzar is a clear, colorless to light straw-colored solution. 
After reconstitution with 0.9% Sodium Chloride Injection, the pH of the 
resulting solution lies in the range of 2.7 to 3.3. The solution should be 
inspected visually for particulate matter and discoloration, prior to 
administration, whenever solution or container permit. If particulate matter or 
discoloration is found, do not administer. Gemzar should be administered by 
intravenous infusion at a dose of 1000 mg/m2 over 30 minutes. 
 
 
Administration: 
Gemzar should be administered by intravenous infusion over 30 minutes. 
 
 
Side Effects: 
Hematologic: In studies in pancreatic cancer, myelosuppression is the dose-
limiting toxicity with Gemzar, but <1% of patients discontinued therapy for 
either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions 
were required by 19% of patients. The incidence of sepsis was less than 1%. 
Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 
16% of patients; less than 1% of patients required platelet transfusions. 
Patients should be monitored for myelosuppression during Gemzar therapy 
and dosage modified or suspended according to the degree of hematologic 
toxicity. 
 
Gastrointestinal: Nausea and vomiting were commonly reported (69%) but 
were usually of mild to moderate severity. Severe nausea and vomiting 
(WHO Grade 3-4) occurred in <15% of patients. Diarrhea was reported by 
19% of patients, and stomatitis by 11% of patients.  
 
Hepatic: In clinical trials, Gemzar was associated with transient elevations of 
1 or both serum transaminases in approximately 70% of patients, but there 
was no evidence of increasing hepatic toxicity with either longer duration of 
exposure to Gemzar or with greater total cumulative dose. Serious 
hepatotoxicity, including liver failure and death, has been reported very rarely 
in patients receiving Gemzar alone or in combination with other potentially 
hepatotoxic drugs (see Hepatic under Post-marketing experience, below).  
 
Renal: In clinical trials, mild proteinuria and hematuria were commonly 
reported. Clinical findings consistent with the Hemolytic Uremic Syndrome 


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(HUS) were reported in 6 of 2429 patients (0.25%) receiving Gemzar in 
clinical trials. Four patients developed HUS on Gemzar therapy, 2 
immediately post-therapy. The diagnosis of HUS should be considered if the 
patient develops anemia with evidence of microangiopathic hemolysis, 
elevation of bilirubin or lactate dehydrogenase (LDH), reticulocytosis, severe 
thrombocytopenia, and/or evidence of renal failure (elevation of serum 
creatinine or BUN). Gemzar therapy should be discontinued immediately. 
Renal failure may not be reversible even with discontinuation of therapy and 
dialysis may be required (see Renal under Post-marketing experience, below).  
 
Fever: The overall incidence of fever was 41%. This is in contrast to the 
incidence of infection (16%) and indicates that Gemzar may cause fever in the 
absence of clinical infection. Fever was frequently associated with other flu-
like symptoms and was usually mild and clinically manageable.  
 
Rash: Rash was reported in 30% of patients. The rash was typically a macular 
or finely granular maculopapular pruritic eruption of mild to moderate 
severity involving the trunk and extremities. Pruritus was reported for 13% of 
patients.  
 
Pulmonary: In clinical trials, dyspnea, unrelated to underlying disease, has 
been reported in association with Gemzar therapy. Dyspnea was occasionally 
accompanied by bronchospasm. Pulmonary toxicity has been reported with 
the use of Gemzar (see Pulmonary under Post-marketing experience, below). 
The etiology of these effects is unknown. If such effects develop, Gemzar 
should be discontinued. Early use of supportive care measures may help 
ameliorate these conditions.  
 
Edema: Edema (13%), peripheral edema (20%), and generalized edema 
(<1%) were reported. Less than 1% of patients discontinued due to edema.  
 
Flu-like Symptoms: “Flu syndrome” was reported for 19% of patients. 
Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and 
myalgia were commonly reported. Fever and asthenia were also reported 
frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise 
were reported infrequently. Less than 1% of patients discontinued due to flu-
like symptoms.  
 
Infection: Infections were reported for 16% of patients. Sepsis was rarely 
reported (<1%).  
 
Alopecia: Hair loss, usually minimal, was reported by 15% of patients.  
 
Neurotoxicity: There was a 10% incidence of mild paresthesias and a <1% 
rate of severe paresthesias. 
 


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Extravasation: Injection-site related events were reported for 4% of patients. 
There were no reports of injection site necrosis. Gemzar is not a vesicant.  
 
Allergic: Bronchospasm was reported for less than 2% of patients. 
Anaphylactoid reaction has been reported rarely. Gemzar should not be 
administered to patients with a known hypersensitivity to this drug (see 
CONTRAINDICATION in the package insert).  
Cardiovascular: During clinical trials, 2% of patients discontinued therapy 
with Gemzar due to cardiovascular events such as myocardial infarction, 
cerebrovascular accident, arrhythmia, and hypertension. Many of these 
patients had a prior history of cardiovascular disease (see Cardiovascular 
under Post-marketing experience, below). 
 
Post-marketing experience: The following adverse events have been identified 
during post-approval use of Gemzar. These events have occurred after 
Gemzar single-agent use and Gemzar in combination with other cytotoxic 
agents. Decisions to include these events are based on the seriousness of the 
event, frequency of reporting, or potential causal connection to Gemzar. 
 
Cardiovascular  Congestive heart failure and myocardial infarction have 
been reported very rarely with the use of Gemzar. Arrhythmias, 
predominantly supraventricular in nature, have been reported very rarely.  
 
Vascular Disorders  Clinical signs of peripheral vasculitis and gangrene have 
been reported very rarely. 
 
Skin  Cellulitis and non-serious injection site reactions in the absence of 
extravasation have been rarely reported. Severe skin reactions, including 
desquamation and bullous skin eruptions, have been reported very rarely.  
 
Hepatic  Increased liver function tests including elevations in aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transferase (GGT), alkaline phosphatase, and bilirubin levels have been 
reported rarely. Serious hepatotoxicity including liver failure and death has 
been reported very rarely in patients receiving Gemzar alone or in 
combination with other potentially hepatotoxic drugs.  
 
Pulmonary  Parenchymal toxicity, including interstitial pneumonitis, 
pulmonary fibrosis, pulmonary edema, and adult respiratory distress 
syndrome (ARDS), has been reported rarely following 1 or more doses of 
Gemzar administered to patients with various malignancies. Some patients 
experienced the onset of pulmonary symptoms up to 2 weeks after the last 
Gemzar dose. Respiratory failure and death occurred very rarely in some 
patients despite discontinuation of therapy.  
 
Renal  Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been 
reported following 1 or more doses of Gemzar. Renal failure leading to death 


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or requiring dialysis, despite discontinuation of therapy, has been rarely 
reported. The majority of the cases of renal failure leading to death were due 
to HUS.  
 
Injury, Poisoning, and Procedural Complications  Radiation recall reactions 
have been reported  
Pregnancy 
 
Pregnancy Category D. Gemzar can cause fetal harm when administered to a 
pregnant woman. Gemcitabine is embryotoxic causing fetal malformations 
(cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice 
(about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine 
is fetotoxic causing fetal malformations (fused pulmonary artery, absence of 
gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the 
recommended human dose on a mg/m2 basis). Embryotoxicity was 
characterized by decreased fetal viability, reduced live litter sizes, and 
developmental delays. There are no studies of Gemzar in pregnant women. If 
Gemzar is used during pregnancy, or if the patient becomes pregnant while 
taking Gemzar, the patient should be apprised of the potential hazard to the 
fetus. 
 
Nursing mothers. It is not known whether Gemzar or its metabolites are 
excreted in human milk. Because many drugs are excreted in human milk and 
because of the potential for serious adverse reactions from Gemzar in nursing 
infants, the mother should be warned and a decision should be made whether 
to discontinue nursing or to discontinue the drug, taking into account the 
importance of the drug to the mother and the potential risk to the infant. 
 
11.0 
REPORTING ADVERSE EVENTS & SERIOUS ADVERSE EVENTS  
 
11.1  
Definitions of Adverse Events: 
 
11.1.1 
Adverse Event (AE) 
 
 
Any untoward medical occurrence in a patient or clinical trial subject administered an 
investigational product and which does not necessarily have a causal relationship with the 
treatment. An adverse event (AE) can, therefore, be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational product. 
 
11.1.2 
Serious Adverse Event (SAE) 
 
 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
following: 
 
 
Results in death 
 


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 
Is life-threatening (defined as an event in which the patient was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
 
Results in persistent or significant disability/incapacity 
 
 
Is a congenital anomaly or birth defect 
 
 
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above). 
Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions not 
resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 
Unexpected Adverse Event 
 
An adverse event not mentioned in the Investigator's Brochure or package insert or the specificity 
or severity of which is not consistent with the Investigator's Brochure or package insert. 
 
11.2 
Adverse Event (AE) Reporting: 
 
Adverse events (AEs) will be recorded from the time of consent and for at least 30 days after 
treatment discontinuation, regardless of whether or not the event(s) are considered related to trial 
medications. All AEs considered related to trial medication will be followed until resolution, 
return to baseline, or deemed clinically insignificant, even if this occurs post-trial. 
 
11.3 
Serious Adverse Event (SAE) Reporting: 
 
11.3.1 
Study Center (Site) Requirements for Reporting SAEs 
 
Investigators and other site personnel must report any SAEs occurring during the course of the 
study within one business day of discovery of the event. This includes events both related and 
unrelated to the investigational product.  
 
The definition of "related" being that there is a reasonable possibility the drug caused the adverse 
experience. 
 
Unrelated 
The Adverse Event is clearly not related to the investigational agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event may be related to the investigational agent(s) 
Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 


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The completed SAE Report Form (see Study Procedure Manual) must be faxed to Hoosier 
Cancer Research Network within 1 working day of discovery of the event. The investigator is 
responsible for informing the IRB and/or the Regulatory Authority of the SAE as per local 
requirements. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the Trial 
Master File at the study site. 
Follow-up information will be faxed to the Hoosier Cancer Research Network, using a new SAE 
Report Form stating that this is a follow-up to the previously reported SAE and giving the date of 
the original report. Each re-occurrence, complication, or progression of the original event should 
be reported as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated, whether 
the blind was broken or not (if applicable), and whether the patient continued or withdrew from 
study participation. 
 
11.3.2 
Death and Immediately Life-Threatening Events  
 
Any death and immediately life-threatening event from any cause while a patient is receiving trial 
treatment on this protocol or up to 30 days after the last dose of trial treatment, or any death and 
immediately life-threatening event occurring more than 30 days after trial treatment has ended but 
which is felt to be treatment related must be reported within one working day of discovery of 
the event. All deaths must be reported primarily for the purposes of SAE reporting; however, 
deaths due unequivocally to progression are not SAEs.  
 
Your local IRB should be notified and their reporting procedure followed. The completed SAE 
Reporting Form should be faxed to Hoosier Cancer Research Network within one working day 
of discovery of the event. 
 
11.3.3 
HCRN Requirements for Reporting SAEs 
 
The Hoosier Cancer Research Network will report any possibly related SAE to BMS within one 
working day of receipt of the SAE Reporting Form and to regulatory authorities (FDA) per 
federal guidelines.  
 
The Hoosier Cancer Research Network will fax a MedWatch to BMS and will provide follow-up 
information as reasonably requested. 
 
11.4 
IND Safety Reports Unrelated to This Trial 
 
IND safety reports not occurring on this trial but involving the study intervention (outside SAEs) 
received from outside sources will be reviewed by the Sponsor Investigator and will be forwarded 
to participating sites for submission to their Institutional Review Boards per their guidelines.  
 
11.5 
Pregnancy 
 


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Sexually active WOCBP must use an effective method of birth control during the course of the study, in a 
manner such that risk of failure is minimized.  
 
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during study 
participation and the potential risk factors for an unintentional pregnancy. The subject must sign an 
informed consent form documenting this discussion. 
 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving ipilimumab. The 
minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy 
test is positive, the subject must not receive ipilimumab and must not be enrolled in the study. 
 
In addition, all WOCBP should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study participation. 
 
If, following initiation of the investigational product, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including during at 
least 6 half-lives after product administration, the investigational product will be permanently discontinued 
in an appropriate manner. The investigator must immediately notify BMS of this event and record the 
pregnancy on the Pregnancy Surveillance Form (not an SAE form). Initial information on a pregnancy must 
be reported immediately to BMS, and the outcome information provided once the outcome is known. 
Completed Pregnancy Surveillance Forms must be forwarded to BMS according to SAE reporting 
procedures. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to the 
sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the subject 
unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up 
procedures should be considered if indicated. In addition, the investigator must report to BMS, and follow-
up on information regarding the course of the pregnancy, including perinatal and neonatal outcome. Infants 
should be followed for a minimum of 8 weeks. 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
Sample size justification 
Though not a standard endpoint for a phase II trial, the current study will utilize 1 year overall survival as 
the primary endpoint. Given that late responses (and variable response patterns such as responses after 
documented progression) have occurred in patients with other solid tumors treated with ipilimumab, and 
given that the use of the irRC and timing of the scans in our study will bias progression-free survival 
endpoints, overall survival will provide the most definitive endpoint to consider the activity of the current 
regimen in the context of historical controls. The 1 year overall survival of patients treated with cisplatin 
and gemcitabine alone is approximately 60%3.  
 
The primary objective is to estimate the 1 year overall survival (OS) rates for gemcitabine, cisplatin, plus 
ipilimumab. The sample size is based on 90% one-sided confidence intervals (CI) calculated at the target 
rate of 80% for 1 year OS. We will recommend the regimen if lower bound of the resulting CI exceeds 
60%. This is equivalent to testing the following hypothesis at Type I error level 0.10: H0: 1-year overall 
survival rate ≤ 60%, vs. Ha: 1-year overall survival rate > 60%. To calculate the sample size, we derive an 


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upper bound for the Greenwood formula for the variance of Kaplan-Meier estimate at 1 year. The upper 
bound is derived by assuming that all patients will be followed for at least 1 year from the enrollment. We 
expect an accrual rate of approximately 1-2 per month. This leads to approximately 17-34 months for 
accrual. With at least one year follow-up for the last subject, we expect the study to finish within 
approximately 2.5-3 years. The upper bound is obtained by maximizing over all possible censoring 
distributions. The resulting sample size is 33 in order to obtain a power level of 0.80. To account for 
potential missing data due to various reasons, we inflate by 10% and enroll 36 subjects. . 
 
The analysis population will be the group who receives at least one cycle of protocol therapy. Therefore 
subjects who experience clinical deterioration and are removed from the study prior to cycle 3 (the first 
cycle with ipilimumab) will still be included in the analysis; however, based on prior studies of first-line 
therapy in patients with metastatic urothelial cancer, we expect this population to be very small. {Hahn, 
2011 #1449} The starting point for survival analysis is the treatment (Gem+Cis) initiation date.  
 
Statistical Analysis 
 
Primary Objective: 
 To determine the 1-year overall survival of patients with advanced/metastatic urothelial cancer 
treated with gemcitabine, cisplatin, plus ipilimumab. 
 
The confidence interval of 1 year overall survival (OS) rates will be constructed based on Kaplan-Meier 
estimate.  
 
Secondary Objectives: 
 To determine the progression-free survival (using irRC) of patients with advanced/metastatic 
urothelial carcinoma treated with gemcitabine, cisplatin, and ipilimumab.  
 
Progression-free survival will be analyzed using KM technique and the Cox regression model for 
exploring association with covariates. 
 
 To determine the disease control rate (complete response + partial response + stable disease using 
irRC and RECIST v1.0 [see Section 8.2]) to treatment with gemcitabine, cisplatin, plus ipilimumab. 
 
Response rates will be analyzed using statistical methods for binary outcomes. 
 
 To determine the safety of treatment with gemcitabine, cisplatin, plus ipilimumab. 
 
Association between immune-related adverse events and overall response rate will be tested using 
Fisher's exact test and Chi-square test. 
 
Exploratory Objectives: 
Please refer the correlative science plan for the detailed statistical analysis (Attachment). Potential 
biomarkers will be assessed by repeating the analysis of each clinical outcome with the level of each 
individual marker included as factor or covariate as appropriate. We will correlate outcomes with changes 
in the frequency of circulating immune cells, tumor antigen-specific CD8+ T cells, and whole blood 


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transcriptional profiling before and after treatment. Significance of this association will be evaluated using 
the Chi-square test for binary outcomes and log-rank tests for time-to-event outcomes. 
 
Stopping rule  
After the first three enrolled patients have completed at least 1 cycle of combination therapy, accrual will 
be held allowing a safety review. The decision to proceed with enrollment will be based on a discussion 
among the principal investigator, co-investigators, and study statistician regarding the frequency and 
severity of adverse events. In addition, an early stopping rule will be employed. If we are confident that 
more than 20% of patients have experienced a nondermatologic immune-related adverse event of grade 3 or 
higher attributable to ipilimumab, that cannot be alleviated or controlled by appropriate care or 
corticosteroid therapy within 14 days after the initiation of supportive care or corticosteroid therapy, the 
study will close to further enrollment. We will therefore monitor the study when 5, 10, 20, and 30 patients 
have completed 6 cycles of treatment. We will continue enrollment while the toxicity evaluation is taking 
place (we will not halt enrollment for the analysis). The study regimen will be considered excessively toxic 
if we observe 3 or more out of 5, 4 or more out of 10, 6 or more out of 20, and 9 or more out of 30 patients. 
We will then stop the trial. These boundaries are determined from the lower bound of 80% exact binomial 
confidence intervals.  
 
For true toxicity rate as 0.05, 0.10, 0.20, 0.30, 0.40 and 0.50, the probabilities of stopping the trial due to 
toxicity monitoring before/at n = 5, 10, 20 and 30 are referenced in Table 10 below. 
Table 10: Probabilities of stopping the trial due to toxicity monitoring rule  
 
True toxicity rate N=5 
N=10 
N=20 
N=30 
0.05 
0.0012 
0.0022 
0.0025 
0.0025 
0.10 
0.0086 
0.0212 
0.0323 
0.0342 
0.20 
0.0579 
0.1718 
0.3339 
0.4196 
0.30 
0.1631 
0.4563 
0.7736 
0.9023 
0.40 
0.3174 
0.7391 
0.9672 
0.9969 
0.50 
0.5000 
0.9141 
0.9982 
1.0000 
 
13.0 
TRIAL MANAGEMENT 
 
13.1 
 Quality Controls and Quality Assurance: 
 
13.1.1  
Study Monitoring 
 
Monitoring visits to the trial sites will be made periodically during the trial, to ensure all aspects 
of the protocol are followed. Source documents will be reviewed for verification of agreement 
with data as submitted via the data collection system. The investigator/institution guarantee 
access to source documents by HCRN or its designee and appropriate regulatory agencies. 
 
The trial site may also be subject to quality assurance audit by BMS or its designee as well as 
inspection by appropriate regulatory agencies. 
 
It is important for the investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 


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13.1.2  
Data and Safety Monitoring Plan 
 
HCRN data safety monitoring activities include: 
 
 
Review of clinical trial conducted for progress and safety 
 
 
Review of all adverse events requiring expedited reporting as defined in the protocol 
 
 
Review of reports generated by data quality control review process  
 
 
Notification of the Sponsor Investigator of recommended action 
 
 
Notification of sites coordinated by the HCRN of adverse events requiring expedited 
reporting and subsequent committee recommendations for study modifications 
 
 


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13.1.3 Data/Safety Monitoring and Reporting Guidelines 
 
HCRN will compile data summary reports for this trial and submit these reports monthly to the 
Sponsor-investigator. HCRN will submit data summary reports a minimum of twice a year to a 
Data Safety Monitoring Committee (DSMC) for review.  
 
13.2  
Data Handling and Record Keeping: 
 
13.2.1 
Case Report Forms 
 
An electronic case report form (eCRF) is required and must be completed for each included 
patient. The completed dataset is the sole property of HCRN and should not be made available in 
any form to third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without written permission from HCRN. 
 
13.2.2 
Record Retention 
 
To enable evaluations and/or audits from Health Authorities/HCRN, the investigator agrees to 
keep records, including the identity of all participating patients (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition. To comply with international regulations, the 
records should be retained by the investigator in compliance with regulations. 
 
During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRFs will 
be generated for each site and transmitted to the site and the site monitor. Corrections will be 
made by the study site personnel. This will be done on an ongoing basis. 
 
13.3 
Changes to the Protocol: 
 
Study procedures will not be changed without the mutual agreement of the Sponsor Investigator, 
Hoosier Cancer Research Network, and BMS. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version of the 
study protocol (amended protocol) will be generated by the Hoosier Cancer Research Network 
and must be approved by each IRB, BMS, and if applicable, also the local regulatory authority. 
Local requirements must be followed. 
 
If a protocol amendment requires a change to the Written Informed Consent Form, then the IRB 
must be notified. Approval of the revised Written Informed Consent Form by the IRB is required 
before the revised form is used.  
 
The principal investigator is responsible for the distribution of these documents to his or her IRB, 
and to the staff at his or her center. The distribution of these documents to the regulatory authority 
will be handled according to local practice. 
 


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BMS’s willingness to supply study drug is predicated upon the review of the protocol. The 
Hoosier Cancer Research Network agrees to provide written notice to BMS of any modifications 
to the protocol or informed consent. 
 
13.4  
Ethics: 
 
13.4.1 
Ethics Review 
 
The final study protocol, including the final version of the Written Informed Consent Form, must 
be approved or given a favorable opinion in writing by an IRB. The investigator must submit 
written approval to the HCRN office before he or she can enroll any patient into the study.  
 
The principal investigator is responsible for informing the IRB of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit patients for the study. The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided 
to the IRB according to local regulations and guidelines. 
 
The investigator is also responsible for providing the IRB with reports of any serious adverse 
drug reactions from any other study conducted with the investigational product. BMS will 
provide this information to the Sponsor Investigator. These reports will be reviewed by the 
Sponsor Investigator and those considered unexpected and possibly related to protocol therapy 
plus all deaths within 30 days of discontinuing treatment will be forwarded to participating sites 
for submission to their Institutional Review Boards per their guidelines. All other events will be 
held and submitted to the sites for continuing review. 
 
13.4.2 
Ethical Conduct of the Study 
 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH Good Clinical Practice, and applicable 
regulatory requirements. 
 
13.5  
Written Informed Consent: 
 
The investigator will ensure the patient is given full and adequate oral and written information 
about the nature, purpose, possible risks and benefits of the study. Patients must also be notified 
they are free to discontinue from the study at any time. The patient should be given the 
opportunity to ask questions and allowed time to consider the information provided. 
 
The patient’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The investigator must store the original, signed Written 
Informed Consent Form. A copy of the signed Written Informed Consent Form must be given to 
the patient. 


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Appendix A: Suggested Management of Immune-related Adverse Events 
 
Inflammatory Events (immune-related Adverse Events or Immune-mediated Adverse Reactions) 
 
Blocking CTLA-4 function may permit the emergence of autoreactive T cells and resultant clinical 
inflammatory AEs primarily involving the skin (dermatitis/pruritus), GI tract (diarrhea/colitis), liver 
(hepatitis), endocrine system (e.g. hypophysitis, adrenal and thyroid abnormalities) and other less frequent 
organs (e.g., uveitis/episcleritis). The majority of these inflammatory AEs manifested during treatment, 
however, a minority occurred weeks to months after stopping ipilimumab. The majority of the 
inflammatory AEs are reversible with the guidance issued below. In rare cases, these inflammatory AEs 
may be fatal. 
 
Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and 
endocrinopathy, and clinical chemistries (including liver function and thyroid function tests) should be 
evaluated at baseline and before each dose of ipilimumab. 
 
Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to 
labeling an adverse event as suspected inflammatory AE. Serological, immunological, and histological data 
should be used to support the diagnosis of an immune-mediated toxicity.  
 
 
Based on the current clinical experience with the use of corticosteroids for the management of treatment-
emergent inflammatory AEs, corticosteroids do not adversely affect the antitumor response in subjects with 
objective responses and concomitant serious inflammatory AEs, such as Grade 3 colitis, requiring 
corticosteroid treatment. In other words, disease control was maintained without relapse or progression 
despite corticosteroid administration for the treatment of ipilimumab-related inflammatory AEs. 
 
Gastrointestinal Toxicities 
 
The lower GI tract was the most common site for ipilimumab-induced GI toxicity. Diarrhea due to 
treatment with ipilimumab ranged from mild to very severe with bloody stools. In some cases, diarrhea 
began as mild and then became severe colitis that was considered life threatening. Ipilimumab treatment 
may increase the possibility of GI perforation for those subjects who may receive high dose IL-2 following 
ipilimumab treatment. Constipation was rarely associated with ipilimumab administration. Delay in 
corticosteroid treatment may be associated with a poor outcome for subjects with high-grade diarrhea. 
 
Liver Toxicities 
 
Patients receiving ipilimumab may develop elevations in liver function tests (LFTs) in the absence of 
clinical symptoms. Occasionally, patients may present with symptoms including right upper quadrant 
abdominal pain or unexplained vomiting. Most of inflammatory hepatitis responded to high-dose 
corticosteroids (IV route recommended).  
All patients require close medical monitoring of LFTs and immediate intervention to prevent serious 
sequelae. LFTs should be routinely assessed and reviewed prior to administration of each dose of 
ipilimumab. 
 
Endocrine Toxicities 


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The most common inflammatory endocrine toxicities occurring in ipilimumab-treated patients are 
hypophysitis and hypopituitarism. Secondary cortisol deficiency (hypoadrenalism), hypothyroidism or 
thyroiditis and; and, less commonly, other endocrinopathies may occur concomitantly with hypophysitis; 
however these may also present as the only or as primary endocrinopathy. Most patients with 
hypopituitarism presented with nonspecific complaints such as fatigue, visual field defects, confusion, or 
impotence. Some patients have had headache as the predominant presentation. The majority of subjects 
with hypopituitarism demonstrated enlarged pituitary glands based on brain magnetic resonance imaging 
(MRI). Low adrenocorticotropic hormone (ACTH) and cortisol were the most common biochemical 
abnormality; abnormal (mostly low) thyroid stimulating hormone (TSH), free T4, T3, testosterone or 
prolactin have also been reported in some subjects. Symptoms of hypopituitarism and other endocrine 
toxicities were generally controlled with appropriate hormone replacement. 
 
Dermatologic Toxicities 
 
Rash and pruritus was among the most common inflammatory AE; however, most cases were mild to 
moderate in severity. Two cases of fatal toxic epidermal necrolysis (TEN), considered drug-related, have 
been reported in clinical trials (ipilimumab and comparator/placebo). 
 
Neurological Toxicities 
 
Neurological manifestations in patients treated with ipilimumab may include motor and/or sensory 
neuropathy. Given the difficulty in definitely establishing an inflammatory etiology, alternative etiologies 
(e.g., tumor progression) should be excluded. Fatal Guillain-Barré syndrome and cases of myasthenia 
gravis have been reported in clinical trials of ipilimumab (Section 5.6.7.3). Unexplained motor neuropathy, 
muscle weakness, or sensory neuropathy should be evaluated and non-inflammatory causes such as disease 
progression, infections, metabolic disorders, and medications should be excluded. 
 
Other Toxicities 
 
Ocular inflammation, manifested as Grade 2 or Grade 3 episcleritis or uveitis, was associated with 
concomitant diarrhea in a few subjects (< 1%) and occasionally occurred in the absence of clinically 
apparent GI symptoms. Other presumed inflammatory AEs reported include, but were not limited to, 
arthritis/arthralgias, pneumonitis, pancreatitis, autoimmune (aseptic) meningitis, autoimmune nephritis, 
pure red cell aplasia, non-infective myocarditis, polymyositis, eosinophilia, pericarditis, urticaria (2%), 
large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, infusion reactions, and 
myasthenia gravis, of which were individually reported for < 1% of subjects unless otherwise noted. 
 
Suggested Evaluation and Treatment for Inflammatory Events 
 
Early diagnosis and treatment intervention for inflammatory events can help prevent the occurrence of 
complications, such as GI perforation. Gastrointestinal (diarrhea and colitis) and skin (rash and pruritus)-
related toxicities are the most common inflammatory events reported in studies with ipilimumab. Suggested 
evaluation procedures for suspected GI tract, liver, skin, endocrine, neurological and ocular toxicities are 
described below.  


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Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and 
endocrinopathy, and clinical chemistries (including liver function and thyroid function tests) should be 
evaluated at baseline and before each dose of ipilimumab. 
  
During evaluation of a suspected immune-mediated AE, all efforts should be made to rule out neoplastic, 
infectious, metabolic, toxic or other etiologic causes. Serological, immunological, imaging, and biopsy with 
histology (e.g., biopsy-proven lymphocytic) data should be used to support the diagnosis of an immune-
mediated toxicity or support an alternative cause of the adverse event. 
 
In general, for severe immune-mediated AEs, ipilimumab should be permanently discontinued and 
systematic high-dose corticosteroid therapy should be initiated. For moderate immune-mediated AEs, 
ipilimumab should be held or delayed and moderate dose corticosteroids should be considered. 
Upon improvement, corticosteroids should be tapered gradually over at least 1 month. 
 
Gastrointestinal Tract 
 
The differential diagnosis for subjects presenting with abdominal pain should include colitis, perforation, or 
pancreatitis. Additionally, a few subjects with abdominal pain also had acute swelling of the cecal wall on 
CT scan that may have represented localized inflammation. 
 
Diarrhea (defined as either first watery stool, or increase in frequency 50% above baseline with urgency or 
nocturnal bowel movement, or bloody stool) should be further evaluated and infectious or alternate 
etiologies ruled out. Subjects should be advised to inform the investigator if any diarrhea occurs, even if it 
is mild. An algorithm for managing subjects with diarrhea or suspected colitis is provided in the figure 
below. 


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The majority of subjects with ipilimumab-induced diarrhea or colitis responded to symptomatic therapy or 
corticosteroids. Prednisone (for oral administration) or methylprednisolone (for IV administration) are 
recommended corticosteroids of choice for colitis. Caution should be taken in the use of narcotics in 
patients with abdominal pain or colitis/diarrhea as narcotic use may mask the signs of colonic perforation.  
 
Permanent discontinuation of ipilimumab and starting high dose corticosteroid therapy (e.g., 
methylprednisolone 1-2 mg/kg/day IV or equivalent) is required for ipilimumab related ≥ Grade 3 
diarrhea/colitis. Upon improvement to grade 1 or less, corticosteroids should be slowly tapered according 
to symptomatic response over at least 1 month. Rapid corticosteroid tapering resulted in recurrence or 
worsening symptoms of enterocolitis, including perforation in some patients. 
 
Patients on IV steroids may be switched to oral corticosteroids (e.g., prednisone) at an equivalent dose and 
start tapering earlier. 
 
For subjects with ipilimumab-related Grade 2 diarrhea/colitis, ipilimumab should be held or delayed (as per 
protocol). Patients may be initially treated conservatively (e.g., with loperamide, fluid replacement). If 
symptoms persist for 5-7 days, worsen or recur, patients should be immediately switched to moderate to 
high dose corticosteroids (e.g., 0.5 - 1 mg/kg prednisone orally or equivalent). Most subjects with 
diarrhea/colitis will rapidly respond to initiation of corticosteroids. Upon improvement to grade 1 or less, 
the dose should be gradually tapered over at least 1-month. Treatment with ipilimumab may resume once 
the symptoms have improved to grade 1 or less. 
 


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Infrequently, subjects will appear refractory to corticosteroids or will flare following taper of 
corticosteroids. In these subjects, unless contraindicated (i.e., sepsis, perforation and other serious 
infections), a single dose of infliximab at 5 mg/kg may provide benefit. Some patients have required a 
subsequent additional dose of 5 mg/kg infliximab, although experience is limited.  
 
For patients with concomitant immune related hepatitis, use of mycophenolate mofetil (MMF) is 
recommended in place of infliximab. For patients with long-term immunosuppressive therapy, administer 
antimicrobial prophylactics as appropriate per institutional guidelines. Such cases should be discussed with 
the Principal Investigator. 
 
If the event is prolonged or severe or is associated with signs of systemic inflammation or acute phase 
reactants (e.g., increased CRP or platelet count; or bandemia), it is recommended that sigmoidoscopy (or 
colonoscopy, if appropriate) with colonic biopsy of 3 to 5 specimens for standard paraffin block be 
performed. If possible, 1 to 2 biopsy specimens should be snap-frozen and stored. All subjects with 
confirmed colitis should also have an ophthalmologic examination, including a slit-lamp exam, to rule out 
uveitis. Tests should also be performed for stool calprotectin and WBCs as outlined below. 
 


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Liver 
 
Liver function tests should always be performed and reviewed prior to administration of all ipilimumab 
doses. Patients treated with ipilimumab may develop elevation in LFT in the absence of clinical symptoms. 
In addition, subjects presenting with right upper quadrant abdominal pain, unexplained nausea, or vomiting 
should have LFTs performed immediately and reviewed before administering the next dose of study drug. 


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Any increase in LFT should be evaluated to rule out non-inflammatory causes of hepatotoxicity including 
infections, disease progression or medications and followed with frequent LFT monitoring at 3-day 
intervals until resolution. An ANA, perinuclear antineutrophil cytoplasmic antibody (pANCA), and anti-
smooth muscle antibody test may be performed if an autoimmune etiology is considered although these 
have been negative in some patients with inflammatory hepatitis due to ipilimumab. 
 
Patients with Grade 2 AST or ALT or total bilirubin elevations (AST/ALT > 2.5 x ULN, total bilirubin 
[Tbili] > 1.5 x ULN) should be followed with frequent LFT monitoring at 3-day intervals until resolution or 
return to baseline. Delay or withhold ipilimumab while investigating alternative etiologies (e.g. tumor 
progression, infectious causes, medication). If elevations persist for more than 5 to 7 days or worsen and no 
alternative etiologies are identified, consider moderate to high dose corticosteroids (e.g., 0.5 to 1 mg/kg/day 
prednisone orally or equivalent). Upon improvement to Grade 1 or less, corticosteroids should be tapered 
over at least 1 month, and treatment with ipilimumab may resume. 
 
Grade 3-4 hepatitis: For patients with Grade 3-4 AST or ALT or total bilirubin elevations (AST/ALT > 
5.0 x ULN, Tbili > 3.0 x ULN), ipilimumab should be  
 
 held or delayed (LFTs ≤ 8 x ULN and Tbili ≤ 5 x ULN ) 
 discontinued (LFTs > 8 x ULN, or Tbili > 5 x ULN) 
 
Systemic IV high dose corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone or equivalent) should be 
administered. For grade 4 events, the recommended dose of methylprednisolone is 2 mg/kg/day IV. 
Consultation with a hepatologist or gastroenterologist is recommended. 
 
Once the LFT and Tbili improve to Grade 2: 
 Corticosteroids should be slowly taper over at least 1 month. 
 Treatment with ipilimumab may resume once patient meets protocol specific retreatment criteria, 
unless ipilimumab was previously discontinued 
 
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose and 
start tapering or earlier. 
 
Liver toxicity refractory to corticosteroids: In patients whose LFTs worsen, or do not decrease with 
corticosteroid therapy within 3 to 5 days or who have an LFT flare during corticosteroid tapering that is not 
responsive to an increase in corticosteroids, consultation with gastroenterologist/hepatologist and addition 
of immunosuppression with MMF 1 g PO BID per institutional guidelines should be considered. For 
patients not responding to mycophenolate mofetil within 3-5 days, contact the medical monitor. 
Additional immunosuppression per institutional guidelines for autoimmune hepatitis /liver transplant may 
be considered. 
 
Patients receiving immunosuppression for more than 4 weeks should be evaluated for prophylaxis of 
opportunistic infections per institutional guidelines. 
 
An algorithm for management of hepatotoxicity is shown below. 


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Skin 
 
A dermatologist should evaluate persistent or severe rash or pruritus. A biopsy should be performed if 
appropriate and if possible, photos of the rash should also be obtained. Patients with low-grade ipilimumab-
related skin toxicity (Grade 1 or 2) may remain on therapy and could be treated with symptomatic therapy 
(e.g., antihistamines). Low-grade symptoms persisting for 1 to 2 weeks and not responding to topical 
corticosteroid, moderate to high dose oral corticosteroid therapy should be initiated (e.g., prednisone 0.5 to 
1 mg/kg once daily or equivalent). High-grade (Grade 3 or 4) symptoms require high-dose IV 
corticosteroid therapy (e.g., methylprednisolone 1 to 2 mg/kg/day or equivalent). A skin biopsy should be 
performed if possible. Once rash or pruritus is controlled to grade 2 or less, corticosteroids may be 
gradually tapered over a period of at least 1 month. Patients on IV steroids may be switched to oral 
corticosteroid (e.g., prednisone) at an equivalent dose and start tapering earlier. 
 
Patients with any high-grade skin related toxicity (Grade 3 regardless of causality and grade 4 if unrelated) 
have to skip or delay ipilimumab (as per protocol) and may only continue treatment with ipilimumab if the 
initial symptoms have improved to ≤ Grade 2. Patients with grade 4 skin toxicities considered to be related 
to ipilimumab have to permanently discontinue ipilimumab. 
 
An algorithm for evaluating patients with skin toxicities is provided below: 
 


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Endocrine 
 
Most subjects with hypopituitarism presented with nonspecific complaints such as fatigue, visual field 
defects, confusion, or impotence. Some have had headache as the predominant presentation. The majority 
of subjects with hypopituitarism demonstrated enlarged pituitary glands based on brain MRI. Low ACTH 
and cortisol were the most common biochemical abnormality; low TSH, free T4, T3, testosterone or 
prolactin have also been reported in some subjects. Subjects with unexplained symptoms such as fatigue, 
myalgias, impotence, mental status changes, or constipation should be investigated for the presence of 
thyroid, pituitary or adrenal endocrinopathies. An endocrinologist should be consulted if an endocrinopathy 
is suspected. If there are any signs of adrenal crisis such as severe dehydration, hypotension, or shock, 
intravenous corticosteroids with mineralocorticoid activity (e.g., methylprednisolone or equivalent) should 
be initiated immediately. If the patient’s symptoms are suggestive of an endocrinopathy but the patient is 
not in adrenal crisis, an endocrine laboratory results should be evaluated before corticosteroid therapy is 
initiated.  
 
Endocrine work up should include at least Thyroid stimulating hormone and free T4 levels should be 
obtained to determine if thyroid abnormalities are present. TSH, prolactin and a morning cortisol level will 
help to differentiate primary adrenal insufficiency from primary pituitary insufficiency. Radiographic 
imaging (e.g., MRI) with pituitary cuts should be performed.  
 
In patients with clinically asymptomatic TSH abnormalities (TSH < 0.5 x LLN, or TSH > 2.0 x ULN, or 
TSH consistently out of range in two subsequent measurements at least 3 weeks apart), free T4 (fT4) 


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should be measured at the next ipilimumab dosing. In primary pituitary endocrinopathy, fT4 abnormalities 
may lag behind TSH abnormalities. 
Therefore: 
 
 If fT4 is normal, fT4 measurements should be continued at each cycle until TSH returns to normal, 
or until endocrinology consult recommends no further testing. 
 If fT4 is abnormal, an endocrinology consultation should be obtained to evaluate whether the 
patient requires substitution or other treatment. Ipilimumab dosing may be continued as long as the 
patient is asymptomatic. 
 
If the pituitary scan and/or endocrine laboratory tests are abnormal, hold or delay ipilimumab (per protocol) 
and a short course of high dose corticosteroids (e.g., 1 to 2 mg/kg/day prednisone or equivalent) should be 
considered in an attempt to treat the presumed pituitary inflammation, but it is currently unknown if this 
will stop or reverse the pituitary dysfunction. Abrupt discontinuation of corticosteroids should be avoided 
due to possible prolonged adrenal suppression. Once symptoms or laboratory abnormalities are controlled, 
and overall patient improvement is evident, patients on IV corticosteroids can be converted to the oral 
equivalent of prednisone and the corticosteroid tapered gradually over a period of at least 1 month. 
 
Appropriate hormone replacement therapy should be instituted if an endocrinopathy is documented, and it 
is possible that subjects may require chronic hormone replacement.  
 
Ipilimumab dosing may resume once symptoms are controlled (with or without hormone substitution).  
 
An endocrinopathy management algorithm is presented below. 


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Neurological 
 
Patients should be monitored for signs and symptoms of motor or sensory neuropathy or muscular 
symptoms. Subjects presenting with sensory symptoms lasting more than 4 days or motor symptoms 
confirmed by physical examinations should be evaluated and non-inflammatory causes such as disease 
progression, infections (including Lyme disease), metabolic syndromes and medications (such as taxanes 
and/or platinum salts) should be ruled out. A neurology consult should be obtained and diagnostic 
characterization of the neurological syndrome (electromyogram, nerve conduction studies) should be 
started.  
 
The next dose of ipilimumab should be held or delayed (as per protocol) if the event of a Grade 2 
neuropathy (sensitive or motor) is considered related to study drug. Treatment may resume upon 
improvement to grade 1 or less. The administration of ipilimumab should be permanently discontinued in 
patients with Grade 3 or 4 sensory neuropathy suspected to be related to study drug. Patients should be 
treated according to institutional guidelines and the administration of high dose IV corticosteroids (e.g., 
methylprednisolone 1 to 2 mg/kg per day or equivalent) should be considered. 
 
The administration of ipilimumab should be permanently discontinued in patients with Grade 3 or 4 motor 
neuropathy regardless of the causality to study drug. Patients with Grade 3 or 4 motor neuropathy who are 
clinically stable should be treated according to institution guidelines and the administration of high dose IV 
corticosteroids therapy (e.g., methylprednisolone 1 to 2 mg/kg per day or equivalent) should be considered. 
 


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Patients with Grade 3 or 4 motor neuropathy who are not clinically stable or who have atypical symptoms 
should be hospitalized and high dose IV administration of corticosteroids should be initiated. Per clinical 
judgment, IV immunoglobulin (IV Ig) or other immunosuppressive therapies (as appropriate) should be 
considered. 
 
When the symptoms improve to Grade 2, corticosteroids may be tapered over at least one month. Patients 
on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose and start 
tapering earlier. 
 
A neuropathy management algorithm is presented below. 
 
 
 
Other 
 
Ocular inflammation (episcleritis or uveitis) was reported in a few subjects. These conditions responded to 
topical corticosteroid therapy. An ophthalmologist should evaluate visual complaints with examination of 
the conjunctiva, anterior and posterior chambers, and retina. Visual field testing and an electroretinogram 
should also be performed. Examination and testing should be documented on the appropriate case report 
form (CRF). Ipilimumab-related uveitis or episcleritis may be treated with topical corticosteroid eye drops.  
 


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Symptoms of abdominal pain associated with elevations of amylase and lipase suggestive of pancreatitis 
may be associated with anti-CTLA-4 monoclonal antibody administration. The differential diagnosis of 
acute abdominal pain should include pancreatitis. Appropriate evaluation should include serum amylase 
and lipase tests. 
 
 
14.0 
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