A Phase II Study of CTLA Blockade by Ipilimumab Plus Androgen Suppression Therapy in Patients With an Incomplete Response to AST Alone for Metastatic Prostate Cancer
Phase: PHASE2
Conditions: Adenocarcinoma of the Prostate, Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer
Sponsor: OHSU Knight Cancer Institute

 
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A Phase II Study of CTLA Blockade by Ipilimumab plus Androgen 
Suppression Therapy in Patients with an Incomplete Response to AST 
Alone for Metastatic Prostate Cancer 
 
 
OHSU PROTOCOL NUMBER: 5254 
PCCTC PROTOCOL NUMBER: 08-004 
BMS PROTOCOL NUMBER: CA184059 
 
 
Principal Investigator:   
Julie N. Graff, MD 
Portland VA Medical Center 
3710 S.W. US Veterans Hospital Rd. 
Mail Code: P3CHEMO 
Portland, OR 97239-1034 
(503) 220-8262, ext. 55688 
(503) 494-6197 (fax) 
graffj@ohsu.edu 
 
Co-investigators: 
 
Tomasz M. Beer, MD 
Director, Prostate Cancer Program 
Oregon Health & Science University 
3303 SW Bond Ave. CH-14R 
(503) 494-0365 
(503) 494-6197 (fax) 
beert@ohsu.edu 
 
Christopher W. Ryan, MD 
Oregon Health & Science University 
3303 SW Bond Ave. CH-14R 
(503) 494-8487 
(503) 494-6197 (fax) 
ryanc@ohsu.edu 
 
Joshi Alumkal, MD 
Oregon Health & Science University 
3303 SW Bond Ave. CH-14R 
(503) 494-8534 
(503) 494-6197 (fax) 
alumkalj@ohsu.edu 
 
 
Jeremy Cetnar, MD 
 
Oregon Health & Science University 
3303 SW Bond Ave. CH-14R 

 
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(503) 494-3257 
 
cetnarj@ohsu.edu
 
 
 
 
Consultants: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lawrence Fong, MD 
 
 
 
 
 
 
 
University of California San Francisco 
 
 
 
 
 
 
Department of Medicine- Hem/Onc 
 
 
 
 
 
 
513 Parnassus Ave 
 
 
 
 
 
 
Room S-772, Box 0511 
 
 
 
 
 
 
San Francisco, CA 94143-0511 
 
 
 
 
 
 
(415) 514-9301 
 
 
 
 
 
 
(415) 476-0459 (fax) 
 
Statistician:  
 
 
Motomi Mori, Ph.D. 
 
 
 
 
Oregon Health & Science University 
(503) 402-2871 
 
Original Protocol Version/Date: 6/1/2011 
Protocol Revision Date: 6/30/14 
 
 

 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................. 2 
SCHEMA ........................................................................................................ 7 
PROTOCOL SYNOPSIS .............................................................................. 7 
1 
INTRODUCTION ....................................................................... 11 
1.1 
Research Hypothesis ................................................................... 11 
1.2 
Product Development Rationale ................................................ 11 
1.2.1 
CTLA-4 and T Cell Activation ....................................................................12 
1.3 
Summary of Results of Investigational Program ..................... 14 
1.3.1 
Pharmacology of Ipilimumab ......................................................................14 
1.3.2 
Pre-Clinical Toxicology of Ipilimumab ......................................................14 
1.3.3 
Human Pharmacokinetics of Ipilimumab ..................................................15 
1.3.4 
Clinical Safety with Ipilimumab..................................................................16 
1.3.5 
Immune-Related Adverse Events (IRAEs) with Ipilimumab ...................17 
1.3.6 
Clinical Efficacy of Ipilimumab ..................................................................20 
1.4 
Overall Risk/Benefit Assessment melanoma and 
prostate cancer ............................................................................ 21 
1.5 
Study Rationale ........................................................................... 23 
2 
STUDY OBJECTIVES ............................................................... 24 
2.1 
Primary Objective ....................................................................... 24 
2.2 
Secondary Objectives .................................................................. 24 
3 
STUDY DESIGN ......................................................................... 24 
4 
SUBJECT SELECTION CRITERIA ....................................... 27 
4.1 
Inclusion Criteria ........................................................................ 28 
4.2 
Exclusion Criteria ....................................................................... 29 
4.3 
Data Safety Monitoring Plan ..................................................... 30 
5 
STUDY THERAPY ..................................................................... 30 

 
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5.1 
Ipilimumab ................................................................................... 30 
5.1.1 
Dose Calculations ..........................................................................................30 
5.1.2 
Storage, Preparation, and Administration .................................................31 
5.1.3 
Dose Modifications ........................................................................................32 
5.1.4 
Discontinuation of Study Therapy ..............................................................33 
5.1.5 
Permanent Discontinuation of Ipilimumab ................................................34 
5.1.6 
Immune-Related Adverse Events (IRAEs): Definition, 
Monitoring, and Treatment .........................................................................34 
5.1.7 
Other Guidance .............................................................................................36 
5.2 
Prohibited and Restricted Therapies During the Study.......... 38 
5.2.1 
Prohibited Therapies ....................................................................................38 
5.2.2 
Restricted Therapies .....................................................................................39 
5.2.3 
Precautions ....................................................................................................39 
6 
STUDY PROCEDURES AND OBSERVATIONS .................. 40 
6.1 
Time and Events Schedule for Protocol CA184059 ................. 40 
6.2 
Procedures by Visit ..................................................................... 42 
6.2.1 
Study Completion or Early Discontinuation Visit .....................................42 
6.2.2 
Study Drug Discontinuation ........................................................................42 
6.3 
Details of Procedures .................................................................. 42 
6.3.1 
Study Materials .............................................................................................42 
6.3.2 
Safety Assessments ........................................................................................42 
6.4 
Criteria for Evaluation ............................................................... 42 
6.4.1 
Safety Evaluation ..........................................................................................42 
6.4.2 
Efficacy Evaluation .......................................................................................43 
6.4.3 
Evaluation of Tumor Response Using mRECIST Criteria .......................45 
6.4.4 
Response Endpoints ......................................................................................47 
7 
INVESTIGATIONAL PRODUCT: IPILIMUMAB ............... 47 
7.1 
Packaging and Labeling ............................................................. 48 
7.2 
Storage, Handling, and Dispensing ........................................... 48 
7.2.1 
Storage ...........................................................................................................48 

 
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7.2.2 
Handling and Disposal .................................................................................48 
7.2.3 
Dispensing ......................................................................................................49 
7.3 
Drug Ordering and Accountability ........................................... 49 
7.3.1 
Initial Orders .................................................................................................49 
7.3.2 
Re-Supply ......................................................................................................49 
7.4 
Ipilimumab Accountability ........................................................ 50 
7.5 
Ipilimumab Destruction ............................................................. 50 
8 
ADVERSE EVENT REPORTING ........................................... 50 
8.1 
Collection of Safety Information ............................................... 50 
8.1.1 
Serious Adverse Events ................................................................................51 
8.1.2 
Nonserious Adverse Events ..........................................................................52 
8.2 
Assignment of Adverse Event Intensity and Relationship 
to Investigational Product .......................................................... 52 
8.3 
Collection and Reporting ............................................................ 53 
8.3.1 
Serious Adverse Events ................................................................................53 
8.3.2 
Handling of Expedited Safety Reports .......................................................55 
8.3.3 
Nonserious Adverse Events ..........................................................................56 
8.3.4 
Pregnancy ......................................................................................................56 
8.3.5 
Other Safety Considerations ........................................................................57 
9 
STATISTICAL METHODOLOGY .......................................... 57 
9.1 
Study Design ................................................................................ 57 
9.2 
Primary and Secondary Endpoints ........................................... 57 
9.3 
Sample Size Justification ............................................................ 57 
9.4 
Analysis Populations ................................................................... 57 
9.5 
Statistical Analysis Plan .............................................................. 58 
9.6 
Safety Analysis ............................................................................. 58 
9.7 
Efficacy Analysis ......................................................................... 58 
10 
ADMINISTRATIVE SECTION ................................................ 59 

 
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10.1 
Compliance with the Protocol and Protocol Revisions............ 59 
10.2 
Informed Consent........................................................................ 59 
10.3 
Records and Reports ................................................................... 60 
10.4 
Good Clinical Practice ................................................................ 60 
10.5 
Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) ................................................................. 60 
10.6 
Records Retention ....................................................................... 61 
APPENDIX 1 
LIST OF ABBREVIATIONS ...................................... 62 
APPENDIX 2 
GENERAL RECOMMENDATIONS FOR 
IMMUNE-RELATED ADVERSE EVENTS (IRAES) ........... 63 
APPENDIX 3 
SUGGESTED WORK-UP AND TREATMENT 
FOR IMMUNE-RELATED ADVERSE EVENTS 
(IRAES) ........................................................................................ 64 
APPENDIX 4 
DIARRHEA MANAGEMENT ALGORITHM ........ 67 
APPENDIX 5 
HEPATOTOXICITY MANAGEMENT 
ALGORITHM ............................................................................. 68 
APPENDIX 6 
ENDOCRINOPATHY MANAGEMENT 
ALGORITHM ............................................................................. 69 
APPENDIX 7 
SAMPLE COLLECTION/HANDLING AND 
SHIPPING ................................................................................... 70 
APPENDIX 8:  ECOG PERFORMANCE STATUS ............................... 72 
REFERENCES ............................................................................................ 73 
 
 

 
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STUDY SCHEMA 
 
Patients with a PSA > 0.2 ng/ml after 6-18 
months of androgen suppression therapy are 
identified, screened, and consented. 
Patients receive a dose of ipilimumab 10 
mg/kg IV every three weeks for the first 
12 weeks. 
For weeks 12-24, patients are observed 
for progression. 
Patients who do not progress by week 24 
will receive ipilimumab 10 mg/kg IV 
every three months for weeks 24-60. 
Patients will be followed for 5 years after 
completion of study treatment 

 
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PROTOCOL SYNOPSIS 
Protocol Title: 
A Phase II Study of CTLA Blockade by Ipilimumab plus 
Androgen Suppression Therapy in Patients with an Incomplete 
Response to AST Alone for Metastatic Prostate Cancer 
Site Numbers & 
Names: 
This study is currently open at Oregon Health & Science 
University and Rutgers Cancer Institute of New Jersey.  
Research 
Hypothesis: 
The early addition of immunotherapy in patients with metastatic 
prostate cancer who have a poor prognosis as a result of an 
incomplete biochemical response to androgen suppression 
therapy (AST) will improve outcomes to approximate outcomes 
in patients who do obtain a complete biochemical response with 
AST. 
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
All patients will receive ipilimumab 10 mg/kg by 90-minute IV 
infusion every three weeks for four doses.  Patients without 
progression at Week 24 will subsequently receive maintenance 
ipilimumab 10 mg/kg IV every 12 weeks for four additional 
doses. Patients will have their PSA checked every three weeks 
during the first four doses of ipilimumab, every six weeks 
between weeks 12 and 24, and every 12 weeks thereafter. Once 
all eight doses of ipilimumab have been given, patients will be 
followed with a serum PSA every 12 weeks (either at the 
research site or at the patient’s treating physician) until 
radiographic progression. Survival status will be assessed by 
telephone every 6 months for as long as patients are alive for up 
to 5 years after their last study visit. There will be a CT scan of 
the chest/abdomen/pelvis and whole body bone scans at baseline, 
12 weeks, 24 weeks, and then every three months until 
radiographic progression. Scans may be performed sooner if 
there are any concerns about progression. Correlative study labs 
will be drawn just prior to ipilimumab administration during the 
first four doses (weeks 1, 4, 7, 10). 

 
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Study Objectives: 
 
The primary endpoint is the proportion of patients who achieve 
an undetectable PSA (≤ 0.2 ng/ml) after initiation of ipilimumab 
therapy. 
 
Secondary endpoints include time to PSA progression, time to 
disease progression by any measure, time to death from any 
cause, maximum percentage of PSA reduction in each patient, 
response in measurable disease by RECIST criteria, measure of 
T cell response by flow cytometry, number of patients with 
immune related Adverse Events (IRAEs) and correlation 
between IRAEs and clinical outcomes. The effect of treatment 
on the ratio of T regulatory cells to T effector cells and 
additional measures of immune response will also be 
determined. To examine correlative biomarkers and their 
relationship to clinical outcomes.  Potential biomarkers include, 
but are not limited to CRP, IGF-1 and –2, or FSH. 
Study Design: 
This is a single arm phase II study to examine the activity of 
ipilimumab plus AST early in metastatic prostate cancer in men 
with an incomplete response to androgen suppression therapy 
(AST). 
Accrual Goal: 
30 patients 
Accrual Rate: 
1 to 2 patients per month 
FPFV: 
LPFV: 
Follow Up: 
Recruitment projected to begin 9/2011 
Final patient registration projected for 6/2016 
Follow-up for survival will continue for up to 5 years after the 
last subject ends the study. 
Correlative 
Studies: 
We will examine the T cell activation markers (HLA-DR, CD25, 
CD26, CD40L, CD62L, CD69, CD71, CD134) as well as the 
ratio of T effector to T regulatory cells before and after treatment 
with ipilimumab. These tests will be performed in the 
immunology laboratory of Larry Fong, MD, at UCSF. We will 
also examine antigens and correlate with response.  

 
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Inclusion Criteria: 
Men with histologically confirmed adenocarcinoma of the 
prostate and radiographically documented metastases treated 
with AST who have a serum PSA > 0.2 ng/mL after 6 to 18 
months of AST. 
 
Eligible patients must also have a documented white blood cell 
(WBC) count  2x109/L, absolute neutrophil count (ANC)  ≥ 
1.0x109/L, a platelet count ≥ 50x109/L, hemoglobin  8 g/dL, 
aspartate aminotransferase (AST)  2.5 x ULN, a serum 
creatinine ≤ 3.0 times institutional ULN, bilirubin  3 x ULN 
unless diagnosed with Gilbert’s syndrome and an ECOG 
performance status ≤ 1. 
Exclusion Criteria: 
Patients with a life expectancy less than 6 months, treatment 
with any investigational agent in the last 28 days, more than 18 
months since initiation of AST, or a concurrent active 
malignancy diagnosed within the last 5 years (other than non-
melanoma skin cancer, or other readily treatable tumors with 
expected cure) will not be eligible for this study. Patients must 
not have a known autoimmune disease, use prednisone > 10 mg 
daily (or its equivalent) orally for any indication, or have chronic 
infections (including hepatitis B or C or HIV). 
Criteria for 
Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
Patients will receive a history and physical exam and multiple 
laboratory tests (PSA, complete chemistry panel and blood 
counts, as well as tests for endocrinopathies) at baseline and 
every 3 weeks during the first 4 doses of therapy. Available labs 
(i.e. the chemistry panel and blood counts) will be reviewed prior 
to administration of ipilimumab. Imaging studies will be done at 
baseline, 12 weeks, 24 weeks and then every six months, or 
sooner if concerning symptoms arise. If there is no evidence of 
radiographic progression on the 24-week scan, patients will go 
on to receive four doses of maintenance ipilimumab therapy 
(weeks 24, 36, 48, 60). They will have a history and physical 
exam at least every three months. Their survival status will be 
assessed by phone survey every 6 months for up to five years 
after the last study visit. 
 
Efficacy will be based on the results of the PSA and imaging 
studies (using PCWG2 and modified RECIST criteria). Safety 
will be monitored using the regular physician examinations and 
laboratory assessments. 

 
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Statistics: 
N=30 (for the final analysis, 10 for the intial analysis).  Using 
the Simon two-stage design for Phase II trials, the initial accrual 
will be 10 patients.  Assuming that 10% of patients receiving 
usual care will achieve an undetectable PSA without additional 
intervention, the trial has a 80% power to detect a rate of 
achieving an undetectable PSA of  30% among patients treated 
with ipilimumab. At least two patients with an undetectable PSA 
will be required in the first 10 patients to continue to stage 2. As 
soon as two patients  achieve an undectable PSA, stage 2 for of 
the study will begin.  If 6 or more of 30 patients have achieved 
an undetectable PSA at 6 months, the study will be considered 
successful and the regimen worthy of further investigation.  This 
design has a type I error rate of 0.05 and a type II error rate of 
0.20.  
Demographic and clinical characteristics will be summarized 
using descriptive statistics (e.g. proportions, mean, standard 
deviation, median, range).  The proportion of patients who 
achieve an undetectable PSA (≤0.2 ng/ml) after initiation of 
ipilimumab therapy will be provided with the exact 95% 
confidence interval.  The Kaplan-Meier method will be used to 
estimate time to PSA progression, time to disease progression by 
any measure and time to death from any cause.  In evaluation of 
time to PSA progression and time to disease progression by any 
measure will be censored for: (1) lost to follow-up at the date of 
last contact, (2) use of additional cancer therapies that would 
interfere with ascertainment of the endpoint of interest (3) death 
from causes other than prostate cancer or treatment of prostate 
cancer. Evaluation of time to death will be censored for lost to 
follow-up at last contact. 
The effects of IRAEs and other immune parameters (e.g., a ratio 
of T regulatory cells to T effector cells) on clinical outcomes will 
be evaluated using logistic regression for binary endpoints (e.g., 
achievement of undetectable PSA) and Cox regression for the 
time to event outcomes (e.g., time to PSA progression).  
 

 
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1 
INTRODUCTION 
1.1 
Research Hypothesis 
The early addition of immunotherapy in patients with metastatic prostate cancer who 
have a poor prognosis as a result of having an incomplete biochemical response to 
androgen suppression therapy will improve outcomes to resemble outcomes seen in those 
patients who do obtain a complete biochemical response with AST alone. 
1.2 
Product Development Rationale 
In 2009, an estimated 27,360 men in the United States died from advanced metastatic 
prostate cancer, making prostate cancer the second most lethal malignancy among US 
men.1 Also, an estimated 192,280 men were diagnosed with prostate cancer, and around 
7,700 of those men had incurable disease (i.e., metastatic) at diagnosis.1 Androgen 
suppression therapy (AST) is the most effective systemic therapy for these patients with 
incurable prostate cancer. Currently, the most promising approach to extending survival 
and protecting quality of life in these men is to identify ways to enhance the depth and 
duration of response to AST. 
 
In a 2006 publication, Hussain, et al., examined outcomes in 1,345 such patients.2 As 
shown below, the PSA nadir maintained after 6 to 7 months of AST was a powerful 
predictor of overall survival.  Those patients who achieved an undetectable PSA fared 
best. The definition of undetectable PSA in this paper was a PSA ≤ 0.2. 
 
PSA (ng/mL)  
 
Number of Patients 
 
Median Survival (months) 
>4 
 
 
 
383 
 
 
 
13 (95% CI, 11-16) 
 
≤4, >0.2 
 
 
360 
 
 
 
44 (95% CI, 39-55) 
≤0.2 
 
 
 
602 
 
 
 
75 (95% CI, 62-91) 
                                                                                                                                                                        
Hussain and colleagues were able to discriminate between men at high and low risk of 
dying from castration resistant prostate cancer (CRPC) at a point in the disease process 
when the disease burden is minimal. This discovery creates a novel opportunity to target 
this minimal volume androgen-independent disease early with the hope of altering the 
grim natural history of this disease state.  Hussain’s data also demonstrate that a complete 
PSA response to initial therapy is likely a pre-requisite for long-term survival.  
 
An emerging class of agents that target immune functions has shown promise in treating 
advanced prostate cancer. It is believed that cancer cells can evade immune detection by 

 
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interacting with the CTLA-4 receptor on the T cells. This interaction downregulates the 
immune response, thus allowing cancer cells to escape detection.3 Immunotherapy with 
anti-CTLA antibody (ipilimumab) shows promise in Phase I studies of men with CRPC 
who have progressed through current therapeutic options.4 At our institution, twenty-six 
metastatic prostate cancer patients have started this therapy. Of thirteen evaluable 
patients, four have had confirmed PSA responses (PSA decrease of 50% or greater from 
reference value confirmed by a second measurement at least 3 weeks later), including one 
with objective radiologic as well as PSA complete response, ongoing for over 2 years as 
of September 2009. Notably, these patients responded despite having considerably more 
extensive and more heavily pre-treated disease than the population targeted in this 
proposal. 
 
We are collaborating with Lawrence Fong, an oncologist with an interest in prostate 
cancer immunology at USCF. All correlative studies will be done in Dr. Fong’s 
laboratory.  The total amount of blood required for these studies is 60 ml just prior to the 
first four ipilimumab doses (weeks 1, 4, 7, 10). We will perform correlative studies 
examining the ratio of T effector to T regulatory cells before and after treatment with 
ipilimumab.Dr. Fong’s lab has identified its own set of prostate cancer antigens. The 
names of these antigens are not specifically outlined because they are proprietary at this 
time.  The results of all studies will be correlated with outcomes and side effects in 
exploratory analyses. 
1.2.1 
CTLA-4 and T Cell Activation 
Figure 1 
Mechanism of Action 
 

 
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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 
costimulation is mediated by engagement of CD28 on the T cell surface by members of 
the B7 family on the antigen-presenting cell (APC).5 (See Figure 1.) 
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.6 
The fact that tumor cells do not express B7 contributes to their poor capacity to elicit 
immune responses.7,8 
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.9,10  
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 
CD28.11Although 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.12 This was initially suggested by the following in vitro observations: 
(1) blockade of CTLA-4/B7 interactions with antibody enhanced T cell responses; 

 
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(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.13,14,15,16 Blocking CTLA-4-B7 interaction 
while preserving signaling via CD28 resulted in enhanced T cell responses in vitro14 
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-4 came 
from examination of mice with a null mutation.17,18,19 CTLA-4 knockout mice appear to 
have spontaneously activated T cells evident at approximately 1 week after birth, 
followed by rampant 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.16 
1.3 
Summary of Results of Investigational Program 
1.3.1 
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. 
1.3.2 
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 

 
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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. 
1.3.3 
Human Pharmacokinetics of Ipilimumab 
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. 

 
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1.3.4 
Clinical Safety with Ipilimumab 
Ipilimumab immunotherapy is currently FDA-approved in patients with unresectable 
advanced melanoma (unresectable Stage III or Stage IV). 
Ipilimumab has been administered to approximately 2633 patients with different cancers 
in 24 completed or ongoing clinical trials as of 31-Mar-2008 with a dose range between 
0.3 mg/kg and 20 mg/kg. Most experience with ipilimumab exists at the 3 mg/kg and 
10 mg/kg dose levels. Patients who received ipilimumab at 3 mg/kg were treated in 
clinical studies conducted early in the development program and received either a single 
or multiple injections. Intra-patient dose escalation indicated that patients who were 
unresponsive at the 3 mg/kg dose level may have responded to 9 mg/kg. Based on 
preliminary data on the 10 mg/kg dose level of ipilimumab, the ongoing clinical program 
investigating ipilimumab in metastatic melanoma utilizes the 10 mg/kg dose level with 
the expectation that 10 mg/kg will prove more beneficial than 3 mg/kg. 
1.3.4.1 
Details of Drug-Related Adverse Events 
Drug-related adverse events (AEs) were reported in studies with ipilimumab as 
monotherapy as well as in combination studies with vaccines, cytokines or 
chemotherapy. The AE profile of ipilimumab is relatively well characterized, with most 
drug-related AEs being immune-related adverse events (IRAEs), which are considered to 
be associated with the mechanism of action of ipilimumab. The most common IRAEs are 
colitis and diarrhea, rash, pruritis, deficiencies of endocrine organs (pituitary, adrenal or 
thyroid), hepatitis, and uveitis. Rare complications are bowel perforations (~1%) 
resulting from underlying severe colitis, which have required surgical intervention. 
1.3.4.2 
Drug-Related Serious Adverse Events 
Drug-related 
Grade 3 
or 
Grade 4 
serious 
adverse 
events 
(SAEs) 
include: 
rash/desquamation, pruritus, uveitis, speech impairment, abdominal pain, diarrhea/colitis, 
nausea/vomiting, transaminase elevation, adrenal insufficiency, panhypopituitarism and 
atrial fibrillation. Some of these events, such as rash/desquamation, pruritus, uveitis, 
diarrhea/colitis, transaminase elevation, adrenal insufficiency and panhypopituitarism, 
may represent drug induced IRAEs (see Section 4.3.4). Refer to the most recent version 
of the Ipilimumab Investigator Brochure for the latest update on SAEs. 
Among subjects treated with ipilimumab 10 mg/kg, SAEs considered possibly, probably, 
or definitely related to study drug were reported for 26% of subjects (176/675). Drug 

 
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related SAEs reported in at least 1% of the 675 subjects at 10 mg/kg included diarrhea 
(10%), colitis (7%), vomiting (3%), dehydration (3%), autoimmune hepatitis (2%), 
hypopituitarism (2%), nausea (2%), abdominal pain (2%), pyrexia (2%), aspartate 
aminotransferase increased (1%), alanine aminotransferase increased (1%), and fatigue 
(1%). 
1.3.5 
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 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. 
Approximately 60% of subjects developed any grade IRAEs which involved 
predominately the gastrointestinal (GI) tract, endocrine glands, liver, or skin. Based on 
data from the safety database, the number of subjects with serious IRAEs was 
approximately 15% (401/2633), including 8.2% for serious GI IRAEs (diarrhea and/or 
colitis), 2.2% of serious endocrinopathy (primarily hypophysitis/hypopituitarism), 2% of 
pericarditis and <1% of serious skin IRAEs. Bowel perforation was reported in 
approximately 1% of subjects. With few exceptions these IRAEs were clinically 
manageable and reversible with supportive care or corticosteroids. In responding patients, 
addition of corticosteroids does not appear to have a temporal relationship to change in 
objective tumor response. 
Additionally, as of February 2006, there has been observation from a National Cancer 
Institute (NCI) study of bowel wall perforation in some patients who were administered a 
high-dose IL-2 following treatment with ipilimumab. Of the 22 patients administered 
high-dose IL-2, three patients experienced bowel wall perforations. This is a higher rate 
than would be expected with high-dose IL-2 treatment alone. All three patients had 
metastatic melanoma and had previously received their last dose of ipilimumab > 77 days 
before the first dose of IL-2. Two of the patients had clinically significant ipilimumab-

 
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related diarrhea or colitis and the symptoms had completely resolved prior to IL-2 
administration. One patient did not experience ipilimumab-related diarrhea. It is unknown 
whether this observation represents a true association or is mechanistically unrelated to 
prior ipilimumab exposure. 
1.3.5.1 
Drug-Related Deaths 
Based on reports from the safety data base as of June 30, 2008, there have been reports of 
death (approximately 1% [28/3000]), 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 multiorgan 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. 
1.3.5.2 
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 studied in subjects with melanoma, including 
0.3 vs 3 vs 10 mg/kg. Table 1 summarizes the overall IRAE frequencies by dose from 
CA184-022 based on safety data from the locked clinical database. 

 
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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 1 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.  
 
1.3.5.3 
Neuropathies 
Isolated cases of motor neuropathy of an autoimmune origin have been reported among 
patients treated with ipilimumab. Two cases have been diagnosed as Guillain-Barre 
syndrome (GBS), only one of which was considered study related. As of July 2, 2008, 
15 cases of neuropathy SAEs have been reported.  Of these, 13 were assessed as 
unrelated to study therapy because alternative etiologies, including brain metastases, 
spinal cord compression, or aterial thrombosis, were identified in almost every case. 
Table 1. 
Summary of Immune-Related AEs 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 

 
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1.3.6 
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. 
Based on preliminary results, ipilimumab is active in patients with advanced stage 
malignant melanoma. The objective responses observed with ipilimumab may be 
considered durable as they have occurred across a spectrum of doses and schedules. 
Based on a preliminary analysis for study MDX010-15 involving ipilimumab 10 mg/kg 
multiple doses, 34.8% of patients (N = 23) were progression-free at 6 months and about 
17.4% were progression-free at 1 year. In comparison, for Study MDX010-08 involving 
ipilimumab 3 mg/kg multiple doses, 10.8% patients (N = 37) had progression-free 
survival at 6 months and 8.4% at 1 year. Ipilimumab has also been studied in 
combination with chemotherapy (dacarbazine), melanoma vaccines (gp100), and 
cytokines (IL-2). Further details on clinical results can be found in the current version of 
the Ipilimumab Investigator Brochure.  
The clinical benefit of ipilimumab extends to prostate cancer patients as well. A pilot trial 
looked at the safety and efficacy in 14 prostate cancer patients with bone metastases and 
varying prior treatment regimens of their prostate cancer.[Small, Clin Cancer Res, 2007]. 
Half had already received chemotherapy prior to enrollment in the trial. Four patients also 
had soft tissue disease. Each patient received a single dose of ipilimumab, 3 mg/kg IV. 
Two patients had a PSA decline of ≥ 50%, and each of those patients elected to receive a 
second dose of ipilimumab 3 mg/kg IV. Neither of those patients had soft tissue lesions 
that could be measured by RECIST criteria. Their PSA responses lasted for 135 and 60 
days, respectively. 
More recently, 45 patients with metastatic, castration-resistant prostate cancer were given 
ipilimumab 10 mg/kg every three weeks for four doses.20 Twenty-nine of the patients 
received a single dose of radiation just prior to the first dose of ipilimumab. Of these 29 
patients, 14 had no exposure to chemotherapy prior to ipilimumab treatment, and 15 had 
received chemotherapy prior to ipilimumab treatment. The use of chemotherapy was 
historical, and not part of this study. The patients with a PSA decline of ≥ 50% were 
more likely to be chemotherapy naïve. The results are in Table 2. Importantly, response 
to ipilimumab appears to be increased with this dose and schedule, over the 3 mg/kg x1. 

 
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Table 2.  
Summary of PSA decline in men with advanced prostate cancer who 
were treated with ipilimumab with and without radiation and who 
either had or had not been previously treated with chemotherapy. 
Sub group 
Ipi alone 
XRT + Ipi 
No chemo 
XRT + Ipi 
Chemo 
All Ipi 
alone 
All XRT + 
Ipi 
All No 
Chemo 
All 
Chemo 
N (45 
patients total 
16 
15 
14 
16 
29 
27 
18 
≥ 50% PSA↓ 
5 
4 
1 
5 
5 
8 
2 
 
This study did not formally compare ipilimumab with radiation versus ipilimumab alone. 
The data presented in Table 2 does not overwhelmingly support or refute the usefulness 
of radiation added to ipilimumab. 
1.3.6.1 
Relationship Between Response and Immune Breakthrough Events in 
Patients with Metastatic Melanoma and Prostate Cancer 
Drug-related AEs of any grade considered to be immune-mediated in nature (IRAEs) 
were reported for 54.0% of subjects in clinical studies of ipilimumab. These IRAEs are a 
consequence of inhibiting CTLA-4 function and most were reported as Grade 1 or 2. An 
association between BORR and higher grade (Grade 3-4) IRAEs was suggested in early 
studies of ipilimumab 3 mg/kg but this association was not observed in 4 Phase 2 studies 
of ipilimumab (CA184022, CA184008, CA184007 and CA184004). There were 
proportionally more subjects with IRAEs of any grade who experienced response or 
stable disease than subjects without IRAEs who experienced response or stable disease, 
but 
due to 
the small sample sizes, 
these observations 
were statistically 
inconclusive.21,22,23 
1.4 
Overall Risk/Benefit Assessment melanoma and prostate 
cancer 
Results from the 3 primary efficacy studies of ipilimumab suggest that the 10 mg/kg dose 
is active and offers the best benefit to risk ratio based on a 27.1% to 35.1% rate of disease 
control and a favorable 1-year survival rate of 48.6% to 59.1% compared with that 
reported in the literature (25.5% to 35%).24,25,26,27 Substantial reductions in total tumor 
burden, including widely disseminated disease in the skin, lung, and/or other visceral 

 
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disease sites, were reported. More than half the responses were reported in subjects 
staged with M1b or M1c advanced melanoma disease, which is most resistant to 
approved therapies. The kinetics of ipilimumab resulted in known patterns of clinical 
activity (CR, PR and SD) as well as novel patterns, characterized by reductions in total 
tumor burden, including existing and new lesions, after initial tumor volume increase 
and/or after appearance of new lesions. In the pretreated population at 10 mg/kg in 2 of 
the 3 studies, disease control after initial tumor volume increase and/or new lesions was 
reported for 9.7% of subjects. Across all 3 studies, stable disease was often accompanied 
by clinically relevant reductions in tumor burden compared to baseline. All patterns of 
response, including SD, appeared to result in favorable survival, based on 1-year survival 
rates. 
Characteristic organ-specific inflammatory IRAEs were reported with ipilimumab 
therapy, typically during induction therapy. IRAEs were mostly reversible within days to 
weeks following cessation of therapy or treatment with symptomatic therapy, 
corticosteroids or other anti-inflammatory agents, depending upon severity. Accumulated 
clinical experience resulted in detailed toxicity management guidelines (also termed 
algorithms), by use of which IRAEs can be effectively managed, especially when IRAEs 
are recognized early and subjects are treated in a timely fashion. This can minimize the 
occurrence of IRAE complications, such as GI perforation/colectomy or hepatic failure.  
Treatment with ipilimumab resulted in clinical activity in pretreated and previously 
untreated subjects with advanced melanoma. Clinically relevant reductions in the tumor 
burden from baseline were reported, together with a preliminary evidence of improved 
overall survival compared with published survival rates. These findings, together with 
evidence of a safety profile that is manageable with careful monitoring and appropriate 
intervention for treatment of immune-related toxicities, suggest an acceptable benefit to 
risk ratio.  
Men with metastatic prostate cancer who do not obtain and maintain a complete 
biochemical response (PSA ≤ 0.2 ng/ml) to AST alone have a very poor prognosis.2 The 
median survival of this study population is only 13 to 44 months, where a PSA > 4.0 
ng/ml after induction AST has the shortest median survival. Chemotherapy using 
docetaxel with prednisone is currently an option for men with CRPC.  While there have 
been no direct comparisons of toxicity between ipilimumab and docetaxel, we anticipate 
that the overall toxicity of chemotherapy is greater.  Since the initial approval of this 
study, several other agents have gained approval in CRPC, namely abiraterone with 

 
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prednisone, enzalutamide and sipuleucel-T. Although they have been shown to improve 
overall survival, their benefit compared to placebo is on the order of 2-4 months, and 
there is still a clear need to improve survival in this group. Furthermore treatment with 
ipilimumab does not disqualify patients from being treated with these other agents. 
The early identification of this aggressive subset of metastatic prostate cancer offers 
significant opportunities for benefit in the form of delayed progression and longer 
survival with successful intervention.  The overall risk-benefit ratio for patients entering 
this protocol is therefore at least comparable to and possibly better than alternative 
options. 
1.5 
Study Rationale 
Ipilimumab is a natural choice for early intervention for several reasons. While there can 
be significant toxicities during the acute phase of treatment, the toxicities are almost 
always manageable and resolve with time-limited treatment. Thus, long-term toxicities in 
men who benefit from this intervention are unlikely. Immunotherapy may be more 
effective when disease burden is limited. Treating this population early will ensure that 
they have a relatively low volume of disease. This therapy has been shown to be active in 
patients who have extremely aggressive disease.  We are targeting the same patients but 
at an earlier time point in the course of their disease. The overall risk benefit ratio for 
patients entering this protocol is therefore at least comparable to, and possibly better than 
alternative options. 
 
This is a single arm phase II study to examine the activity and safety of ipilimumab early 
in the course of metastatic prostate cancer, in patients with an incomplete response to 
androgen suppression therapy. Men who do not achieve a complete response to AST have 
a significantly shortened median survival. Early immune-based therapy may delay 
disease progression and prolong survival in this subset of patients. 
 
The primary endpoint is the fraction of patients who achieve an undetectable PSA (≤ 0.2 
ng/ml). The Hussain paper has shown that men who achieve and maintain an 
undetectable PSA have a significantly longer median survival.2 We will recruit 30 men to 
this study. 
 
Secondary endpoints include time to PSA progression, time to progression by any 
measure, time to death from any cause, number of patients with immune breakthrough 
events and correlation of these with PSA declines and correlative studies looking at the 

 
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ratios of T regulatory cells and T effector cells before each of the first four doses of 
ipilimumab. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Proportion of patients who achieve an undetectable PSA (≤ 0.2 ng/ml) after initiation of 
Ipilimumab therapy. 
2.2 
Secondary Objectives 
 Time to PSA progression 
 Time to progression by any measure 
 Maximum percentage of PSA reduction in each patient 
 Number of patients with IRAEs and correlation of these with complete PSA 
response, time to progression, and T cell measurements 
 Measures of T cell response to therapy with flow cytometry 
 Response in Measurable disease by modified RECIST criteria 
 Time to death from any cause. 
 To examine correlative biomarkers and their relationship to clinical outcomes.  
Potential biomarkers include, but are not limited to CRP, IGF-1 and –2, or FSH.  
 Bank samples for future molecular correlative studies, biomarker, or other studies. 
 
3 
STUDY DESIGN 
3.1   Pre-treatment Evaluation 
3.1.1   Clinical evaluation 
o Patient’s eligibility will be determined with the aid of an eligibility 
checklist. 
o Eligible patients will be informed of the details of the study, including 
potential risks and benefits. 
o Signed, informed consent will be obtained before any study-related 
procedures occur. 

 
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o A complete patient history and physical examination will be done. 
o All concomitant medications including vitamins, herbs, and supplements 
will be recorded.   
3.1.2   Laboratory  
All screening labs must be done within 28 days of first treatment. Cycle 1 
Day 1 labs do not need to be repeated if screening labs were within 7 days 
of Cycle 1 Day 1.  
o Serum PSA . 
o Complete Blood Count with automated differential  
o Chemistry panel including ALT, AST, Alkaline Phosphatase,  Total or 
Direct Bilirubin, BUN, Creatinine, Electrolytes (Sodium, Potassium and 
Chloride), Calcium, and Glucose  
o Autoimmune panel including TSH and free T4 
o LDH 
o Testosterone  
o Investigational blood samples will be obtained within 0 to 7 days prior to 
treatment (for the baseline) and just prior to each of doses of Cycle 2, 3, 
4.  
o Hepatitis panel and HIV will be tested if the study patient has engaged in 
high risk behaviors, such as using intravenous drugs or engaging in 
unprotected sex outside of a long term relationship. This determination 
will be made by the treating oncologist. 
3.1.3   Imaging and Diagnostic 
A radionuclide bone scan and CT scan (chest, abdomen and pelvis) will be 
obtained at baseline within 28 days of initiation of treatment. 
 
3.2   Registration Procedure 
A centralized registration procedure will be used. After eligibility screening, 
patients selected to participate will be registered with the lead center (OHSU) first, 
then their study site/institution.  
3.2.1  Lead Site Registration: To initiate lead site registration, study 
sites/institutions should forward copies of the signed informed consent, HIPAA 
research authorization, the study registration form (eligibility checklist), plus all 
source documentation verifying eligibility, to the lead center by fax or e-mail. 
Upon receipt of these forms, sponsor will confirm patient eligibility with study 
personnel; assign a unique patient study identification number, and complete 

 
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patient registration. Treatment must not commence until the patient has received 
his identification number. 
Patient Registration: 
 
Erin Tucker, OHSU 
Phone:  (503) 494-8729 
Fax:  (503) 494-6197 
 
Email: TUCKERER@OHSU.EDU  
3.2.2   Institutional Registration: Patient registration at each study site/institution will 
be conducted according to the institution’s established policies. Prior to registration, 
patients will be asked to sign and date an Institutional Review Board (IRB)-approved 
consent form and HIPAA research authorization. 3.3   Follow up with Monitoring, 
Dose Delays and Dose Modifications 
3.3.1 During the first four doses of ipilimumab treatment: 
o Adverse events will be recorded every 3 weeks or as they occur. 
o Physical examination and vital signs will be performed every 3 weeks and 
documented in the medical record. 
o Complete Blood Count with automated differential, PSA, Chemistry Panel 
(Calcium, ALT, AST, Alkaline Phosphatase, Total Bilirubin, BUN, 
Creatinine, Glucose, Sodium, Potassium, Chloride) and Autoimmune 
Panel (,TSH, free T4)  will be obtained on day 1 of the first four 21-day 
cycles.         
o Available lab results will be reviewed prior to administration of 
ipilimumab. 
o Imaging: A radionuclide bone scan and CT scan (chest, abdomen and 
pelvis) will be obtained at baseline, week 12, week 24, and every three 
months thereafter until radiographic progression. Scans may be obtained 
sooner for concerning symptoms. 
o Correlation studies: Investigational serum samples will be obtained at 
baseline and on the first day of cycles 2 through 4. See Appendix 7 for 
details.  Baseline draw will occur within 7 days of the first dose and must 
occur before the treatment dose is administered. 
3.3.2 After Completion of initial 4 cycles of ipilimumab: 
o Serum PSA will be drawn every 6 weeks for weeks 12-24, then every 12 
weeks. 
o Complete blood count with automatic differential, comprehensive 
chemistry panel and Autoimmune Panel (TSH, free T4) will be obtained 
prior to administration of each dose of ipilimumab, which will be given to 
eligible patients every 12 weeks beginning at week 24. 

 
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o Available lab results (i.e. chemistries and blood counts) will be reviewed 
prior to administration of ipilimumab. 
o Imaging and Diagnostic: A radionuclide bone scan and CT scan (chest, 
abdomen and pelvis) will be obtained at baseline, week 12, week 24, and 
every three months thereafter until radiographic progression. Scans may 
be obtained sooner for concerning symptoms. 
3.4   Correlative studies 
Investigational blood samples will be obtained on the first day of cycles 1 through 4. Any 
specimens not consumed by the analyses in this protocol will be banked for future 
research in the Cancer Research Specimen Bank (OHSU IRB 2816).  See Appendix 7 for 
details. 
 
3.5   End of Treatment Cycles 
Patients who progress radiographically on ipilimumab after completion of the initial four 
doses will not receive more immunotherapy once progression has been documented. For 
soft-tissue lesions, the RECIST criteria for progression (see 6.4.2) will be used. For bone 
lesions, there should be  2 new lesions confirmed on a second scan at least 4 weeks later. 
Progression will not be assessed until completion of the initial 4 cycles of treatment in 
order to avoid premature discontinuation of therapy. 
3.6 
Follow-up visits after completion of ipilimumab therapy 
Patients will be followed with a history, physical exam, CT and NM bone scan and serum 
PSA quarterly along with treatment visits during the maintenance treatment phase, until 
radiographic progression.   If a patient has not met radiographic progression by Week 60 
visit, the patient will be followed by PSA and scans until radiographic progression. 
Following radiographic progression, patients will be followed by semi-annual phone 
surveys with the patient, his family, or his treating physician to collect data on treatment 
status and overall survival for up to 5 years after all protocol treatment has been 
completed. 
 
4 
SUBJECT SELECTION CRITERIA 
For entry into the study, the following criteria MUST be met. Any exceptions from the 
protocol-specific selection criteria must be approved by the Principal Investigator and/or 
the Institutional Review Board (IRB) before enrollment. 

 
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4.1 
Inclusion Criteria  
1) Willing and able to give written informed consent. 
2) Histologic diagnosis of adenocarcinoma of the prostate. 
3) A PSA of > 0.2 ng/ml after 6-18 months of androgen suppression therapy, which 
may consist of LHRH agonist or antagonist alone or the combination of an LHRH 
agonist or antagonist plus an antiandrogen, such as bicalutamide. Androgen 
suppression therapy will continue without interruption. 
4) Radiographic evidence of regional or distant metastasis at the time of study 
enrollment or at the time of diagnosis. 
5) Required values for initial laboratory tests: 
 WBC 
 2000/uL 
 ANC 
 1000/uL 
 Platelets 
 50 x 103/uL 
 Hemoglobin 
 8 g/dL 
 Creatinine 
 3.0 x ULN 
 AST/ALT 
 2.5 x ULN for patients without liver metastasis 
 Bilirubin 
 3.0 x ULN, (except patients with Gilbert’s Syndrome, who 
 
must have a total bilirubin less than 3.0 mg/dL) 
 
6) No known active or chronic infection with HIV, Hepatitis B, or Hepatitis C. 
Patients should be assessed for high risk behaviors that may result in these 
infections, such as intravenous drug use or multiple sexual partners. The 
assessment should be noted. 
7) ECOG ≤ 1. 
8) Men  18 years of age. 
9) Patients receiving any herbal product known to decrease PSA levels (i.e. saw 
palmetto and PC-SPES), or any immunosuppressive dose of systemic or 
absorbable topical corticosteroid (except prednisone up to 10 mg orally q day, or 
its equivalent), must discontinue the agent for at least 2 weeks prior to screening. 
Progressive disease must be documented after discontinuation of these products. 
10) Patients receiving bisphosphonate therapy must have been on stable doses for at 
least 4 weeks with stable symptoms prior to the first infusion with ipilimumab. 

 
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11) Total testosterone < 50 ng/ml, except in patients with prior orchiectomy, where 
testosterone does not need to be measured. Patients must continue their LHRH 
agonist therapy throughout study duration. 
12)  Life expectancy  6 months. This must be documented. 
13) Patients who are sexually active with a partner who could become pregnant are to 
use an effective form of barrier contraception, such as condoms or a partner using 
oral contraceptive pills. Persons of reproductive potential must agree to use an 
adequate method of contraception throughout treatment and for at least 8 weeks 
after ipilimumab is stopped. 
14) If a patient enters the trial on AST that consists of both an LHRH agonist and an 
oral antiandrogen, both agents should be continued throughout the study.  If an 
antiandrogen is stopped prior to study entry, it should be stopped 4 weeks before 
for nilutamide and flutamide and 6 weeks before for bicalutamide to ensure that a 
withdrawal phenomenon does not interfere with interpretation of efficacy results. 
4.2 
Exclusion Criteria  
1) Radiation to any area of the body < 28 days prior to randomization. 
2) Any other active malignancy with the exception of adequately treated basal or 
squamous cell skin cancer or superficial bladder cancer. Autoimmune disease: 
Patients with a history of inflammatory bowel disease are excluded from this 
study, as are patients with a history of symptomatic disease (eg, rheumatoid 
arthritis, 
systemic 
progressive 
sclerosis 
[scleroderma], 
systemic 
lupus 
erythematosus, autoimmune vasculitis [eg, Wegener’s Granulomatosis]); motor 
neuropathy considered of autoimmune origin (e.g. Myasthenia Gravis, Guillain-
Barre Syndrome). Those with immune-mediated skin toxicity (i.e. Toxic 
Epidermal Necrolysis, Stevens-Johnson Syndrome) will also be excluded. 
3) Any 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. 
4) Any non-oncology vaccine therapy used for prevention of infectious diseases (for 
up to 1 month before or after any dose of ipilimumab). 
5) A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 
inhibitor or agonist. 
6) Concomitant therapy with any of the following: IL-2, interferon, or other non-
study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive 

 
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agents (OTC/herbal/prescribed); immunostimulant agents, other than the study 
agent; other investigational therapies; or chronic use of systemic corticosteroids 
(greater than prednisone 10 mg orally per day, or its equivalent). 
7) Prisoners or patients who are compulsorily detained (involuntarily incarcerated) 
for treatment of either a psychiatric or physical (i.e., infectious) illness. 
 
4.3 
Data Safety Monitoring Plan 
The Data and Safety Monitoring Plan is outlined in a separate document and is NCI 
approved. 
5 
STUDY THERAPY 
All patients will receive ipilimumab 10 mg/kg IV over 90 minutes on day 1 of each 21-
day cycle for four cycles. Those patients who have not progressed (radiographically) will 
also receive the same dose of ipilimumab once every three months for an additional four 
doses. Each patient’s available lab results (i.e. chemistries and blood counts) will be 
reviewed prior to each ipilimumab infusion. 
5.1 
Ipilimumab 
Each patient will receive ipilimumab 10 mg/kg IV over 90 minutes (not bolus or IV 
push). 
Ipilimumab (BMS-734016) 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 nonspecific cross-reactivity in normal 
human tissues, as demonstrated by immunohistochemistry. Ipilimumab does cross-react 
with CTLA-4 in non-human primates, including cynomolgus monkeys. 
5.1.1 
Dose Calculations 
Dose calculations will be based on the weight obtained on Cycle 1 Day 1 and will only 
change if the weight increases or decreases by more than 10%. 
Calculate Total Dose as follows: 
 
Patient body weight in kg x [10 mg] = total dose in mg 

 
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Calculate Total Infusion Volume as follows: 
 
Total dose in mg ÷ 5 mg/mL = infusion volume in mL 
Calculate Rate of Infusion as follows: 
 
Infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min. 
For example, a patient weighing 114 kg (250 lb) would be administered 1140 mg of 
ipilimumab (114 kg x 10 mg/kg = 1140 mg) with an infusion volume of 228 mL (1140 
mg ÷ 5 mg/mL = 228 mL) at a rate of approximately 2.5 mL/min (228 mL ÷ 90 minutes) 
in 90 minutes. 
5.1.2 
Storage, Preparation, and Administration 
Ipilimumab Injection, 50 mg/vial (5 mg/mL) or 200 mg/vial (5 mg/mL), must be stored 
refrigerated (2°C to 8°C) and protected from light. Ipilimumab injection must not be 
frozen. Partially used vials or empty vials of Ipilimumab Injection should be discarded at 
the site according to appropriate drug disposal procedures. 
Ipilimumab injection may be diluted in 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP to concentrations between 1 mg/mL and 4 mg/mL and stored in 
PVC, non-PVC or glass containers for up to 24 hours at 2-8ºC or RT/RL.  
Recommended safety measures for preparation and handling include protective clothing, 
gloves, and safety cabinets. 
5.1.2.1 
Preparation and Administration Guidelines 
The supplies needed for ipilimumab preparation and administration include calibrated 
syringes and infusion containers. The product may be infused using a volumetric pump at 
the protocol-specific dose(s) and rate(s) through a PVC IV solution infusion set with a 
0.2 μm or 1.2 μm in-line polyethersulfone or 1.2 μm positively charged nylon filter to 
complete the infusion in 90 minutes, with a 10-mL normal saline flush at the completion 
of the infusion. 
 
1) 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. 
2) Aseptically withdraw the required volume of ipilimumab solution into a syringe. 
Insert the needle at an angle into the ipilimumab vial by placing the needle – bevel 
side down – against the glass, with the tip touching the neck of the vial. The initial 
solution concentration is 5 mg/mL. [Note: A sufficient excess of ipilimumab is 
incorporated into each vial to account for withdrawal losses]. 

 
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3) 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. 
4) Inject ipilimumab solution withdrawn into an appropriate size evacuated infusion bag 
to produce a final infusion volume that has been calculated from the weight of the 
patient. For example, if preparing a 10mg/kg treatment for a 65 kg patient you will 
use 13 vials (or 650 mg), the drug solution volume will be 10 mL per vial or 130 mL 
total.  
5) If the total dose calculates to less than 90 mL of solution then the total dose needed 
should be diluted to a total volume of 90 mL in 0.9% sodium chloride.  
6) Mix by GENTLY inverting several times. DO NOT shake. 
7) 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. 
8) Do not draw into each vial more than once. Any partial vials should be safely 
discarded and should not be stored for reuse. 
 
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. 
5.1.3 
Dose Modifications 
Patients may develop study drug-related toxicities that may require skipping doses or 
dose discontinuation. Some of these adverse events may be consistent with potentially 
drug-related immune-mediated phenomena; termed IRAEs (Appendix 3). Details of how 
to dose study medication in the present of adverse drug reactions that may or may not be 
IRAEs are addressed below. 
Treatment modifications will be made based on specified safety criteria. Patients will 
delay or discontinue treatment with ipilimumab if they experience at least one adverse 
event, specified below, considered by the investigator to be certainly, probably, or 
possibly related to ipilimumab treatment. The following criteria will be used to determine 
dosing delay, restarting doses, or discontinuing ipilimumab. 
There are no dose modifications because Ipilimumab is much less effective at lower 
doses. 
Delay ipilimumab dosing for the following related adverse events: 

 
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It may be necessary to skip study drug dosing for the following related adverse event(s): 
 Any  Grade 2 non-skin related adverse event (including IBEs), except for laboratory 
abnormalities 
 Any  Grade 3 laboratory abnormality. 
It is necessary to skip study drug dosing for the following adverse events: 
 Any  Grade 3 skin-related adverse event regardless of causality. 
 
Restart ipilimumab dosing if/when the adverse event(s) resolve(s) to ≤ Grade 1 
severity or returns to baseline within 3 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 [+/- 3 days], the next scheduled dose will be omitted. 
 
5.1.4 
Discontinuation of Study Therapy 
Subjects MUST be discontinued from study therapy AND withdrawn from the study for 
the following reasons: 
 Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
 Any clinical adverse event, laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued treatment with study therapy 
is not in the best interest of the subject 
 Termination of the study by Bristol-Myers Squibb (BMS). 
 Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness. 
 Progression of disease, as defined by radiographic progression, after 12 weeks of 
therapy. Furthermore, all radiographic progression must be confirmed by a repeat 
scan done at least 4 weeks after the suspicious scan. Immune response is not a part of 
this algorithm. 
 

 
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5.1.5 
Permanent Discontinuation of Ipilimumab 
5.1.5.1 
Permanent Discontinuation for Related Adverse Events 
 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 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. 
 
5.1.5.2 
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: 
 Ocular toxicity that has responded to topical therapy. 
 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. 
5.1.6 
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 

 
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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. See Appendix 3 for suggested 
work-up and treatment of IRAEs. 
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. See Appendix 4 for 
additional details. 

 
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5.1.7 
Other Guidance 
5.1.7.1 
 Immune-Related Adverse Events Considered to be Related to the 
ipilimumab 
Previous studies have shown that 74% (about 3 in 4) of treated patients develop a side 
effect of any grade of severity due to the immune system attacking normal cells. About 
22% (about 1 in 4) of patients have a serious immune-related adverse event.  Serious side 
effects may be fatal or life-threatening, require you to be hospitalized, may permanently 
disable you, make you weak and unable to function at your current level, or may put your 
health at risk or require surgery or intervention by your study doctor. 
These immune-related side effects have usually been controlled by stopping the 
ipilimumab treatment and if needed, with medications, including steroids (medications 
that are used to decrease inflammation). If you develop an immune-related event, the 
symptoms may take several months to improve. These immune-related adverse events 
can relate to: Stomach/Intestine, Rash, Eye, Endocrine Glands, Liver, Other Organs, 
Meningitis, immune-related motor neuropathy, nephritis, skin disorders and joint pain. 
Patients receiving the Ipilimumab sometimes experience a serious skin toxicity, though 
this is very rare.  If a patient develops a skin toxicity, a biopsy is recommended.  If a 
biopsy is done, a portion of it may be sent to an independent doctor for review. 
While receiving treatment with the ipilimumab, patients may be at risk of side effects 
(such as fever, low blood pressure, chills, flushing, nausea and/or vomiting) that occur 
during or shortly after the infusion (within 24 hours). If these events occur during the 
infusion, they may be treated by slowing or stopping the infusion, or with treatment such 
as fluids given into your vein or other common medications. These events can also occur 
hours after the completion of the infusion. 
5.1.7.2 
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. 

 
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 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. 
 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 solumedrol 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). 

 
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5.1.7.3 
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 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. 
5.2 
Prohibited and Restricted Therapies During the Study 
5.2.1 
Prohibited Therapies 
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. 
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 
 Immunostimulant agents, other than study medication 
 Chronic systemic corticosteroids 
 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). 
 Any radiation therapies  
 Any herbal product known to decrease PSA (eg, Saw Palmetto, PC-SPES) 
 

 
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5.2.2 
Restricted Therapies 
If a patient enters the trial on AST that consists of a LHRH agonist and an oral 
antiandrogen, both agents should be continued throughout the study.  Patients entering 
the trial may have stopped previous AST before starting this study for various reasons 
including but not limited to: AEs related to AST therapy, disease progression on AST, or 
at the discretion of the treating physician. If an antiandrogen is stopped prior to study 
entry, it should be stopped 4 weeks before for nilutamide and flutamide and 6 weeks 
before for bicalutamide to ensure that a withdrawal phenomenon does not interfere with 
interpretation of efficacy results.  
 
5.2.3 
Precautions 
Caution is advised when considering treatment with high-dose IL-2 in patients who have 
previously been administered ipilimumab, particularly in patients who experienced 
ipilimumab-related diarrhea/colitis. Colonoscopy or sigmoidoscopy with biopsy may be 
advisable prior to IL-2 administration once the patient is no longer receiving ipilimumab. 
Notably, IL-2 is not currently used for prostate cancer.

 
 
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6 
STUDY PROCEDURES AND OBSERVATIONS 
6.1 
Time and Events Schedule for Protocol CA184059 
Test / Procedure 
Scree
ning# 
Induction* 
(Cycles 1-4) 
Between Treatments 
Maintenance*  
(Cycles 5-8) 
Every 6 Month 
Follow Up* 
Wk 
1** 
Wk 
4 
Wk 
7 
Wk 
10 
Wk 
12 
Wk 
18 
Wk 
23/24 
Wk 24 
Wk 36 
Wk 48 
Wk 60 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history, concurrent medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum samples for hepatitis 
panel and HIV, if high index 
of suspicion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood collection for 
correlative studies1 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Bone Scan2 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
Chest, Abdomen & Pelvis 
CT2 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 

 
 
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CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry Panel: 
Creatinine, BUN, electrolytes 
(sodium, potassium, 
chloride), glucose, bilirubin 
alkaline phosphatase, ALT, 
AST, calcium, 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Autoimmune Profile: TSH, 
free T4 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
PSA4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concurrent medications 
(include documentation of 
androgen suppression 
therapy) 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Adverse Effects Recorded 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Ipilimumab 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Telephone Contact 
 
 
 
 
 
 
 
 
 
 
 
 
X 
* Cycle 1-8 procedures can be done +/- 3 days and Long Term Follow-Up can be done +/- 2 weeks.  
**PSA, Autoimmune profile, LDH, CBC Diff, Chem panel including Creatinine, BUN, electrolytes (sodium, potassium, chloride), 
glucose, bilirubin, alkaline phosphatase, ALT, AST, calcium, phosphorus and Correlative baseline samples DO NOT need to be 
repeated on Cycle 1 Day 1 if done within 7 Days of Cycle 1 Day 1 
#Screening procedures must be done within 28 days of first treatment 
1 Per outlined correlative studies   
2  Imaging Studies will also be done every three months until radiographic progression  
3  Available labs (i.e. chemistries and blood counts) will be reviewed prior to each infusion 
4 PSA will be done until radiographic progression  
 

 
 
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6.2 
Procedures by Visit 
The Time and Events Schedule summarizes the frequency and timing of various 
measurements. 
6.2.1 
Study Completion or Early Discontinuation Visit 
At the time of study early withdrawal, the reason for early withdrawal and any new or 
continuing adverse events should be documented. 
6.2.2 
Study Drug Discontinuation 
If study drug administration is discontinued, the reason for discontinuation will be 
recorded. 
6.3 
Details of Procedures 
6.3.1 
Study Materials 
Bristol-Myers Squibb (BMS) will provide ipilimumab at no cost for this study. 
6.3.2 
Safety Assessments 
All patients who receive at least one dose of ipilimumab will be considered evaluable for 
safety parameters. Additionally, any occurrence of a SAE from time of consent forward, 
up to and including follow-up visits will be reported. See Section 8: Adverse Event 
Reporting. 
Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) 
Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE), 
Version 4.0 
(http://ctep.cancer.gov). Safety assessments will be based on medical review of adverse 
event reports and the results of vital sign measurements, physical examinations, and 
clinical laboratory tests. 
6.4 
Criteria for Evaluation 
6.4.1 
Safety Evaluation 
Refer to the NCI CTCAE, Version 4.0 (http://ctep.cancer.gov). SAEs will be assessed 
every three weeks during the first four cycles of ipilimumab and every 12 weeks during 
the fifth through eighth cycle of ipilimumab. 

 
 
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6.4.2 
Efficacy Evaluation 
The primary endpoint is fraction of patients who achieve an undetectable PSA (≤ 0.2 
ng/ml). Pursuant to that endpoint, we will check the PSA every 3 weeks during the first 4 
cycles and every 6 weeks during weeks 12-24, then every three months as the patient is 
being followed (planned follow up through year 5). 
 
The secondary endpoints explore the objective responses achieved in the realm of non-
progression of disease and tumor regression, as well as provide an opportunity to learn 
more about the immune response itself. Part of this assessment is PSA-based and part is 
based on radiographs (bone scans and CT scans). We will use the procedures described 
for the primary endpoint, above, to look at response endpoints. Additionally, a CT scan of 
the chest/abdomen/pelvis and bone scan at baseline, week 12, week 24 and every 6 
months thereafter will be done for comparison. We will also perform a history and 
physical prior each cycle to detect new pain that could indicate cancer progression. After 
the 8 cycles of ipilimumab, patients will have their PSA checked every 3 months, either 
at the study center or by an outside provider. Their survival status will be assessed by 
telephone survey every 6 months for a maximum of 5 years. For the correlative work, we 
will collect blood samples prior to each infusion of ipilimumab and quantify the immune 
response. Once the study is complete, we will compare the objective response with the 
depth of the immune response. 
6.4.2.1 
Definitions of PSA-Related Secondary Endpoints  
PSA progression: PSA increase of ≥ 25% and at least 2 ng/mL from baseline or nadir 
PSA achieved, confirmed by a second measurement at least three weeks later. 
PSA nadir: Lowest PSA reached that was confirmed by a second equal or lower 
measurement. 
 
PSA response: As recommended by the PCWG2 definitions. We will not apply a strict 
definition for PSA response. The primary endpoint is the proportion of patients with a 
PSA < 0.2 ng/ml on this study. Waterfall plots will be used to describe PSA changes 
while on study. 
Maximum percentage of PSA reduction in each patient. Percentage of PSA reduction 
will be defined as [1 - (lowest PSA attained on study)/(PSA at study entry)] x 100. This 
formula only applies to PSAs that have decreased, and not those that have remained 
constant, i.e. the same as the baseline measurement. 
 

 
 
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6.4.2.2 
Definition of Measurable and Non-Measurable Lesions 
The guidelines contained here are based on recommendations of the Prostate Cancer 
Clinical Trials Working Group’s 2007 definitions (PCWG2).28 
The PCWG2 definitions use modified RECIST criteria. 
Measurable lesions are visceral or extranodal lesions that are ≥ 1 cm in one direction. 
Lymph nodes are measurable lesions if they are ≥ 2 cm in one direction. Tumor in the 
prostate may also be used as a measurable lesion. 
Non-measurable lesions are those lesions that do not meet the size criteria given above. 
Other 
non-measurable 
lesions 
are 
cysts, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial effusions and lymphangitis cutis/pulmonis. 
Bone lesions will not be considered measurable lesions. 
All measurable and non-measurable lesions should be measured at Screening and at the 
defined tumor assessment time points.  Extra assessments may be performed, as clinically 
indicated, if there is a suspicion of progression. 
6.4.2.2 Definition of Index/Non-Index Lesions 
All measurable lesions, up to a maximum of five lesions per organ and ten lesions in 
total, should be identified as index lesions to be measured and recorded on the medical 
record at Screening. The index lesions should be representative of all involved organs. In 
addition, index lesions should be selected based on their size (lesions with the longest 
diameters), their suitability for accurate repeat assessment by imaging techniques, and 
how representative they are of the patient’s tumor burden. At Screening, a sum of the 
longest diameters for all index lesions will be calculated and considered the baseline sum 
of the longest diameters. Response criteria to be followed are listed below. The baseline 
sum will be used as the reference point to determine the objective tumor response of the 
index lesions at tumor assessment (TA). 
 
Measurable lesions, other than index lesions, and all sites of non-measurable disease, will 
be identified as non-index lesions. Non-index lesions will be recorded on the medical 
record and should be evaluated at the same assessment time points as the index lesions. In 
subsequent assessments, non-index lesions will be recorded as “stable or decreased 
disease”, “absent”, or “progression”. 
 

 
 
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6.4.3 
Evaluation of Tumor Response Using mRECIST Criteria 
6.4.3.1 
Definition of Index Lesion Response Using mRECIST 
* Complete 
Response (CR): 
Disappearance of all target lesions 
* Partial Response 
(PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
* Progressive 
Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new 
lesions 
* Stable Disease 
(SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
 
 
6.4.3.2 
Definition of Non -Index Lesion Response Using mRECIST 
* Complete 
Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level. Must be confirmed by a scan done within 
4-12 weeks after the first scan. 
* Incomplete 
Response/Stable 
Disease (SD):  
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits 
* Progressive 
Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions* 
 
*Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be confirmed later on by 
the review panel (or study chair). 
 
Evaluation of Bone Lesions: 
For bone lesions, a minimum of two new lesions must be seen on bone scan to be 
determined progression of disease. Any lesion on bone scan suspected to be flare or 
inflammation, another study (such as CT or MRI scan) should be done to document the 

 
 
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presence of a new lesion.  Bone scan interpretation will follow PCWG2 
recommendations. 
 
6.4.3.3 
Determination of Overall Response Using mRECIST 
Overall Response (OR) is determined as the combination of assessments of index and 
non-index lesions using the following criteria:  
Index Lesion 
Assessment 
Non-Index Lesion 
Assessment 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
CR or SD 
No 
PR 
SD 
CR or SD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any  
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Best OR is the best confirmed response designation over the study as a whole, recorded 
between the date of first dose until the last tumor assessment for the individual patient in 
the study. The assessment of response will be at 6 months or sooner if progression is 
suspected. For the assessment of best OR, all available assessments per patient are 
considered. CR or PR determinations included in the best OR 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. It 
may be done between 4 and 12 weeks after the first scan that showed a response. 
Imaging of the chest, abdomen and pelvis is required at screening (i.e., baseline) and at 
each tumor assessment visit, regardless of the location of known metastases. Specifically, 
a CT scan of the chest, abdomen and pelvis will be done at baseline, 12 weeks, and every 
12 weeks while on the study. Similar methods of tumor assessment and similar 
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and during subsequent tumor assessments. Imaging-based evaluation is preferred to 
clinical examination. 
If progressive disease is assessed based only on a new lesion(s) found on bone scans, 
additional imaging studies of the lesion(s) should be performed to confirm the malignant 
nature of the new findings on the bone scan. Increased intensity of uptake in previously 
abnormal areas on bone scans is not considered progressive disease, unless the lesions 
seen on the correlative imaging studies performed of this area meet the criteria for 
progression. New areas of abnormal uptake on a bone scan represent progressive disease. 
 
6.4.4 
Response Endpoints 
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 
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, apparent mRECIST progression may represent infiltration of 
lymphocytes into the original tumor or blood. In conventional studies, such apparent 
radiographic progression or relevant laboratory parameter increases during the first 12 
weeks of the study would constitute PD and lead to discontinuation of imaging to detect 
response, thus disregarding the potential for subsequent immune-mediated clinical 
response. In this study, it may not represent actual tumor progression. 
Therefore, patients with tumor progression 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. Investigational 
Product: 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. 

 
 
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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 non-investigational products. In this protocol, there are no non-
investigational product(s). 
Identification 
Ipilimumab is available in 5 mg/mL single-use vials (10 mL or 40 mL). The sterile 
solution in the vial is clear and colorless. Ipilimumab is administered via intravenous 
infusion only. 
6.5 
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. Ipilimumab will be supplied at a concentration of 5 mg/mL in 
vials containing 10 ml or 40 mL solution. 
6.6 
Storage, Handling, and Dispensing 
6.6.1 
Storage 
Ipilimumab must be stored in a secure area according to local regulations. The 
investigator must ensure that it is stored in accordance with the environmental conditions 
as determined by BMS and defined in the Investigator Brochure or SmPC/reference label. 
Ipilimumab must be stored at a temperature  2C and  8C. 
6.6.2 
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. 

 
 
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6.6.3 
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. 
6.7 
Drug Ordering and Accountability 
6.7.1 
Initial Orders 
Following submission and approval of the required regulatory documents, a supply of 
ipilimumab may be ordered from BMS. Investigators must complete a Drug Request 
Form and email it to marianne.simone@bms.com and dsc.wfd@bms.com.  Please fax to 
(203) 677-6489 (U.S.) if you cannot send the form electronically. 
Ipilimumab vials (10 mL and 40 mL) are shipped in quantities of ten. Allow 5 business 
days for shipment of drug from BMS receipt of the ipilimumab Clinical Supply Shipment 
Request form. Drug is protocol specific, but not patient specific. 
All product will be shipped via Federal Express in a temperature-controlled container. 
Shipments will be made from BMS on Monday through Thursday for delivery onsite 
Tuesday through Friday. There will be no weekend or holiday delivery of drugs. It is 
possible that sites may have more than one ipilimumab clinical study ongoing at the same 
time. It is imperative that only product designated for this protocol number be used for 
this study. To help segregate product for this study from other investigational or marketed 
product, stickers bearing the BMS protocol number will be provided and should be 
affixed to the front of the outer carton just above the company names so as not to obscure 
any marking. 
6.7.2 
Re-Supply 
Reorders should be emailed directly to BMS using marianne.simone@bms.com and 
dsc.wfd@bms.com for shipment within 5 business days. When assessing need for 
resupply, institutions should keep in mind the number of vials used per treatment dose, 
and that shipments may take 5 business days from BMS receipt of request. Drug is not 
patient specific. Be sure to check with your pharmacy regarding existing investigational 
stock to assure optimal use of drug on hand. 

 
 
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6.8 
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. 
6.9 
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. 
7 
ADVERSE EVENT REPORTING 
7.1 
Collection of Safety Information 
The OHSU IRB defines an Unanticipated Problem (UP) as an event that is not expected 
given the nature of the research procedures and the patient population being studied and 
suggests that the research places patients or others at a greater risk of harm or discomfort 
related to the research than was previously known or recognized. Harm to a patient need 
not occur for an event to be a UP. 
Reportable Adverse Event – AEs which qualify as unanticipated problems that must be 
reported by the PI to the IRB and by the IRB to the Institutional Official and to OHRP are 
categorized as follows:  

 
 
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 On Protocol Serious Adverse Events (SAEs) that are unexpected and 
related or possibly related to participation in the research.  
 On Protocol SAEs or AEs that are expected in some patients, are related or 
possibly related, but are determined to be occurring at a significantly 
higher frequency or severity than expected.  
 On or Off Protocol Unexpected SAEs or AEs that are related or possibly 
related, regardless of severity, that may alter the IRB’s analysis of the risk 
versus potential benefit of the research and, as a result, warrant 
consideration of substantive changes in the research protocol or informed 
consent process/document.  
Other events that are On or Off Protocol and unexpected that may place patients or others 
at a greater risk of harm or discomfort than was previously known or recognized. Harm to 
a patient need not have occurred. 
All Reportable Adverse Events, as defined in this section occurring after patient 
enrollment must be reported to the Principal Investigator, Dr. Julie Graff at 
503.220.8262, extension 55688, or graffj@ohsu.edu. The Principal Investigator has the 
obligation to report all serious adverse experiences to the FDA, OHSU IRB, Bristol-
Myers Squibb, and other participating sites in accordance with the following guidelines. 
 
7.1.1 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see “note” below for exceptions) 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/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 subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 

 
 
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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 that do not result in hospitalization.) 
 Although overdose and cancer are not always serious by regulatory definition, these 
events should be reported on an SAE form and sent to BMS in an expedited manner. 
An overdose is defined as the accidental or intentional ingestion or infusion of any 
dose of a product that is considered both excessive and medically important. 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
 a visit to the emergency room or other hospital department for less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event) 
 elective surgery, planned before signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy) 
 medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases 
 admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
Note that all pregnancies, regardless of outcome, must be reported to the sponsor on a 
Pregnancy Surveillance Form, not an SAE form. All pregnancies must be reported and 
followed to outcome, including pregnancies that occur in the female partner of a male 
study subject. 
7.1.2 
Nonserious Adverse Events 
All adverse events that are not classified as serious. 
7.2 
Assignment of Adverse Event Intensity and Relationship to 
Investigational Product 
All adverse events, including those that are serious, will be graded according to the 
National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE), 
Version 4.0. 
The following categories and definitions of causal relationship to investigational product 
as determined by a physician should be used for adverse events: 

 
 
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 Certain: There is a reasonable causal relationship between the investigational product 
and the AE. The event responds to withdrawal of investigational product 
(dechallenge), and recurs with rechallenge when clinically feasible. 
 Probable: There is a reasonable causal relationship between the investigational 
product and the AE. The event responds to dechallenge. Rechallenge is not required. 
 Possible: There is reasonable causal relationship between the investigational product 
and the AE. Dechallenge information is lacking or unclear. 
 Not likely: There is a temporal relationship to investigational product administration, 
but there is not a reasonable causal relationship between the investigational product 
and the AE. 
 Not Related: There is not a temporal relationship to investigational product 
administration (too early, or late, or investigational product not taken), or there is a 
reasonable causal relationship between noninvestigational product, concurrent 
disease, or circumstance and the AE. 
The expression “reasonable causal relationship” is meant to convey in general that there 
are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 
7.3 
Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects 
should not be questioned regarding the specific occurrence of one or more AEs.) 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all AEs: 
onset, duration, intensity, seriousness, relationship to investigational product, action 
taken, and treatment required. If treatment for the AE was administered, it should be 
recorded in the medical record. 
The investigator shall supply the sponsor and Ethics Committee with any additional 
requested information, notably for reported deaths of subjects. 
7.3.1 
Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified procedures. 
All SAEs must be collected that occur within 70 days of discontinuation of dosing of the 
investigational product. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). The investigator should notify 

 
 
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BMS of any SAE occurring after this time period that is believed to be certainly, 
probably, or possibly related to the investigational product or protocol-specified 
procedure. 
All SAEs whether related or unrelated to the ipilimumab, must be immediately reported 
to BMS (by the investigator or designee) within 24 hours of becoming aware of the event. 
If only limited information is initially available, follow-up reports are required. The 
original SAE form must be kept on file at the study site. 
 
Participating centers will notify the Lead Site, OHSU, of all SAEs within 24 hours of 
becoming aware of the event. Reporting will occur by MedWatch Form 3500A with 
supporting documentation. OHSU will report this information to BMS and/or the FDA, 
as appropriate.   
 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later than 7 
days (death or life-threatening event) or 15 days (all other SAEs) after the investigator’s 
or institution’s initial receipt of the information. BMS will be provided with a 
simultaneous copy of all adverse events filed with the FDA. SAEs should be reported on 
the MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 

 
 
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Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
Serious adverse events, whether related or unrelated to investigational product, must be 
recorded on the SAE page and reported expeditiously to BMS (or designee) to comply 
with regulatory requirements. An SAE report should be completed for any event where 
doubt exists regarding its status of seriousness.  
All SAEs must be immediately reported by confirmed facsimile transmission (fax) and 
mailing of the completed SAE page. In some instances where a facsimile machine is not 
available, overnight express mail may be used. If only limited information is initially 
available, follow-up reports are required. (Note: Follow-up SAE reports should include 
the same investigator term(s) initially reported.) In selected circumstances, the protocol 
may specify conditions that require additional telephone reporting.  
If the investigator believes that an SAE is not related to the investigational product, but is 
potentially related to the conditions of the study (such as withdrawal of previous therapy, 
or a complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE page. 
If an ongoing SAE changes in its intensity or relationship to the investigational product, a 
follow-up SAE report should be sent immediately to the sponsor. As follow-up 
information becomes available it should be sent immediately using the same procedure 
used for transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilization. 
7.3.2 
Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are 
suspected (certainly, probably, or possibly related to the investigational product) and 
unexpected (ie, not previously described in the Investigator Brochure). In the European 
Union (EU), an event meeting these criteria is termed a Suspected, Unexpected Serious 
Adverse Reaction (SUSAR). Investigator notification of these events will be in the form 
of an expedited safety report (ESR).  
Other important findings which may be reported by the sponsor as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of 

 
 
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efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (eg, animal) study, important safety recommendations from a 
study data monitoring committee, or sponsor decision to end or temporarily halt a clinical 
study for safety reasons. 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the Investigator Brochure. Where required by local regulations or when there is a central 
IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information.  
In addition, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate reports). 
7.3.3 
Nonserious Adverse Events 
The collection of nonserious AE information should begin at initiation of investigational 
product. Nonserious AE information should also be collected from the start of a placebo 
lead-in period or other observational period intended to establish a baseline status for the 
subjects.  
If an ongoing nonserious AE worsens in its intensity, or if its relationship to the 
investigational product changes, a new nonserious AE entry for the event should be 
completed. Nonserious AEs should be followed to resolution or stabilization, or reported 
as SAEs if they become serious. Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of investigational product, or those that are present at the 
end of study participation. Subjects with nonserious AEs at study completion should 
receive post-treatment follow-up as appropriate. 
All identified nonserious AEs must be recorded and described in the medical record. 
7.3.4 
Pregnancy 
All participants will be male. If a female partner becomes pregnant during the research 
study, the female partner will be asked to sign a consent to follow the pregnancy for 
outcomes and any possible side effects from the study drug.  

 
 
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7.3.5 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded in the medical 
record. 
8 
STATISTICAL METHODOLOGY 
8.1 
Study Design 
This is a single arm phase II trial. 
8.2 
Primary and Secondary Endpoints 
The primary endpoint is the achievement of an undetectable PSA defined as PSA ≤ 0.2 
ng/mg after initiation of ipilimumab therapy.  The secondary endpoints are:  time to PSA 
progression, time to disease progression by any measure, time to death from any cause, 
number of patients with immune related Adverse Events (IRAEs), correlation between 
IRAEs and clinical outcomes, and the ratio of T regulatory cells to T effector cells, and 
additional measures of immune responses. 
8.3 
Sample Size Justification 
N=30 (for the final analysis, 10 for the intial analysis).  Using the Simon two-stage 
design for Phase II trials, the initial accrual will be 10 patients.  Assuming that 10% of 
patients receiving usual care will achieve an undetectable PSA (PSA ≤ 0.2)  without 
additional intervention, the trial has a 80% power to detect a rate of achieving an 
undetectable PSA of  30% among patients treated with ipilimumab.  At least two 
patients with an undetectable PSA will be required in the first 10 patients to continue to 
stage 2. As soon as two patients having achieved an undectable PSA are identified, stage 
2 for of the study will begin.  If 6 or more of 30 patients have achieved an undetectable 
PSA at 6 months, the study will be considered successful and the regimen worthy of 
further investigation.  This design has a type I error rate of 0.05 and a type II error rate of 
0.20. 
8.4 
Analysis Populations 
An Intention to Treat (ITT) population includes all patients who sign the consent and are 
assigned to a treatment regardless of the actual drug dose the patients receive.  Safety 
analysis population includes all patients who receive at least one drug dose.  Per Protocol 

 
 
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Population includes those who receive the prescribed dose of the drug per protocol and 
excludes patients who drop out of the study prematurely.  Whenever possible, we will use 
the ITT population to analyze the primary and secondary endpoints provided that their 
primary and secondary endpoints are measured.  As a secondary analysis, per protocol 
population will be used for the analysis of the primary and secondary endpoints.  Safety 
analysis population will be used to analyze safety and toxicity data. 
8.5 
Statistical Analysis Plan 
Demographic and clinical characteristics will be summarized using descriptive statistics (e.g. 
proportions, mean, standard deviation, median, range).  The proportion of patients who achieve 
an undetectable PSA (≤ 0.2 ng/ml) after initiation of ipilimumab therapy will be provided with 
the exact 95% confidence interval.    The Kaplan-Meier method will be used to estimate time to 
PSA progression, time to disease progression by any measure and time to death from any cause.  
In evaluation of time to PSA progression and time to disease progression by any measure will be 
censored for: 
 
1) 
lost to follow-up at the date of last contact 
2) 
use of additional cancer therapies that would interfere with ascertainment of the endpoint 
of interest 
3) 
death from a causes other than prostate cancer or treatment of prostate cancer. 
 
Evaluation of time to death will be censored for lost to follow-up at last contact. 
 
The effects of IRAEs and other immune parameters (e.g., a ratio of T regulatory cells to T 
effector cells) on clinical outcomes will be evaluated using logistic regression for binary 
endpoints (e.g., achievement of undetectable PSA) and Cox regression for the time to event 
outcomes (e.g., time to PSA progression).  
8.6 
Safety Analysis 
All toxicity and safety data including immune related Adverse Events (IRAEs) will be 
tabulated for each treatment group and summarized according to major organ categories of the 
NCI CTCAE v 4.0. 
8.7 
Efficacy Analysis 
See section 9.5 

 
 
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9 
ADMINISTRATIVE SECTION 
9.1 
Compliance with the Protocol and Protocol Revisions 
The protocol and informed consent form for this study must be reviewed and approved in 
writing by the OHSU Knight Cancer Institute  Clinical Research Review Committee 
(CRRC) and Institutional Review Board (IRB) at OHSU prior to any patient being 
registered on this study at OHSU.  In addition, the protocol and informed consent must be 
reviewed by the IRB of each institution participating in this Prostate Cancer Clinical 
Trials Consortium (PCCTC) study before any patients may be registered from those 
individual institutions. 
 
Any modification of this protocol must be documented in the form of a protocol revision 
or amendment signed by the principal investigator and approved by the OHSU CRRC 
and OHSU IRB, before the revision or amendment may be implemented. The only 
circumstance in which the amendment may be initiated without regulatory approval is for 
a change necessary to eliminate an apparent and immediate hazard to the patient. In that 
event, the investigator must notify the CRRC and IRB in writing within 10 working days 
after the implementation. Investigators holding the IND must notify FDA of substantive 
changes to the protocol. 
 
9.2 
Informed Consent 
Investigators must ensure that subjects, or, in those situations where consent cannot be 
given by subjects, their legally acceptable representative, are clearly and fully informed 
about the purpose, potential risks, and other critical issues regarding clinical studies in 
which they volunteer to participate. Freely given written informed consent must be 
obtained from every subject or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative, prior to clinical study participation, 
including informed consent for any screening procedures conducted to establish subject 
eligibility for the study. 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 

 
 
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9.3 
Records and Reports 
If the investigator relocates or for any reason withdraws from the study, the study records 
must be transferred to an agreed upon designee, such as another institution, another 
investigator, or to the OHSU Knight Cancer Institute Clinical Research Management. 
Records must be maintained according to sponsor or FDA requirements. 
9.4 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in accordance with 
the ethical principles underlying European Union Directive 2001/20/EC and the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to 
initiation of the study. 
All potential serious breaches must be reported to BMS immediately. A serious breach is 
a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective task(s). This study will not use the 
services of study personnel where sanctions have been invoked or where there has been 
scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
Systems with procedures that ensure the quality of every aspect of the study will be 
implemented. 
9.5 
Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment 
materials/process (e.g., advertisements), and any other written information to be provided 
to subjects. The investigator should also provide the IRB/IEC with a copy of the 

 
 
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Investigator Brochure or product labeling, information to be provided to subjects and any 
updates.  
The investigator should provide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures 
9.6 
Records Retention 
The Investigator must retain Ipilimumab disposition records, source documents, and case 
histories designed to record all observations and other data pertinent to the investigation 
(e.g. case report form) for the maximum period required by applicable regulations and 
guidelines, or Institution procedures. 
 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed upon designee (e.g., another Investigator, IRB). 
Documentation of such transfer must be provided to BMS. 

 
 
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APPENDIX 1 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ANC 
Absolute Neutrophil Count 
AST 
BID 
Androgen Suppression Therapy 
Twice a Day 
BMS 
Bristol-Myers Squibb Company 
CT scan 
Computed Axial Tomography scan 
CBC 
Complete Blood Count 
CR 
Complete Response 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
HIPAA 
Health Insurance Portability and Accountability Act 
IRB 
Institutional Review Board 
irRC 
Immune related response criteria 
MRI 
Magnetic Resonance Imaging 
PCWG2 
PD 
Prostate Cancer Working Group 2 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 
QD 
Once Daily 
QoL 
Quality Of Life 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SPD 
Sum of the products diameters 
SD 
Stable Disease 
TNM Staging 
Tumor, Node and Metastasis Staging 
TA 
Tumor assessment 
 

 
 
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APPENDIX 2 
GENERAL RECOMMENDATIONS FOR IMMUNE-
RELATED ADVERSE EVENTS (IRAES) 
 
 

 
 
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APPENDIX 3 
SUGGESTED WORK-UP AND TREATMENT FOR 
IMMUNE-RELATED ADVERSE EVENTS (IRAES) 
An IRAE is defined as an adverse event of unknown etiology, associated with drug 
exposure and is consistent with an immune phenomenon. Efforts should be made to rule 
out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an 
adverse event a non-dermatologic, immune-mediated event. Serological, immunological, 
and histological (biopsy) data should be used to support the diagnosis of an immune-
mediated toxicity. Documentation of test results should be included in the patient’s 
medical record. 
Gastrointestinal (diarrhea) and skin (rash)-related toxicities have been the most common 
IRAEs noted in prior studies with ipilimumab. Suggested work-up procedures for 
suspected IRAEs of the gastrointestinal tract, liver, skin, eye, pituitary, and adrenal gland 
are listed below. When symptomatic therapy is inadequate or inappropriate, an IRAE 
should be treated with steroids followed by a slow taper. 
Gastrointestinal Tract: 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. Patients 
should be advised to inform the investigator if any diarrhea occurs, even if it is mild. An 
algorithm for working up patients with diarrhea or suspected colitis is provided in 
Appendix 4. 
If the event is of significant duration or magnitude 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 with 3 to 5 specimens for standard paraffin block be performed. If 
possible, 1 to 2 biopsy specimens should be snap frozen and stored. All patients with 
confirmed colitis should also have an opthomological examination, including a slit-lamp 
exam, to rule out uveitis. Tests should also be performed for WBCs and for stool 
calprotectin. 
Patients with colitis should discontinue any non-steroidal anti-inflammatory medications 
or any other medications known to exacerbate colitis symptoms. Investigators should use 
their clinical judgment as to whether corticosteroids are necessary to treat colitis 
associated with ipilimumab therapy and as to what dose should be used. As guidance 
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corticosteroid treatment. For severe symptoms, prednisone 60 mg or equivalent may be 
required to control initial symptoms and the dose should be gradually tapered over at 
least one month in duration. Lower doses of prednisone may be considered for less severe 
cases of colitis. It is suggested that prednisone (for oral administration) or solumedrol (for 
intravenous administration) be corticosteroid of choice in the treatment of colitis.  
Liver: Elevation of LFTs  3 fold from baseline should instigate an investigation into the 
underlying etiology for suspected IRAEs. Neoplastic, concurrent medications, viral 
hepatitis, and toxic etiologies should be considered and addressed, as appropriate. 
Imaging of the liver, gall bladder, and bile duct should be performed to rule out 
neoplastic or other causes for the increased LFTs. An ANA, pANCA, and anti-smooth 
muscle antibody test should be performed if an autoimmune etiology is considered. 
Consultation with a hepatologist is appropriate for a suspected liver IRAE and a biopsy 
should be considered. 
Patients presenting with right upper-quadrant abdominal pain and/or unexplained nausea 
or vomiting should have LFTs performed immediately and reviewed before administering 
the next dose of study drug. Treating physicians should discuss, with the CRO Medical 
Monitor, unexplained increases in LFTs  3 fold from baseline prior to any additional 
study drug administration. 
Pancreas: Symptoms of abdominal pain associated with elevations of amylase and 
lipase, suggestive of pancreatitis, may rarely be associated with anti-CTLA-4 monoclonal 
antibody administration. The differential diagnosis of acute abdominal pain should 
include pancreatitis. Appropriate workup should include serum amylase and lipase tests.  
Skin: A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy 
should be performed if appropriate and if possible, photos of the rash should also be 
obtained. Low-grade ipilimumab mediated rash and pruritus IRAEs have been treated 
with symptomatic therapy (e.g., antihistamines). Topical or parenteral corticosteroids 
may be required for more severe symptoms. 
Eye: 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. Patients with ipilimumab related uveitis or 
episcleritis have been treated with topical corticosteroid eye drops. 

 
 
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Endocrine: Patients 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. TSH 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. 
Appropriate hormone replacement therapy should be instituted if an endocrinopathy is 
documented.  
Suspected IRAEs should be documented in the patient’s medical record.  

 
 
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APPENDIX 4 DIARRHEA MANAGEMENT 
ALGORITHM
 
 
GRADE 1 
Increase of < 4 stools 
per day over 
baseline; mild 
increase in ostomy 
output compared with 
baseline 
GRADE 2 
Increase of 4-6 stools 
per day over 
baseline; IV fluids 
indicated < 24 hrs; 
moderate increase in 
ostomy output 
compared to baseline; 
not interfering with 
ADL 
GRADE 3 
Increase of  7 stools per 
day over baseline; incon-
tinence; IV fluids  24 
hrs; hospitalization; 
severe increase in ostomy 
output compared to 
baseline; interfering with 
ADL 
GRADE 4 
Life-threatening 
consequences (eg, 
hemodynamic 
collapse) 
GRADE 5 
Death 

 
 
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APPENDIX 5 
HEPATOTOXICITY MANAGEMENT 
ALGORITHM 
The most current experience with immune-related hepatitis has allowed further 
development of this management algorithm to include recommendations for treatment. 
HEPATOTOXICITY THERAPEUTIC INTERVENTION 
ALGORITHM 
 

 
 
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APPENDIX 6 ENDOCRINOPATHY MANAGEMENT 
ALGORITHM
 
 

 
 
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APPENDIX 7 
SAMPLE COLLECTION/HANDLING AND 
SHIPPING 
Correlative studies will be drawn just prior to administration of ipilimumab doses 1 through 4. 
After drawing the samples, the tubes should be processed as soon as possible, ideally within 1 
hour of the blood draw. (It is recommended that the serum aliquots be frozen and whole blood be 
refrigerated within 2 hours of processing.) 
1) Collect 10mL of blood into each of the six tubes: 5 green top (heparin), 1 red top. All 
tubes to be obtained from a local vendor. 
GREEN TOP TUBE INSTRUCTIONS: 
2) Invert the green top tubes several times to mix well and put them on ice. 
3) Store the investigational samples in an upright position at 4°C until ready for shipping. 
4) When ready for shipping, put the tubes in a plastic biohazard bag (obtained from a local 
vendor) and seal the bag. Please ship specimens in a Styrofoam shipping container 
(obtained from a local vendor). Place enough cold packs at 4-24C (obtained from a local 
vendor) to cover the bottom of the Styrofoam container. 
RED TOP TUBE INSTRUCTIONS: 
5) Centrifuge the red top tube at 3000 rpm for 10-15 minutes. 
6) Using a polyethylene transfer pipette, draw off the serum and transfer it into 1 mL 
Cryovials. Use 2 Cryovials for serum. Cap and label the Cryovial with Patient Study 
Number, date and time point (i.e. Screening, Cycle X, or off study). 
7) Freeze and store the Investigational samples in an upright position at -80°C until shipped 
to OHSU on dry ice. 
8) When ready for shipping, place the samples in a plastic biohazard bag and seal the bag. 
Cover the bottom of a separate (not from step 4) Styrofoam container with dry ice. Place 
the biohazard bag containing the samples on the dry ice and cover with 7 to 10 pounds of 
additional dry ice. 
SHIPPING INSTRUCTIONS: 
9) Shipments can be sent Monday through Thursday, via overnight delivery. (DO NOT 
SHIP SAMPLES ON FRIDAY.) Please notify the receiving Study Coordinator of 
incoming samples by phone or email prior to shipment. Ship to the address below. 
 

 
 
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DERRICK DOMANN-SCHOLZ , OREGON HEALTH & SCIENCE 
UNIVERSITY 
3303 SW Bond Avenue, CH14R 
CHH 14040 
Portland, OR, 97239 
PHONE:  (503) 494-6179 
FAX:  (503) 494-6197 
EMAIL: domannsc@ohsu.edu 
 
OHSU will batch and ship the samples to be analyzed at theUniversity of California San 
Francisco. 

 
 
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APPENDIX 8:  ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.  

 
 
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