A Phase 2 Study of Ipilimumab in Women With Metastatic or Recurrent HPV-Related Cervical Carcinoma of Either Squamous Cell or Adenocarcinoma Histologies
Phase: PHASE2
Conditions: Cervical Adenocarcinoma, Cervical Squamous Cell Carcinoma, Human Papillomavirus Infection, Recurrent Cervical Carcinoma, Stage IVA Cervical Cancer AJCC v6 and v7, Stage IVB Cervical Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

i 
SUMMARY OF CHANGES 
 
For Protocol Amendment # 6 
 
NCI Protocol #: 
 
9209 
Local Protocol #: 
 
PHL-085 
Protocol Version / Date: 
Initial / 13Jul2012 
A1 / 07Nov2012 
A2 / 29Aug2013 
A3 / 30Apr2014 
A4 / 01Aug2014 
A5 / 30Sep2014 
A6 / 31Jan2018 
 
The following revision is in response to CTEP CTCAE v4.0 to CTCAEv5.0 Conversion request 
letter dated Jan 12/2018. 
 
# 
Section 
Page(s) 
Change 
1. 
7.2 
45 
Changes (highlighted text inserted, strikethrough text deleted): 
 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting until March 31, 
2018 for AE reporting.  CTCAE version 5.0 will be utilized for AE reporting 
beginning April 1, 2018. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.04.0.  A copy of the CTCAE version 
5.04.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Rationale: CTCAE version has been updated as per CTEP request letter 
dated Jan 12/2018 

NCI 9209 / PHL-085 
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1 
NCI Protocol #: 
 
9209 
Local Protocol #: 
 
PHL-085 
Protocol Version / Date: 
Initial / 13Jul2012 
A1 / 07Nov2012 
A2 / 29Aug2013 
A3 / 30Apr2014 
A4 / 01Aug2014 
A5 / 30Sep2014 
A6 / 31Jan2018 
 
TITLE:  A Phase 2 Study of Ipilimumab in women with metastatic or recurrent HPV-related 
cervical carcinoma of either squamous cell or adenocarcinoma histologies 
 
 
Coordinating Center: 
 
 
The Princess Margaret Hospital Phase II Consortium (PMHC) 
 
*Principal Investigator: 
Dr. Amit Oza 
 
610 University Avenue 
 
Princess Margaret Hospital 
 
Toronto Ontario M5G2M9 
 
Phone: 416-946-2818 
 
Fax: 416-946-4467 
 
amit.oza@uhn.ca 
 
Co-Investigators: 
Dr. Katia Tonkin 
 
11560 University Ave 
 
Cross Cancer Institute 
 
Edmonton Alberta T6G 1Z2 
 
Phone: 780-432-8514 
 
Fax: 780-432-8888 
 
katia.tonkin@albertahealthservices.ca 
 
 
Dr. Hal Hirte 
 
Juravinski Cancer Centre  
 
 
 
699 Concession St. 
 
Hamilton Ontario L8V 5C2 
 
Phone: (905) 387-9495 
 
Fax: (905) 575-6326 
 
hal.hirte@hrcc.on.ca 
 
Dr. Stephen Welch 
London Regional Cancer Program 
790 Commissioners Road East 
London Ontario N6A 4L6 
Phone: (519) 685-8640 
Fax: (519) 685-8624 

NCI 9209 / PHL-085 
31Jan2018 
 
2 
Stephen.welch@lhsc.on.ca 
 
Dr. Anna Tinker  
BC Cancer Agency 
600 West Tenth Avenue 
Vancouver British Columbia V5Z 4E6 
Phone: (604) 877-6000 
Fax: (604) 877-6217atinker@bccancer.bc.ca 
 
Dr. Prafull Ghatage 
Tom Baker Cancer Centre 
1331-29th Street, NW 
Calgary Alberta T2N 4N2 
Phone: (403) 521-3721 
Fax: (403) 521-3593 
Prafull.Ghatage@albertahealthservices.ca 
 
Dr. Johanne Weberpals 
Ottawa Regional Cancer Centre 
501 Smyth Road 
Ottawa Ontario 
Phone: (613) 737-8899 x76462  
Fax: (613) 737-8828 
 jweberpals@Ottawahospital.on.ca 
 
Dr. Lainie Martin 
Fox Chase Cancer Center 
333 Cottman Ave, Room C307 
Philadelphia Pensylvannia 19111-2497 
Phone: (215)728-3889 
Fax: (215)728-3639 
lainie.Martin@fccc.edu 
 
Dr. Mihaela Cristea 
City of Hope 
1500 E. Duarte Road 
Duarte, CA 91010 
Phone: (626) 256-4673 
Fax: (626) 930-5461 
mcristea@coh.org 
 

NCI 9209 / PHL-085 
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3 
Dr. Stephen Koehler 
City of Hope Medical Group, Inc. 
209 Fair Oaks Avenue 
South Pasadena, CA 91030 
Phone: (626) 396-2900 
Fax: (626) 396-2770 
Skoehler@cohmg.com 
      
Dr. Edwin Alvarez 
University of California, Davis Cancer Center 
4860 Y Street, Suite 2500 
Sacromento, CA 95817 
Ph: 916-734-6900 
Fax:  916-734-6666  
Email:  edwin.alvarez@ucdmc.ucdavis.edu 
 
Dr. Gini Fleming 
University of Chicago Medical Center 
5841 South Maryland Ave., MC 2115 
Chicago, IL 60637 
Phone: (773) 702-6712 
Fax: (773) 702-0963 
gfleming@medicine.bsd.uchicago.edu 
 
 
Statistician: 
 
Study Coordinator: 
Lisa Wang 
  
Smitha Udagani 
Princess Margaret Hospital 
 
 
 
 
Princess Margaret Hospital 
610 University Avenue 
 
 
 
 
610 University Avenue 
Toronto Ontario M5G 2M9  
Toronto, Ontario M5G 2M9 
Phone: 416-946-4501 ext. 4883  
 
 
 
Phone: (416) 946-4501 ext. 3408 
Fax: 416-946-2048 
 
 
 
 
Fax: (416) 946-2016 
lisawang@uhnres.utoronto.ca 
smitha.udagani@uhn.ca 
 
 
Responsible Data Manager: 
Chantale Blattler 
Princess Margaret Hospital 
610 University Avenue 
Toronto Ontario M5G 2M9  
Phone: 416-946-4501 ext. 3692 
Fax: 416-946-2016 
chantale.blattler@uhn.ca 
 
 
NCI Supplied Agent(s): Ipilimumab (NSC 732442) 

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4 
Response rate (RR) assessment as per RECIST 1.1and irRC 
CT evaluation during cycle 4, week 18 and 20 
Correlative studies: serum collection pre-study, multi on-study + 
follow-up time points  
Eligible patients with metastatic or recurrent cervical carcinoma of 
squamous cell or adenocarcinoma histology 
ECOG 0-1
Ipilimumab administered IV 
Schedule: One dose every 21 days for four cycles 
Dose: 3mg/kg 
Enrollment: 6 evaluable patients 
Patient evaluation as per phase II of trial 
PHASE I RUN IN 
PHASE II – stage 1 
Ipilimumab administered IV 
Schedule: One dose every 21 days for four cycles 
Dose: 10mg/kg 
Enrollment: 18 evaluable patients 
No objective response 
   Trial halted 
   ≥1 objective response 
Open to stage II 
Algorithm for more specific guidance Enrollment of additional 14 patients 
(total 32) 
WEEK 24 
Objective response 
Stabilization of disease 
Clinically stable patients with 
mild PD as per RECIST 1.1 
ECOG 0-1 
Disease Progression 
ECOG <1    
Patient withdrawn 
Off study follow up
(Grade 3 or 4)MAINTENANCE PHASE 
Ipilimumab 10mg/kg (3mg/kg for eligible phase I run in patients) 
Schedule: Once every 12 weeks for 4 additional cycles  
CT evaluation every 12 weeks (weeks 24, 36, 48, 60) and every 3 
months thereafter 
Correlative studies: serum collection on days Ipilimumab is infused 
If >2 dose-
limiting events 
run in phase will 
be expanded to 
total of 12 
patients
Trial will be 
halted if >4/12 
patients 
experience DLT
SCHEMA 

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5 
TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ........................................................................................................... i 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives ...................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease – Cervical Cancer .............................................................................7 
2.2 
CTEP IND Agents ...................................................................................................9 
2.3 
Other Agent(s) .......................................................................................................21 
2.4 
Rationale ................................................................................................................21 
2.5 
Correlative Studies Background ............................................................................22 
3. 
PATIENT SELECTION ....................................................................................................22 
3.1 
Eligibility Criteria ..................................................................................................22 
3.2 
Exclusion Criteria ..................................................................................................24 
3.3 
Pregnancy ...............................................................................................................25 
3.4 
Inclusion of Women and Minorities ......................................................................25 
Accrual Targets ..................................................................................................................26 
4. 
REGISTRATION PROCEDURES ...................................................................................27 
4.1 
General Guidelines .................................................................................................27 
4.2 
Registration Process ...............................................................................................27 
5. 
TREATMENT PLAN ........................................................................................................28 
5.1 
Agent Administration .............................................................................................28 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................29 
5.3 
Duration of Therapy ...............................................................................................30 
5.4 
Duration of Follow Up ...........................................................................................31 
5.5 
Criteria for Removal from Study ...........................................................................31 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................32 
6.1 
Ipilimumab Dose Skipping Rule ............................................................................32 
6.2 
Discontinuation of Study Therapy .........................................................................34 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................43 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................43 
7.2 
Adverse Event Characteristics ...............................................................................45 
7.3 
Expedited Adverse Event Reporting ......................................................................46 
7.4 
Routine Adverse Event Reporting .........................................................................48 
7.5 
Secondary Malignancy ...........................................................................................48 
7.6 
Second Malignancy ................................................................................................48 

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6 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................48 
8.1 
CTEP IND Agent(s) ...............................................................................................48 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................51 
9.1 
Biomarker Studies ..................................................................................................51 
9.2 
Special Studies .......................................................................................................53 
10. 
STUDY CALENDAR .......................................................................................................54 
11. 
MEASUREMENT OF EFFECT........................................................................................56 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................56 
11.2 
Other Response Parameters ...................................................................................62 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................62 
12.1 
Data Reporting .......................................................................................................62 
12.2 
CTEP Multicenter Guidelines ................................................................................63 
12.3 
Collaborative Agreements Language .....................................................................63 
13. 
STATISTICAL CONSIDERATIONS...............................................................................65 
13.1 
Study Design/Endpoints.........................................................................................65 
13.2 
Sample Size/Accrual Rate ......................................................................................65 
13.3 
Stratification Factors ..............................................................................................65 
13.4 
Analysis of Secondary Endpoints ..........................................................................65 
13.5 
Reporting and Exclusions ......................................................................................66 
REFERENCES ..............................................................................................................................67 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................74 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ....................................................75 
APPENDIX C 
Management of Immune-Related Adverse Events, Diarrhea, 
Hepatotoxicity, Endocrinopathy, and Neuropathy* ...................................77 
APPENDIX D 
Immune Related Response Criteria (irRC)* ..............................................83 
APPENDIX E 
Data Management Guidelines ....................................................................85 
 

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7 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
• To assess the safety of Ipilimumab in eligible patients with recurrent or metastatic cervical 
cancer 
• To assess the antitumor activity of Ipilimumab in eligible patients with recurrent or 
metastatic cervical cancer via assessment of objective response rates (ORR). 
 
1.2 
Secondary Objectives 
 
• To assess the antitumor activity of Ipilimumab through secondary endpoints including of 
disease stabilization and PFS. 
• Assessment of antitumor activity of Ipilimumab using immune-related response criteria 
(irRC) 
• Assessment of the predictive value of baseline C-reactive protein  
• Assess the biologic responses of exposure to Ipilimumab via correlative studies involving 
analysis of lymphocyte subsets and assessment of cervical cancer-antigen specific T cells 
anti-tumor response. 
• Evaluation of archival tissue with regard to markers of immune population in correlation 
with clinical stage and response to treatment   
 
 
2. BACKGROUND 
 
2.1 
Study Disease – Cervical Cancer 
 
Cervical cancer is the second leading cause of cancer-related mortality in women world-wide. 
Over half a million new cases of the disease are diagnosed annually resulting in approximately 
260,000 deaths [Frazer 2004]. The incidence of cervical cancer world-wide is not expected to 
decrease in the near future, despite the existence of the well-established Pap smear screening tool 
and the recent introduction of effective prophylactic vaccination. Therefore, there is an ongoing 
need for the development of effective treatments for women suffering from invasive carcinoma 
of the cervix.    
 
Cervical cancer and Human Papillomavirus (HPV) 
 
Strong epidemiological and molecular evidence have established the importance of human 
papillomavirus (HPV) in the development of cervical cancer [Munoz 2000]. Persistent infection 
with a high-risk HPV genotype leads to a substantial increase in the risk of cervical 
intraepithelial neoplasia (CIN), which if untreated will progress to invasive cancer. HPV 
infection is most clearly associated with squamous cell carcinoma (SCC) but has also been 
reported in women diagnosed with adenocarcinoma of the cervix [Frazer 2004].  
 
The HPV virus has a double-stranded DNA genome surrounded by a protein capsid comprising a 
highly immunogenic L1 protein [Legatt, Frazer 2007]. Following binding to the basement 

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8 
membrane, viral uptake into basal keratinocytes occurs. These epithelial cells support the 
replication of the viral episome and cell transformation occurs following the integration of the 
viral genome into the host cell DNA. The non-structural viral proteins E6 and E7 are considered 
oncoproteins causing cell transformation by inhibiting cell apoptosis and by promoting 
degradation of p53 thereby facilitating continued cell proliferation despite cell damage presence 
[Bhat, Mattarollo, Gosmann et al.].   
 
The oncoproteins E6 and E7 are consistently expressed in cervical cancer cells and as such may 
be considered to be tumor-associated antigens (TAA). Given that these proteins are absent from 
normal cells and selectively expressed in tumor cells they can serve as logical targets for the cell-
mediated immune response. Equally, they become potential targets for immunotherapy strategies 
[Valdespino, gorodezky, Vianney et al. 2005].  
 
The rationale for immunotherapy based treatments in cervical cancer 
 
The etiological link between HPV and cervical cancer is undisputed. Epidemiologic data 
demonstrates a significant increased risk of HPV-related cancer development in 
immunosuppressed individuals. An increased incidence of cervical dysplasia, genital 
papillomavirus infection and lower genital neoplasia is well documented in individuals infected 
by the human immunodeficiency virus (HIV) as well as renal transplant patients receiving long 
term immunosuppressive medications [Laga, Icenogle, Marsella et al. 1992; Halpert, Fruchter, 
Sedlis et al. 1986]. These observations suggest that the immune system is central to the 
prevention of development of these tumors when functioning appropriately.  
 
The natural humoral response to HPV viral capsids can be detected in 50-70% of individuals by 
6 months post-infection. Some individuals never seroconvert and whilst a proportion of 
individuals continue to demonstrate high levels of antibody post infection, this does not appear to 
prevent future infections [Insinga, Perez, Wheeler et al 2010]. Despite this poor natural humoral 
response, systemic administration of HPV capsid protein in combination with adjuvant elicits a 
vigorous host-antibody response in most individuals. This response is effective in preventing 
persistent HPV infection as well as CIN and malignancy development. It forms the basis for the 
recently introduced prophylactic vaccinations and further strengthens the belief that immune 
modulation may serve as an effective treatment strategy in this disease setting [harper, Franco, 
Wheeler et al 2006; Munoz, Manalastas, Pipisuttithum et al. 2009]. 
 
Data suggests that HPV infection does invoke a cellular immune response. Several groups have 
demonstrated the presence of T cell infiltrates following HPV infection but variability of results 
is such that the exact role of T-helper cells and cytotoxic T-cells in the immune modulation of 
this infection remain only partially understood. CD4 T cell infiltrates have been associated with 
HPV persistence and linked with increasing cervical dysplasia [Molling, deGrijl, Glim et al. 
2007; Jaafar, Righi, Lindstrom et al. 2009]. In contrast, CD8 T cells appear abundant in 
regressing lesions [Woo, van den Hende, Sterling et al. 2010]. These data collectively suggest 
that cytotoxic T cells may limit disease progression whereas regulatory T cells may be involved 
in creating a tolerant immunologic environment. This in turn may contribute to viral immune 
evasion and the persistence of HPV infection resulting in progression of disease [Bhat, 
Mattarollo, Gosmann et al 2011]. Immune modulating therapies which may be formulated to 
enhance the innate immune response to cervical cancer cells or alternatively to repress immuno-

NCI 9209 / PHL-085 
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9 
protective pathways may be a successful therapeutic strategy to combat this disease. 
 
2.2 
CTEP IND Agents 
 
2.2.1 Ipilimumab 
 
Ipilimumab (MDX-010, MDX-CTLA4, and BMS-734016) is being developed by CTEP as an 
anticancer agent in collaboration with Bristol-Myers-Squibb (BMS).  On March 25, 2011, the 
FDA approved Ipilimumab injection (YERVOY, BMS) for the treatment of unresectable or 
metastatic melanoma.  Ipilimumab is a human IgG1κ monoclonal antibody (mAb); it is specific 
for human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152) expressed on 
activated T cells.  Ipilimumab is now produced and formulated from transfected Chinese hamster 
ovary (CHO) cells.   
 
CTLA-4 is a negative regulator of T-cell responses following T-cell stimulation (Thompson and 
Allison, 1997; Kuhns et al., 2000).  CTLA-4 knockout mice suffer from a fatal 
lymphoproliferative disorder, supporting the idea that CTLA-4 functions as a negative regulator 
of T-cell responses in vivo (Tivol et al., 1995; Waterhouse et al., 1995; Chambers et al., 1997).  
Disrupting CTLA-4 interaction with its ligands B7-1 (CD80) and B7-2 (CD86), which are 
expressed on antigen-presenting cells (APCs), with Ipilimumab, augments immune responses 
(Investigator Brochure, 2011).  In vivo blockade of CTLA-4, utilizing anti-CTLA-4 mAb, 
induced regression of established tumors and enhanced antitumor immune responses in several 
murine tumor models.  Blockade of CTLA-4-mediated signals is effective in inducing rejection 
of immunogenic cancers in mice.  Moreover, when anti-CTLA-4 mAb is used in conjunction 
with granulocyte macrophage-colony stimulating factor (GM-CSF)-secreting tumor vaccines, 
poorly immunogenic cancers in mice are rejected.  These findings suggest that CTLA-4 
blockade, alone or in combination with antigenic stimulation and other immune modulating 
agents can induce a potent antitumor response.   
 
Pharmacology of Ipilimumab 
 
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 or B7.2 negative cell lines, and stains the appropriate cells without non-specific 
cross-reactivity in normal human tissues.  Ipilimumab does cross-react with CTLA-4 in non-
human primates including cynomolgus monkeys.  Blockade of CTLA-4/B7 interactions 
enhanced T-cell responses to CD3 / CD28, peptide antigens, or super antigens in mice (Walunas, 
et al., 1994; Kearney, et al., 1995; Krummel and Allison 1995; Krummel, Sullivan, and Allison, 
1996).  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.  Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), 
appeared healthy and gave birth to healthy CTLA-4+/- heterozygous offspring.  Mated CTLA-
4+/- heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, 
CTLA-4-/-).  Since thymocyte differentiation and selection proceed normally in 

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10 
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 post- thymic T-cell responses in the periphery 
following stimulation of naïve, memory, and effector T cells (Krummel, Sullivan, and Allison, 
1996).   
 
Pharmacokinetics  
 
The pharmacokinetics (PK) of Ipilimumab was studied in 499 patients with unresectable or 
metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg administered once every 3 
weeks (q3w) for four doses.  Peak concentration (Cmax), trough concentration (Cmin), and area 
under the curve (AUC) of Ipilimumab were found to be dose proportional within the dose range 
examined.  Upon repeated dosing of Ipilimumab administered q3w, Ipilimumab clearance was 
found to be time-invariant, and minimal systemic accumulation was observed as evident by an 
accumulation index of 1.5-fold or less.  Ipilimumab steady-state concentration was reached by 
the third dose.  The following mean (percent coefficient of variation) parameters were generated 
through population PK analysis: terminal half-life of 14.7 days (30.1%); systemic clearance (CL) 
of 15.3 mL/h (38.5%); and volume of distribution at steady-state (Vss) of 7.21 L (10.5%).  The 
mean (±SD) Ipilimumab Cmin achieved at steady-state with the 3-mg/kg regimen was 21.8 
mcg/mL (±11.2). 
 
Specific Populations: Cross-study analyses were performed on data from patients with a variety 
of conditions, including 420 patients with melanoma who received single or multiple infusions of 
Ipilimumab at doses of 0.3, 3, or 10 mg/kg.  The effects of various covariates on Ipilimumab PK 
were assessed in population PK analyses. 
Ipilimumab CL increased with increasing body weight; however, no dose adjustment of 
Ipilimumab is required for body weight after administration on a mg/kg basis. 
The following factors had no clinically meaningful effect on the CL of Ipilimumab: age (range 
26 to 86 years), gender, concomitant use of budesonide, performance status, HLA-A2*0201 
status, positive anti-Ipilimumab antibody status, prior use of systemic anticancer therapy, or 
baseline lactate dehydrogenase (LDH) levels.  The effect of race was not examined as there were 
insufficient numbers of patients in non-Caucasian ethnic groups. 
 
Renal Impairment: Creatinine clearance at baseline did not have a clinically important effect on 
Ipilimumab PK in patients with calculated creatinine clearance values of 29 mL/min or greater. 
 
Hepatic Impairment: Baseline AST, total bilirubin, and ALT levels did not have a clinically 
important effect on Ipilimumab PK in patients with various degrees of hepatic impairment. 
 
Clinical Pharmacodynamics 
 
 
 
In clinical studies, Ipilimumab increased absolute lymphocytes counts (ALC) in peripheral blood 
(Investigator Brochure, 2011).  However, CD4+/CD8+ ratio did not appear to be affected.  
Across three phase 2 studies in 463 subjects with advanced melanoma, Ipilimumab increased 
ALC in a dose-dependent manner, with the largest increase observed at 10 mg/kg dose.  ALC 
continued to increase over time during the induction treatment at least until week 12 at the 3 

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11 
mg/kg and 10 mg/kg dose, but not at the 0.3 mg/kg dose.  The slope of ALC increase also 
suggested the 10 mg/kg dose is more biologically active than the 3.0 mg/kg or 0.3 mg/kg dose.   
 
Mechanism of Action 
 
The proposed mechanism of action for Ipilimumab is T-cell potentiating through interference of 
the interaction of CTLA-4 with B7 (CD80 or CD86) molecules on APCs, with subsequent 
blockade of the inhibitory function of CTLA-4 (Investigator Brochure, 2011).  Ipilimumab 
impacts tumor cells indirectly, and measurable clinical effects emerge after the immunological 
effects.  Tumor infiltration with lymphocytes and the associated inflammation is likely the 
cornerstone of the effect of Ipilimumab and can manifest in various patterns of clinical activity 
leading to tumor control.  These immunologic responses may take time to develop and so tumor 
responses may be delayed and tumor progression may occur during the initial period followed by 
responses.  In some cases, tumor response based on tumor infiltration with immune cells may be 
preceded by an apparent increase in initial tumor volume and/or the appearance of new lesions, 
which may be taken for tumor progression on radiological evaluations. Delayed responses 
following increasing tumor size or appearance of new lesions have been seen in approximately 
10-20% of patients with metastatic melanoma.  For patients who are not experiencing rapid 
clinical deterioration, allowing sufficient time to observe responses including disease 
stabilization or confirmation of progression is recommended; as discussed in the section “Overall 
Risk/Benefit Assessment” may allow better assessment of clinical activity and avoid 
unnecessarily initiating additional therapies in subjects who might be benefitting from treatment.  
Immune-related (ir) response criteria were developed based on these observations in patients 
with melanoma to systematically categorize novel patterns of clinical activity and are currently 
being prospectively evaluated in clinical studies. 
             
Nonclinical Toxicology  
 
Please note relevant toxicity for single agent Ipilimumab has been almost completely derived from clinical 
studies.  
 
In a study using cynomolgus macaques, anti-melanocyte responses were observed in animals 
given up to four doses of 10 mg/kg Ipilimumab after receiving a melanoma cell vaccine (Keler et 
al., 2003).  Depigmentation has been observed in other nonclinical immunotherapy studies that 
involve treatment with melanoma peptides (Hara et al., 1995; Naftzger et al., 1996; Bloom et al., 
1997; Overwijk et al., 1998; Weber et al., 1998; Overwijk et al., 1999).  The symptoms in 
animals appear to resemble vitiligo observed in clinical immunotherapy trials of melanoma 
patients and may be an unavoidable consequence of treatment (Rosenberg and White, 1996). 
 
Additional repeat-dose toxicity studies conducted using cynomolgus macaques demonstrated that 
the IV administration of ≤30 mg/kg every 3 days for three doses, 10 mg/kg weekly for 1 month, 
1 mg/kg weekly for 10 weeks, or 10 mg/kg monthly for 6 months was generally well tolerated, 
without significant clinical, immunotoxicological, or histopathological findings (Investigator 
Brochure, 2011).  However, when Ipilimumab was administered in combination with another 
immunomodulatory antibody (BMS-663513, a fully human anti-CD137 mAb) and simian 
immunodeficiency virus (SIV) DNA, two immune-related adverse events (irAEs) were observed:  

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12 
severe colitis requiring euthanasia in one monkey and reversible dermatitis/rash in the inguinal 
area and peripheral lymphadenopathy in another monkey. 
 
Complete information on the pre-clinical toxicology studies can be found in the Ipilimumab 
Investigator Brochure (IB).  Non-clinical toxicity assessments included in vitro cynomolgus 
monkeys alone and in the presence of vaccines.  Low to moderate ADCC activity was noted at 
concentrations up to 50 mcg/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.  No mortality 
or signs of toxicity were observed in three independent 14-day intravenous (IV) 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. 
 
Clinical Development of Ipilimumab   
 
Company-Sponsored Studies 
BMS and Medarex (acquired by BMS in September 2009) have co-sponsored an extensive 
clinical development program for Ipilimumab, encompassing more than 4000 subjects in several 
cancer types in 33 completed and ongoing studies (Investigator Brochure, 2011).  The focus of 
the clinical program is in melanoma, prostate cancer, and lung cancer, with advanced melanoma 
being the most comprehensively studied indication.  Ipilimumab is being investigated both as 
single agent and in combination with other modalities such as chemotherapy, radiation therapy, 
and other immunotherapy. 
 
Phase 3 programs are ongoing in melanoma and prostate cancer (Investigator Brochure, 2011).  
In the phase 3 combination study of Ipilimumab with glycoprotein 100 (gp100) peptide vaccine 
(melanoma study MDX010-20), Ipilimumab was administered at a dose of 3 mg/kg of body 
weight, with or without gp100 q3w for up to four treatments (Hodi et al., 2010).  The median 
overall survival (OS) in the Ipilimumab plus gp100 group was 10.0 months (95% confidence 
interval [CI], 8.5 to 11.5 months) compared with 6.4 months (95% CI, 5.5 to 8.7 months) in the 
gp100-alone group (hazard ratio [HR] for death, 0.68; p<0.001).  Grade 3 or 4 immune related 
events (irAEs) occurred in 10 to 15% of patients treated with Ipilimumab and in 3% of patients 
treated with gp100 alone.   
 
A second phase 3 study in melanoma was reported for Ipilimumab in combination with 
dacarbazine versus dacarbazine alone in previously untreated advanced melanoma.  CA184024 
evaluated the addition of 10 mg/kg Ipilimumab to dacarbazine in patients with previously 
untreated, metastatic melanoma.  A total of 502 patients were randomized to receive up to 8 
cycles of dacarbazine 850 mg/m2 q3w, with either Ipilimumab 10 mg or placebo for cycles 1-4 
and as maintenance after completion of chemotherapy. Ipilimumab AEs were consistent with 
previous studies and predominantly affected skin, GI tract, liver, and the endocrine system.  
Events were managed with established guidelines and were generally responsive to dose 
interruption/discontinuation, corticosteroids and/or other immunosuppresants.   

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13 
 
There are two ongoing studies of Ipilimumab as adjuvant monotherapy for high-risk Stage III 
melanoma (CA184029 and ECOG 1609)  
 
Two phase 3 studies are ongoing in subjects with castration-resistant prostate cancer who have 
received prior chemotherapy (CA184043, Ipilimumab in combination with radiation therapy) 
and those who are chemotherapy-naïve (CA184095, Ipilimumab monotherapy). 
 
An ongoing large phase 2 study (CA184041) is investigating the addition of Ipilimumab to 
carboplatin and paclitaxel using two different schedules (concurrent and phased) in subjects with 
non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) (Investigator Brochure, 
2011).  The results demonstrate an improved immune-related progression-free survival (irPFS) 
for the subjects who received combination therapy with paclitaxel/carboplatin/Ipilimumab 
compared with paclitaxel/carboplatin alone.  The improvement in irPFS with the combination 
therapy met the prespecified protocol criteria for significance for both the concurrent and phased 
schedules (p=0.0935 and 0.0258, respectively).  Using modified World Health Organization 
(mWHO) criteria (a key secondary endpoint), PFS was significantly improved with the phased 
schedule but not the concurrent schedule (p=0.0240 and 0.2502, respectively). 
 
Other Clinical Studies with Ipilimumab 
 
Renal cell carcinoma (RCC) 
Yang and colleagues presented data on a phase 2 study of Ipilimumab conducted in patients with 
metastatic RCC (Yang et al., 2007).   Sequential cohorts received either 3 mg/kg followed by 1 
mg/kg or all doses at 3 mg/kg q3w.  One of 21 patients receiving the lower dose had a PR.  Five 
of 40 patients at the higher dose had PRs (95% CI, cohort response rate 4 to 27%) and responses 
were seen in patients who had previously not responded to IL-2.  Thirty-three percent of patients 
experienced grade 3 or 4 irAEs.  There was a highly significant association between autoimmune 
events and tumor regression (response rate = 30% with AE, 0% without AE).  The authors 
concluded that CTLA-4 blockade with Ipilimumab induced cancer regression in some patients 
with metastatic clear cell renal cancer, even if they had not responded to other immunotherapies.   
 
Melanoma (Ipilimumab plus bevacizumab) 
At the 2011 ASCO meeting Hodi and colleagues presented results on 21 evaluable patients (22 
patients enrolled) with unresectable stage III or stage IV melanoma treated with the combination 
of 10 mg/kg Ipilimumab and 7.5 mg/kg bevacizumab on a phase 1 study (Hodi et al., 2011).  
AEs included giant cell arteritis (1), hypophysitis (3), thyroiditis (4), grade 3-4 hepatitis (2), 
bilateral uveitis (2), and grade 2 colitis (2); 5 patients required systemic steroids and stopped 
treatment.  All toxicities were resolved.  Eight PRs and 6 SDs were observed.  All responses 
were durable (>6 months).  Post-treatment biopsies in 12 patients revealed activated vessel 
endothelium with extensive T-cell trafficking non-productive central angiogenesis, and 
peripheral blood monitoring revealed a marked increase in CD4/CCR7/CD45RO central memory 
cells in the majority of patients,  not seen with Ipilimumab alone.  The authors concluded that the 
combination of Ipilimumab with bevacizumab can be safely administered with clinical activity 
and correlatives suggesting synergistic effects.  
 

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14 
Bladder cancer 
Carthon and colleaugues reported immunodulatory effects following a brief exposure of anti-
CTLA-4 in patients with urothelial carcinoma of the bladder requiring surgery (BMS study 
CA184027) (Carthon et al., 2010).  12 patients were enrolled (6 patients received 3 mg/kg/dose 
of Ipilimumab and another 6 patients received 10 mg/kg/dose for two doses prior to surgery).  
The treatment was found to be tolerable in the cohort of patients with 11 of 12 patients receiving 
both doses of antibody.  Grade 1-2 diarrhea and rash were the most common drug-related AEs.  
The only noted grade 3 irAEs were ischemic papillopathy and diarrhea, which were both 
responsive to treatment with steroids.   
 
Liakou and colleagues found that CD4 T cells from peripheral blood and tumor tissues of all 
bladder cancer patients treated with anti-CTLA-4 antibody had markedly increased expression of 
inducible costimulator (ICOS) (Liakou et al., 2008).  These CD4+ICOShi T cells produced 
interferon-gamma (IFN-γ) and could recognize the tumor antigen NY-ESO-1.  Increase in 
CD4+ICOShi cells led to an increase in the ratio of effector to regulatory T cells.  The authors 
indicated that these immunologic changes were reported in both tumor tissues and peripheral 
blood as a result of treatment with anti-CTLA-4 antibody, and they may be used to guide dosing 
and scheduling of this agent to improve clinical responses.  A sustained increased frequency of 
CD4+ICOShi T cells may serve as a biomarker of anti-CTLA-4 activity and/or of clinical benefit 
for patients who are being treated with this novel agent (Carthon et al., 2010).   
 
Pancreatic cancer 
Royal and colleagues presented the results on 27 patients (metastatic disease: 20 and locally 
advanced: 7) (Royal et al., 2010).  Three subjects experienced ≥ grade 3 irAEs (colitis:1, 
encephalitis:1, hypophysitis:1).  One subject experienced a delayed response after initial 
progressive disease.  In this subject, new metastases after 2 doses of Ipilimumab established 
progressive disease.  However, continued administration of the agent per protocol resulted in 
significant delayed regression of the primary lesion and 20 hepatic metastases with normalization 
of tumor markers and clinically significant improvement of performance status.  The 
investigators concluded that single agent Ipilimumab at 3.0 mg/kg/dose was ineffective for the 
treatment of advanced pancreatic cancer.  However, a significant delayed response in one subject 
of this trial suggests that immunotherapeutic approaches to pancreatic cancer deserve further 
exploration. 
 
CTEP-Sponsored Studies 
The DCTD, NCI, has sponsored nine studies with Ipilimumab including one pilot study (5744, 
lymphoma), three phase 1 studies (5708 [ovarian], 6082 [solid tumors], and 7458 [solid tumors]), 
one phase 1/2 study (6359 [non-Hodgkin’s lymphoma]) with single agent Ipilimumab, two phase 
1 combination studies in prostate cancer with GM-CSF (6032) and with prostate-specific antigen 
(PSA)-TRICOM vaccine (7207), one phase 2 combination study of Ipilimumab with GM-CSF 
(E1608, melanoma) and one phase 3 study (E1609) of adjuvant Ipilimumab therapy versus high-
dose interferon alpha-2b in patients with resected high-risk melanoma.   
 
Results from 11 patients (colon, n=3; non-Hodgkin’s lymphoma, n=4; prostate, n=4) who 
received Ipilimumab on study 5744 included tumor regression in 2 patients with lymphoma; 1 of 
whom (follicular lymphoma patient) had a partial response (PR) of 14-month duration 

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15 
(O’Mahony et al., 2007).  Ipilimumab was well tolerated with predominantly grade 1/2 
toxicities.  One drug-related grade 3 AE was observed.  Tregs, as detected by expression of 
CD4+CD25+CD62L+, declined at early time points but rebounded to levels at or above baseline 
values at the time of the next infusion.  The investigators concluded that Ipilimumab treatment 
depressed Treg numbers at early time points in the treatment cycle but was not accompanied by 
an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a 
variety of investigational anticancer vaccines.   
 
Hodi and colleagues reported preliminary results on 20 patients (11 metastatic melanoma 
patients and 9 metastatic ovarian carcinoma patients) on study 5708 (Hodi et al., 2008).  None of 
the 11 patients from the metastatic melanoma cohort manifested grade 3 or 4 inflammatory 
toxicities; however, all subjects revealed mild inflammatory pathologies associated with low-
level constitutional symptoms.  The most common toxicity (10/11 subjects) was a grade 1-2 
reticular and erythematous rash on the trunk and/or extremities that arose between 3 days and 3 
weeks after antibody administration and then gradually resolved without specific intervention.  
Biopsies of involved skin revealed low-grade interface dermatitis, minor to moderate 
mononuclear infiltrates surrounding the superficial dermal vasculature, and increased mucin 
deposition in the papillary and reticular dermis.  These pathologic features resembled those 
observed in mild cutaneous forms of systemic lupus erythematosis.  Three PRs (range, 21-34+ 
months) and five events of stable disease (SD) (range, 4-25 months) were observed.  One PR and 
three SDs (2, 4, and 6+ months) were observed in the ovarian carcinoma group.  The 
investigators concluded that selective targeting of antitumor regulatory T cells (Treg) may 
constitute a complementary strategy for combination of Ipilimumab and GM-CSF-based antigen 
tumor cell vaccine therapy.  
 
Results from 29 patients with malignancies that were recurrent or progressive after allogeneic 
hematopoietic cell transplantation (allo-HCT) demonstrated that drug was well tolerated at single 
doses up to 3 mg/kg (Bashey et al., 2009).  Four patients experienced organ-specific irAEs of 
reversible grade 3 arthritis, grade 2 hyperthyroidism, dyspnea, and grade 4 pneumonitis.  Three 
patients had objective responses: one PR lasting for 2 months, and two durable complete 
responses (CRs).  Two additional patients with Hodgkin’s disease who had evidence of rapid 
disease progression prior to Ipilimumab treatment achieved SD for 3 and 6 months, following 
infusion at the 3 mg/kg dose level.  Median OS was 24.7 months.  At a 3.0 mg/kg dose, active 
serum concentrations of Ipilimumab were maintained for 30 days following a single infusion.  
Zhou and colleagues reported immunophenotypes of peripheral blood T cells, including T-cell 
reconstitution, activation, and Treg expression, in 29 patients before and after a single-dose 
infusion of Ipilimumab (Zhou et al., 2011).  CTLA-4 blockade by a single infusion of 
Ipilimumab increased CD4+ and CD4+HLA-DR+ T lymphocyte counts and intracellular CTLA-4 
expression at the highest dose level (3.0 mg/kg).  There was no significant change in Treg cell 
numbers after Ipilimumab infusion.  These data demonstrate that significant changes in T-cell 
populations occur on exposure to a single dose of Ipilimumab.   
 
Harzstark and colleagues reported results on 36 patients with hormone refractory metastatic 
prostate cancer (Harzstark et al., 2010).  Of six patients treated with Ipilimumab at a dose of 3 
mg/kg, three patients had confirmed PSA declines of ≥50%, with a time to progression (TTP) of 
22, 26, and 103 weeks.  One of these patients had a PR in hepatic metastases.  Grade 3 IrAEs 

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16 
consisted of rash in five patients, panhypopituitarism in one patient, temporal arteritis in one 
patient, and diarrhea in three patients.  Non-irAEs included grade 3 and 4 cerebrovascular events 
(one patient each), grade 3 angina (one patient), grade 3 atrial fibrillation (one patient), grade 3 
fatigue (four patients), and grade 5 pulmonary embolism (one patient).  One patient treated at 10 
mg/kg had a PSA decline of ≥50% with a TTP of 39 weeks.  Higher doses of treatment with 
MDX-010 + GM-CSF induced the expansion of activated circulating CD25+, CD69+, and CD8+ 
T cells more frequently than was seen in patients who received the same doses of either MDX-
010 or GM-CSF alone (Fong et al., 2009).  The sera screening with protein arrays showed that 
the treatment can induce antibody responses to the testicular antigen NY-ESO-1.   
 
Patients with metastatic prostate cancer were treated with ProstVac vaccine and Ipilimumab 
before chemotherapy.  The median OS for all patients on study was 31.8 months with a 74% 
survival probability at 24 months (Madan et al., 2010).  The median Halabi predicted OS for all 
patients was 18.5 months.  There was no significant difference in OS at different dose levels of 
antibody (range 1-10 mg).  A unique effect of the vaccines on the rate of tumor growth may be a 
novel method to evaluate the anti-tumor effects of the vaccine (Stein et al., 2011).  The authors 
suggested that the addition of immune checkpoint inhibition may augment the clinical benefit of 
vaccines.  
 
Ansell and colleagues reported data on 18 treated patients with NHL (Ansell et al., 2009).  Two 
clinical responses were observed:  one patient with diffuse large B-cell lymphoma (BCL) had an 
ongoing CR (>31 months), and one with follicular lymphoma had a PR lasting 19 months.  In 5 
of 16 cases tested, T-cell proliferation to recall antigens was >2 fold increased after Ipilimumab 
therapy.  The investigators have found that blockade of CTLA-4 signaling with the use of 
Ipilimumab is well tolerated at the doses used.  Ipilimumab has antitumor activity in patients 
with BCL, resulting in durable responses in a minority of patients.  Ipilimumab at 3 mg/kg 
monthly for 4 months can be given safely and is the dose that recommended for future 
combination studies.   
 
Clinical Safety   
 
Safety Experience  
The most common treatment-related AEs (those considered possibly, probably, or definitely 
related to study drug by the investigator) associated with the use of Ipilimumab were immune 
related irAEs (Investigator Brochure, 2011).  The irAEs primarily involved the gastrointestinal 
(GI) tract (e.g., diarrhea and colitis) and skin (e.g., pruritus and rash), and less frequently, the 
liver, endocrine glands (including the thyroid, pituitary, and adrenal glands) and nervous system.  
IrAEs were generally managed with either symptomatic therapy (grade 1-2 events), systemic 
corticosteroids (grade 3-4 events), or other immunosuppressants (e.g., infliximab, mycophenolate 
mofetil) for steroid-unresponsive GI or hepatic irAEs, as appropriate.  Management of irAEs was 
usually paired with omission of dosing for mild or moderate events and permanent 
discontinuation for severe irAEs.  Ipilimumab can result in severe and fatal immune-mediated 
reactions due to T-cell activation and proliferation.  Fatalities due to GI perforation, hepatic 
failure, toxic epidermal necrolysis, and Guillain-Barré syndrome have been reported in clinical 
trials of Ipilimumab.   
 

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Clinical trials are conducted under widely varying conditions so that extrapolation to novel 
settings and combinations regarding rates and severity of events may be unreliable.  Given the 
expected rate of toxicity which may require stopping study drug but may also be related to a 
therapeutic immunologic response, alternative DLT criteria are discussed in section 6.  
 
Min and colleagues reported three patients who received Ipilimumab alone or combined with 
bevacizumab therapy and developed thyroiditis, and the first report of euthyroid Graves’ 
ophthalmopathy (Min et al., 2011).  They recommend that all patients on Ipilimumab alone or 
combined with bevacizumab therapy have baseline thyroid function tests and careful monitoring 
for new onset of thyroid disease, particularly during the first 3 months of treatment. See specific 
events in section 5.  
 
Safety Profile of Ipilimumab at a Dose of 10 mg/kg (Phase 2 data) 
The safety profile of Ipilimumab as monotherapy over multiple doses at a dose of 10 mg/kg in 
325 subjects was determined from 4 completed melanoma studies.  Overall, the incidence of 
grade 3/4 AEs attributable to study drug was 31%.  The target organ system, the incidence, and 
the severity of the most commonly observed irAEs vary among studies and with drug 
combinations.  Typically, the severity but not necessarily the overall incidence increases with 
dose.  Additional information on specific events is provided in section 7.1 and the IB:   
 
Summary of irAE Safety Data for 10 mg/kg in Melanoma 
 
Total 
Low-grade 
(Grade 1 - 2) 
(%) 
High-grade 
(Grade 3 - 4) (%) 
Median Time to 
Resolution of 
Grade 2 - 4 irAEs 
(weeks) 
All irAEs 
72.3 
46.2 
25.2 
- 
Skin (e.g., rash, 
pruritus) 
52.0 
49.2 
2.8 
6.14 
GI (e.g., colitis, diarrhea) 
37.2 
24.9 
12.3 
2.29 
Liver (e.g., LFT 
elevations) 
8.0 
0.9 
6.8 
4.0 
Endocrine (e.g., 
hypophysitis, hypothyroid) 
6.2 
3.7 
2.5 
20.1 
 
Pregnancy 
Preliminary results are available in cynomolgus monkeys.  Pregnant monkeys received 
Ipilimumab every 21 days from the onset of organogenesis in the first trimester through delivery, 
at dose levels either 2.6 or 7.2 times higher than the clinical dose of 3 mg/kg of Ipilimumab (by 
AUC).  No treatment-related adverse effects on reproduction were detected during the first two 
trimesters of pregnancy.  Beginning in the third trimester, the Ipilimumab groups experienced 
higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth 
weight), and higher incidences of infant mortality in a dose-related manner compared to controls.  
Based on animal data, Ipilimumab may cause fetal harm.  The use of Ipilimumab during human 
pregnancy has not been formally studied in clinical trials.  There have been 7 known pregnancies 
during Ipilimumab treatment: in 3 female subjects and in the partners of 4 male study subjects.  
Two (2) of the 3 female pregnancies ended with elected terminations.  The third female subject 
had a history of seizures and delivered the baby at 36 weeks gestation.  The baby had respiratory 
complications that resolved by birth week 16.  Three (3) of the 4 partners of male study subjects 

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had full term, normal babies.  The fourth baby had small ureters, which are expected to grow as 
the baby matures.  Although these outcomes do not indicate that stillbirths or other severe 
abnormalities will occur, pregnancy should be avoided during treatment with Ipilimumab.  
 
Immunogenicity 
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against 
Ipilimumab in an electrochemiluminescent (ECL) based assay.  This assay has substantial 
limitations in detecting anti-Ipilimumab antibodies in the presence of Ipilimumab. Infusion-
related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not 
reported in these 11 patients nor were neutralizing antibodies against Ipilimumab detected.  
Because trough levels of Ipilimumab interfere with the ECL assay results, a subset analysis was 
performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable 
patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against 
Ipilimumab.  These results are highly dependent on methodology, and comparison of incidence 
of antibodies to Ipilimumab with the incidences of antibodies to other products may be 
misleading. 
 
Study Results and Clinical Efficacy  
The clinical efficacy of Ipilimumab as a single agent at a dose of 3 mg/kg administered q3w for 4 
doses has been established in MDX010-20 (a randomized, controlled study in second line, 
locally advanced/metastatic melanoma), which led to approval of Ipilimumab by the FDA.  In 
study CA184024, the addition of 10 mg/kg Ipilimumab to dacarbazine led to a prolongation of 
overall survival in patients with previously untreated melanoma.  
 
In melanoma studies, disease stabilization in subjects receiving Ipilimumab is characteristic of 
anti-tumor activity.  Stable disease, sometimes of long duration, or slow steady decline of tumor 
lesion size over long periods of time, has been observed.  Some subjects demonstrate initial 
tumor volume increase before response, possibly due to T-cell infiltration as shown by biopsies 
or to the time required for immunologic activation.  Consequently, an initial determination of 
progressive disease and consequently PFS may not capture all patterns response and may 
underestimate the clinical activity of Ipilimumab.  Please see section “Considerations for Using 
Immune-Related Tumor Assessment Criteria (irRC).”  
 
 
10 mg/kg Dosing with Ipilimumab 
Several additional trials studied the efficacy and safety of 10 mg/kg dosing, and additional 
information gained from these trials is listed below: 
• A dose of 10 mg/kg may be necessary to ensure blockade of the CTLA-4 pathway; in vitro, a 
concentration of 20 mcg/mL of Ipilimumab was the minimal concentration able to fully 
abrogate the binding of CTLA-4 to B7.1 and B7.2.  With a dose of 3 mg/kg q3w, 30% 
achieved a trough concentration of Ipilimumab greater than 20 g/mL, compared to 95% of 
subjects treated at 10 mg/kg q3w. 
 
• In addition, in all Ipilimumab trials examined to date, mean Absolute Lymphocyte Count 
(ALC) increased after Ipilimumab treatment throughout the 12-week induction-dosing 
period, in a dose-dependent manner.  In an analysis of Ipilimumab at 0.3, 3, or 10 mg/kg in 
melanoma studies CA184007, CA184008, and CA184022 combined, the rate of change in 

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19 
ALC after Ipilimumab treatment was significantly associated with dose (p = 0.0003), with 
the largest rate at 10 mg/kg Ipilimumab.  Moreover, the rate of change in ALC over the first 
half of the induction-dosing period was significantly associated with clinical activity in these 
studies (p = 0.009), where clinical activity was defined as CR, PR, or prolonged SD (i.e., SD 
lasting at least 6 months from first dose). Although these analyses alone could not determine 
whether the rate of change in ALC was specifically associated with clinical activity in 
response to Ipilimumab treatment, as opposed to being generally prognostic, these results do 
suggest a potential benefit to higher rates of ALC increase after Ipilimumab treatment.  
Among the 3 doses evaluated, 10 mg/kg Ipilimumab led to the greatest such rates. 
 
• In the 3 primary studies conducted in advanced melanoma (CA184007, CA184008, and 
CA184022), subjects treated with 10 mg/kg single agent Ipilimumab had the highest 
response, disease control rates, median OS as well as 1-year and 2-year survival rates 
compared to lower  doses. The CA184022 data are summarized in Table below. 
 
Dose, Schedule, and Regimen 
 
While optimal doses and schedules for Ipilimumab have not yet been determined, in proposed 
proof of principle studies demonstration of efficacy at 10 mg/kg would allow future studies to 
explore biologic and clinical efficacy at lower doses with reduced toxicity. For most studies in 
new combinations or settings, a short phase 1 component at 3 mg would be appropriate with a 5 
or 6 mg/kg dose added as an additional cohort if needed.    
 
A recommended dose of 10 mg/kg is proposed by the manufacturer for most studies of 
Ipilimumab.  In melanoma, a similar survival benefit was demonstrated in phase 3 trials at the 3 
mg/kg and at 10 mg/kg with DTIC.  However, the incidence of grade >3 toxicity was 15 and 
25% respectively.   
 
Based on Phase 2 studies, response rates of Ipilimumab appear to be dose dependent up to 10 
mg/kg. Exposure-response analyses [Cminss Analysis of PK data from patients treated with 
Ipilimumab at 0.3 mg/kg (N=47), 3 mg/kg (N=60) and 10 mg/kg (N=311)], showed that the 
target Cminss target threshold of 20 mcg/ml was exceeded in 0%, 30% and 95% subjects 
respectively.  The slope of change in absolute lymphocyte count (ALC) correlated with clinical 
benefit and T-cell activation markers such as HLA-class II expression may also be dose 
dependent.  Responses have not been compared systematically in randomized phase 2 or phase 3 
studies in patients with tumor types other than melanoma.  
 
Regarding schedule, the typical schedule for advanced melanoma at present is once q3w for four 
doses followed by a maintenance phase of four doses every 12 weeks.  Of interest, Ipilimumab 
was evaluated in NSCLC and SCLC using a dose of 10 mg/kg given concomitantly or following 
initial paclitaxel/cisplatin.  When used in the phased schedule, 10 mg significantly improved 
irPFS and mWHO defined responses but not PFS determined by Response Evaluation Criteria in 
Solid Tumors (RECIST).  There also was a trend for an improvement in OS in both indications.  
Doses less than 10 mg/kg have not been evaluated in either NSCLC or SCLC.  
 
Studies comparing doses in non-melanoma and combinations have not been widely done.  There 

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20 
are also no clear data that peak levels, Cmin, AUC, exposure and number of doses given, or the 
occurrence of autoimmune events, predict responses in individual patients.  We note that the 
incidence of specific events such as hypophysitis may vary from study to study and with 
different combinations of agents.  The severity and possibly time to onset but not necessarily the 
frequency of events increases with dose.  In addition, there are rare but serious events such as 
toxic epidermal necrolysis (TEN) for which a dose relationship has not been established. Case 
report forms should include data on the prior treatment, timing, number of doses, duration of 
event, response to treatment, and complications to allow comparisons among studies.   
 
Considerations in Using Immune-Related Tumor Assessment Criteria (irRC) 
 
New end point definitions for trials of immunologic agents have been proposed based on novel 
patterns of clinical activity in malignant melanoma (Wolchok, et al.  2009; Hoos, et al.  2010). 
These alternative definitions allow time for immunologically mediated effectors to develop that 
may result in late tumor responses even after initial progression by RECIST.  Also, in some 
patients, tumors necrosis and inflammation may increase tumor size radiographically prior to 
response.  Changing the definitions of OR and PD may alter (increase) the number patients 
achieving responses and the duration of PFS.  
 
On a protocol by protocol basis, we would consider allowing study treatment to continue during 
initial progression up to the 12-16 week assessment to allow time for responses to be observed, if 
the patient is clinically stable, there is no deterioration in PS, and there is no need for immediate 
additional treatment.  While maintaining standard definitions of progression and response, we 
would allow new lesions and some progression beyond 20% increases in tumor measurements 
during the initial treatment period to allow time for responses to develop (these delayed tumor 
responses may be seen in 10-20% of melanoma patients who initially progress during the initial 
treatment cycles and evaluation).  We do not have experience with response patterns with 
combination therapy nor in diseases other than melanoma.  Please use standard response 
definitions as the primary end point in these studies.   
 
Note that the proposed irRC may be incorporated as secondary end points to compare to standard 
criteria and evaluate alternative patterns of response in various disease setting and treatment 
regimens.  A copy of the proposed criteria is presented in Appendix D.  
 
Patients who demonstrate mixed responses, stable disease, or objective responses by standard 
RECIST following initial progression may be identified separately as “delayed SD, PR, or CR”.   
 
Overall Risk/Benefit Assessment 
 
The unique immune-based mechanism of action is reflected in the clinical patterns of anti-cancer 
activity in some patients.  Ipilimumab affects tumor cells indirectly, and measurable clinical 
effects emerge after the immunological effects.  Tumor infiltration with lymphocytes and the 
associated inflammation (documented by biopsy in some subjects) is likely the cornerstone of the 
effect of Ipilimumab and can manifest in various patterns of clinical activity leading to tumor 
control.  In some cases, response may be preceded by an apparent increase in initial tumor 
volume and/or the appearance of new lesions, which may be mistaken for tumor progression on 

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21 
radiological evaluations.  Therefore, in subjects who are not experiencing rapid clinical 
deterioration, confirmation of progression is recommended, at the investigator’s discretion, to 
better understand the prognosis as well as to avoid unnecessarily initiating potentially toxic 
alternative therapies in subjects who might be benefitting from treatment.  Immune-related (ir) 
response criteria were developed based on these observations to systematically categorize novel 
patterns of clinical activity and are currently being prospectively evaluated in clinical studies. 
 
In metastatic diseases, stabilization is more common than response, and in some instances is 
associated with slow, steady decline in tumor burden over many months, sometimes improving 
to partial and/or complete responses.  Thus, the immune-based mechanism of action of 
Ipilimumab results in durable disease control, sometimes with novel patterns of response, which 
contribute to its improvement in OS. 
 
The immune-based mechanism of action is also reflected in the safety profile.  The most 
common drug-related AEs are immune-mediated, consistent with the mechanism of action of the 
drug and generally medically manageable with topical and/or systemic immunosuppressants.  As 
previously discussed, the immune-mediated adverse reactions primarily involve the GI tract, 
skin, liver, endocrine glands, and nervous system. 
The early diagnosis of immune-mediated adverse reactions is important to initiate therapy and 
minimize complications.  Immune-mediated adverse reactions are generally manageable using 
symptomatic or immunosuppressive therapy as recommended through detailed diagnosis and 
management guidelines, as described fully in the current IB.  The management guidelines for 
general immune-mediated adverse reactions and Ipilimumab-related GI toxicities, hepatotoxicity, 
endocrinopathy, and neuropathy are provided in the appendices of the current IB. 
 
2.3 
Other Agent(s) 
 
N/A 
 
2.4 
Rationale 
 
The undisputed etiologic link between HPV and cervical cancer as well as the preclinical data 
suggestive of a central immune-modulated response to HPV makes cervical cancer a logical 
target for investigational drugs with immune modulating properties. Ipilimumab as previously 
described acts via inhibition of CTLA4 which leads to inhibition of self-induced immuno-
suppressive activity thereby augmenting the immune response directed against cancer cell 
presence.  
 
Preclinical data has convincingly demonstrated T-cell induction as a means of inducing local 
immune suppression of HPV-associated disease. Specifically, Tumor-infiltrating regulatory T 
cells (Tregs) seem to play a role in local immune suppression in HPV-associated disease. Tregs 
have been found at higher concentrations in CIN2/3 relative to HPV infection without 
premalignant changes [Jordanova 2008]. A low ratio of CD8+/regulatory T cells is associated 
with poor outcome [Tuve, Chen, Liu et al 2007]. A mouse model for cervical cancer (TC-1 cells) 
was developed and used to investigate the effects of Treg depletion as well as CTLA4 blockade. 
The group found that Treg depletion alone was not sufficient to control tumor growth. They also 

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22 
found that systemic CTLA4 blockade did not results in tumor regression but rather induced 
hepatitis. They subsequently injected CTLA4 antibody locally into tumors and found that this did 
delay the progression of tumors. In addition this local CTLA4 blockade resulted in a reversal of 
the intratumoral Treg/CD8 ratio secondary to an increase in CD8 production. A combination of 
local CTLA4 blockade and Treg inhibition caused permanent tumor regression as a consequence 
of immune response activation [Tuve, Chen, Liu et al 2007]. 
 
In summary, the non-tumor specific nature of the mechanism of action of CTLA4 blockade 
alongside the accumulating evidence suggesting activity in a wide range of tumors supports its 
investigation in the context of cervical cancer. This rationale is further strengthened by the 
significant body of evidence suggesting that HPV related neoplasia would be responsive to 
immunotherapy treatments. We propose assessing the efficacy of Ipilimumab in recurrent and 
metastatic cervical cancer patients, for whom the limited treatment options available afford 
minimal benefit. 
 
2.5 
Correlative Studies Background 
 
Biomarkers for Clinical Studies 
 
Retrospective analysis of advanced melanoma patients treated with Ipilimumab showed that 
increased expression of proliferation and polarization markers in CD4+ and CD8+ cells, 
decreased CCR7 and IL-7R on CD4+ T cells, and upregulated Granzyme B in CD8+ T cells may 
serve as pharmacodynamic indicators of the effects of Ipilimumab (Weber et al., 2011).  
Increased activation markers ICOS and eomesodermin (EOMES) were significantly associated 
with fewer AEs and less favorable outcome, respectively, but baseline elevated expression of 
EOMES appears to predict favorable relapse-free survival in this analysis.   
 
ICOS potentially could be a useful marker for CD4+ T-cell responses generated after CTLA-4 
blockade (Simpson et al., 2010).  Human leukocyte antigen (HLA-DR) expression could also 
potentially serve as a T-cell marker (Small et al., 2007; Zhou et al., 2011).   
 
Retrospective gene expression analysis was performed on 46 primary or metastatic melanoma 
tumors, collected in a phase 2 study in advanced melanoma patients (CA184004) (Ji et al., 
2011).  Ipilimumab treatment was associated with downregulation of a number of melanoma-
associated transcripts in the tumors within 3 weeks after administering the first dose.  Expression 
of immune-related genes such as CD8A, GZMA, LCK, CXCL-9, -10, -11, and CXCR3 in 
tumors at week 3 post-treatment was associated with the total lymphocyte infiltrate, clinical 
benefit, and overall survival.  The preliminary results suggest that high pre-existing immune 
activity favors a clinical response to Ipilimumab therapy.  These analyses also provide a list of 
candidate biomarkers with potential predictive value for response to Ipilimumab. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 

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23 
3.1.1 Patients must have histologically or cytologically confirmed metastatic or recurrent 
cervical cancer of squamous, adenocarcinoma or mixed histology type not suited to 
definitive localized therapy. HPV status will be confirmed for all patients following 
enrollment. 
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as >10 mm with CT scan, MRI, or calipers 
by clinical exam.  See Section 11 for the evaluation of measurable disease.  
 
3.1.3 Previous Therapy: 
 
 
3.1.3.1 Patients may have undergone surgery and/or received definitive radiation or 
chemo-radiation for localized disease in the past. 
 
 
3.1.3.2 Radiation treatment with curative intent (radical chemoradiotherapy or adjuvant 
chemoradiotherapy) must have been completed ≥ 3 months prior to enrollment.  
                    Note: Patients who completed Palliative radiation therapy 2 weeks before start of 
Ipilimumab are allowed as long as this does not affect measurable disease 
            3.1.3.3 Patients must have been exposed to platinum chemotherapy either as part of 
definitive chemo-radiation OR as first line systemic treatment for metastatic disease.   
 
 
3.1.3.4 Patients MAY have received up to two prior lines of systemic chemotherapy for 
metastatic or recurrent disease. Patients with metastatic disease at first presentation 
MUST have received one platinum based line of chemotherapy. 
 
 
 
3.1.3.5 All chemotherapy must have been completed ≥ 4 weeks prior to enrollment with 
radiologic evidence of radiological disease progression. 
 
3.1.4 Age >18 years. Because no dosing or adverse event data are currently available on the 
use of Ipilimumab in patients <18 years of age, children are excluded from this study.  
 
3.1.5 ECOG performance status 0-1. 
 
3.1.6 Life expectancy of greater than 3 months. 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes   
 
 
 
>3.0 x 109/L 
− 
absolute neutrophil count  
>1.5 x 109/L 
− 
platelets    
 
 
 
>100 x 109/L 
− 
total bilirubin  
 
 
 
within normal institutional limits (except in Gilbert’s  
syndrome) 
− 
TSH 
 
 
 
 
 
 
< ULN 
− 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
− 
creatinine  
 
 
 
 
<1.25 ULN 
OR 
− 
creatinine clearance  
 
>50mL/min/1.73 m2 as calculated by the Cockroft and 
Gault formula 
 

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24 
3.1.8 All radiology studies must be performed ≤ 3 weeks prior to the start of therapy 
 
3.1.9 Subjects with treated and asymptomatic brain metastases are eligible. Patients that 
received palliative radiation (for brain metastases) are eligible  if they have been 
asymptomatic for at least 2 weeks with use of maintenance steroid therapy, and last 
received radiation at least 4 weeks prior to start of therapy. 
 
3.1.10 Ability to understand and willing to sign a written informed consent document. 
 
3.1.11 Ongoing prior toxicities related to previous treatments must be recovered to < grade 1 at 
the time of registration (with the exception of alopecia or skin depigmentation). 
 
3.1.12 Patients are willing to undergo tumour biopsy pre-treatment (within 14 days prior to 
registration) and post-treatment (within the first week of cycle 2 onset). Patients who 
consent but have tumour that is not amenable to safe biopsy will be allowed to enter the 
trial / continue therapy as per protocol if this has been addressed and permission is 
granted from the lead consortium PI prior to registration continuation of treatment. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy < 4 weeks prior to enrollment (<6 weeks for 
nitrosoureas or mitomycin C) or who had radiation therapy with curative intent < 
3months prior to enrollment (< 2 weeks for palliative radiation therapy) or those who 
have not recovered (< grade 1) from adverse events related to previous treatments are 
excluded. 
 
3.2.2 Patients with a history of prior treatment with Ipilimumab or other CTLA4 agonists or 
antagonists, anti-PD 1 antibody, CD137 agonist or other immune activating therapy such 
as anti-CD 40 antibody are excluded. 
 
3.2.3 Patients who are receiving any other investigational agents. 
 
3.2.4 Autoimmune disease: Patients with a history of inflammatory bowel disease, including 
ulcerative colitis and Crohn’s Disease, are excluded from this study, as are patients with a 
history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis 
[scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s 
Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g. 
Guillain-Barre Syndrome and Myasthenia Gravis, multiple sclerosis.). 
 
3.2.5 Patients requiring immunosuppressive agents, unless required for treating potential 
immune related adverse effects. Steroids at their lowest effective dose in patients with 
radiated brain metastases is permitted. 
 
3.2.6 Patients with known immune impairment who may be unable to respond to anti-CTLA 4 
antibody. 
 

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25 
3.2.7 Any other prior malignancy from which the patient has been disease free for less than 3 
years, with the exception of adequately treated and cured basal or squamous cell skin 
cancer, superficial bladder cancer, carcinoma in situ of any site or any other cancer. 
 
3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Ipilimumab. 
 
3.2.9 Excluded Medication 
3.2.9.1 Patients requiring systemic steroids are excluded, as these drugs may interfere 
with the activity of Ipilimumab if administered at the time of the first Ipilimumab dose.  
3.2.9.2 Narcotics should be used with caution as they may mask the signs and symptoms 
of serious gastrointestinal irAEs including intestinal perforation. 
 
3.2.10 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
 
 
Patients with chronic Hepatitis B or hepatitis C infections should be excluded because of 
potential effects on immune function and/ or drug interactions. 
 
3.2.11 Pregnant women are excluded from this study because Ipilimumab is an agent with the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with Ipilimumab, breastfeeding should be discontinued if the mother is treated with 
Ipilimumab. 
 
3.2.12 Patients with active or chronic infection with HIV who have raised viral loads or 
uncontrolled disease are ineligible because of the potential for anticipated and unknown 
adverse immune related effects secondary to treatment with Ipilimumab. Those patients 
however who exhibit minimal viral loads with good control whilst on stable anti-viral 
regimen may be considered if they meet all other eligibility criteria. 
 
3.3 
Pregnancy 
 
The effects of Ipilimumab on the developing human fetus are unknown. Due to potential 
teratogenic effects, women of child-bearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration 
of study participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician immediately.   
 
3.4 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial.  This study is designed to include 
minorities as appropriate. However, the trial is not designed to measure differences in 
intervention effects. The population of Southern Ontario is ethnically diverse. The proportion of 
different ethnic groups in the community is provided in the table below. Universal access to 

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26 
health care will ensure that there is no discrimination on the basis of race or gender (Guide to 
Canadian Human Rights Act: www.chrc-ccdp.ca/public/guidechra.pdf). Individual hospital 
registries and databases do not routinely collect racial data, under the direction of the Canadian 
Human Rights Code. 
 
The population demographics and distribution of minorities in Southern Ontario is included in 
the following table: 
 
Table: Visible minority population by Consortium Provinces  (2001 Census)  
 
British Columbia Alberta 
Ontario 
Nova Scotia 
Total 
Total population of province 
3,868,870 
2,941,150 
11,285,550 
897,570 
18,993,140 
Visible Minorities 
Population % 
Population % 
Population % 
Population % 
Population % 
Black 
25,465 
1% 31,390 
1% 411,095 
4% 19,670 
2% 487,620 
3% 
Asian 
768,435 
20% 268,660 
9% 1,513,825 13% 12,630 
1% 2,563,550 13% 
Latin American (Hispanic) 
23,880 
1% 18,745 
1% 106,835 
1% 520 
0% 149,980 
1% 
Visible minority, not included 
elsewhere 
4,195 
0% 4,220 
0% 78,915 
1% 1,170 
0% 88,500 
0% 
Multiple visible minority 
14,465 
0% 6,910 
0% 42,375 
0% 535 
0% 64,285 
0% 
Total Visible minority 
population 
836,440 
22% 329,925 
11% 2,153,045 19% 34,525 
4% 3,353,936 18% 
Source: Statistics Canada, Census of Population.  
 
Data (2004) from our consortium has been compiled regarding the representation of 
minorities on previous clinical trials, and the distribution is as follows: 
 
Population Percentage of Minority and 
Gender of entering PMHC Trials 
 
2002 
2003 
2004 
Visible Minorities 
 
 
 
Black 
3.6 
0 
2.8 
Asian 
7.2 
9.0 
8.4 
Hispanic 
2.4 
3.0 
1.7 
Total  
13.2 
12 
12.9 
Women 
44.6 
49.3 
46.9 
 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
4 
0 
4 
Not Hispanic or Latino 
40 
0 
40 
Ethnic Category: Total of all subjects 
44 
0 
44 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 

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27 
Asian 
5 
0 
5 
Black or African American 
4 
0 
4 
Native Hawaiian or other Pacific Islander 
1 
0 
1 
White 
34 
0 
34 
Racial Category: Total of all subjects 
44 
0 
44 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
The Study Coordinator at the Princess Margaret Hospital Consortium Central Office will enter 
eligible patients on study centrally.  All sites should call the Study Coordinator (listed on cover 
page) to verify dose level availabilities.  The required forms (Eligibility Checklist) will be 
provided upon site activation. 
 
Following registration, patients should begin protocol treatment within 72 hours.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator (cc the central 
office study coordinator).  If a patient does not receive protocol therapy following registration, 
the patient’s registration on the study may be cancelled.  The Study Coordinator should be 
notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  A participating site may order agents only after the initial IRB 
approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
4.2 
Registration Process 
 
Prior to registering a patient, each institution must have submitted all necessary regulatory 
documentation to the PMH Phase II Consortium Central Office.  The eligibility CRF will only be 
sent once this has been received.   
 
No patient can receive protocol treatment until registration with the Central Office has taken 
place.  All eligibility criteria must be met at the time of registration.  There will be no exceptions.  
Any questions should be addressed with the Central Office prior to registration.   
 
To register a patient, the following documents are to be completed by the research nurse or data 
manager and sent / faxed to the Central Office Study Coordinator: 
• 
Signed patient consent form 
• 
Eligibility Checklist CRF signed by the investigator  
 
To complete the registration process, central office will review the checklist and once eligibility 
has been confirmed: 
• 
Assign a patient study number 
• 
Assign the patient a dose 
• 
Register the patient on the study 

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28 
• 
Fax or e-mail the confirmation worksheet with the patient study number and dose to the 
participating site 
 
To ensure immediate attention is given to the faxed checklist, each site is advised to also call the 
study coordinator listed on the front sheet. Patient registration will be accepted between the 
hours of 9am to 5pm Monday to Friday, excluding Canadian statutory holidays when the central 
office will be closed. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
• All patients will receive single agent Ipilimumab administered as an intravenous infusion 
over 90 minutes.  One cycle is 21 days for the phase I and II. 
 
• Phase I Run In (safety phase):   
o An initial cohort of 6 patients will receive four doses of Ipilimumab administered at a 
dose of 3mg/kg once every 21 days.  
o Patients in this cohort will be monitored for 12 weeks from treatment onset.  Should 3 
or more of the initial 6 patients suffer one of the following SAE considered to be 
dose-limiting, the phase I cohort will be expanded to include an additional 6 patients, 
12 in total:  
▪ 1. Patients experiencing unexpected non-autoimmune related grade 3 adverse 
effects.  
▪ 2. Patients experiencing grade 4 adverse effects.  
▪ 3. Patients experiencing autoimmune related adverse effects which do not respond 
to steroid treatment and do not resolve to a grade 1 level within a 4 week 
period of initiation of steroid treatment. If an expanded phase I is required 
monitoring of SAE’s will continue without modification for the expanded 
cohort.  
o  If more than 4 individuals demonstrate SAE’s considered to be dose limiting as per 
the afore-mentioned criteria, the trial will be halted and not proceed to the second 
stage.  
o  All patients from the first phase of the study who are eligible to proceed to the 
maintenance phase of treatment will continue to receive Ipilimumab at a dose of 
3mg/kg and will not escalate to a dose of 10mg/kg. They will be evaluated and 
monitored in a similar way to patients in phase II of the study. 
• Phase II: 
o  An additional 18 evaluable patients will be enrolled and will receive four cycles of 
Ipilimumab administered at a dose of 10mg/kg once every three weeks.  

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29 
o  A safety assessment will be conducted after 12 patients have been treated. If >4 have 
DLT by same definition as Phase I run in, the study will be put on hold and 
discussed with CTEP.  
o  If one patient has an objective response by week 24, the trial will continue to the 
second stage and an additional 14 evaluable patients will be enrolled. 
 
• Tumor assessment will be done at week 12 (+/- 1 week), at week 18 and 24. Patients 
demonstrating clinical or radiological progression of disease or toxicity prohibiting 
ongoing participation of study will be taken off study. Patients showing evidence of an 
objective response or stabilization of disease subsequent to treatment will continue on 
study unless they become ineligible for alternative reasons. Modified RECIST 1.1 criteria 
may be used at week 12 and beyond to determine on going eligibility. This will allow 
patients with modest progression of disease (≤ 30% uni-dimensional growth in 
measurable lesions, development of no more than two new lesions) but stable clinical 
condition with no alteration in ECOG to continue to participate at the investigators 
discretion. 
 
• Maintenance Phase:   
o One cycle is 12 weeks. 
o Eligibility for this treatment will be assessed at 24 weeks (-1 week). Should the 
patient’s performance status remain at the required level (ECOG 0-1) and radiologic 
assessment of disease continue to confirm response or stabilization of disease 
secondary to treatment, patients may enter the maintenance phase of treatment.  
o Ipilimumab will be administered at 10mg/kg (or 3mg/kg for the phase I cohort) once 
every 12 weeks for four additional treatments. Response to treatment will be 
evaluated once every 12 weeks and formal RECIST 1.1 criteria alone will be used to 
determine on-going participation on study during the maintenance phase of the trial.  
 
5.1.1 Ipilimumab 
 
• Ipilimumab is an intravenous treatment which may be given at any time of day. No 
particular instruction is required with regard to the ingestion of food prior or during 
treatment. 
• All patients will receive 650mg of oral acetaminophen for the prevention of fever, prior 
to receiving Ipilimumab. If the patient has an allergy or intolerance to acetaminophen, the 
patient can take ibuprofen 400mg prior to receiving ipilimumab. In case of allergy to 
both, acetanminophen and ibuprofen, the case should be discussed with the sponsor. 
• Ipilimumab will then be administered intravenously over 90 minutes. 
In the event that a patient develops rigors or chills during or following administration of 
Ipilimumab, intravenous Meperidine HCl at a dose of 25mg is recommended. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 Concomitant Medications 
 
• There are no known interactions between Ipilimumab and the cytochrome P450 system 

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30 
• The chronic use of systemic steroids for other comorbidities should be avoided, or the 
subject should be on the lowest clinically effective dose, as these drugs may interfere 
with the activity of Ipilimumab if administered at the time of the first Ipilimumab dose. 
Patients with a suspected immune adverse event are allowed to receive oral 
corticosteroids according to the toxicity management guidelines. 
• Opioid medications should be used with caution as these may mask the signs and 
symptoms of serious gastrointestinal immune related adverse effects including intestinal 
perforation. 
 
5.2.2 Supportive Care Guidelines  (refer to appendix C) 
 
• Rash. Patients experiencing rash following treatment with Ipilimumab will be advised to 
administer hydrocortisone cream 1% twice daily in addition to moisturizing lotion as 
needed until resolution of symptoms. Should symptoms not resolve, oral corticosteroid 
treatment will be initiated.  
• Diarrhea. This is a common side effect which if left undetected and untreated may 
become potentially serious. Patients will be educated as to the importance of monitoring 
bowel movements and informing trial staff of early signs of diarrhea. At the first sign of 
diarrhea patients are advised to take 4mg of Loperamide HCl followed by an additional 
2mg once every four hours OR after each loose stool, whichever occurs first, to a 
maximum daily dose of 16mg. This treatment should continue until the patient is free 
from symptoms of diarrhea for at least 12 hours.  Should diarrhea remain unresolved and 
only after consultation with treating physician, Budesonide SR may be recommended. 
Patients will receive 9mg daily of budesonide for an initial period of two weeks. Patients 
will then be advised to reduce the daily dose of budesonide to 6mg for an additional two 
weeks and subsequently 3mg for a final two weeks before discontinuing this medication.  
 
5.3 
Duration of Therapy  
 
Treatment may continue for 4 cycles followed by four maintenance phase treatment 
cycles or until one of the following criteria applies at which point the patient is to be 
discontinued from study therapy and withdrawn from study: 
 
• 
The development of PD by RECIST criteria with modifications to allow continued 
treatment as outlined: 
• 
possibility for investigator discretion at week 12 and beyond for patients 
demonstrating radiologic PD but otherwise stable clinical condition (see section 5.6) 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s) (discretion of the physician) or an adverse event that 
results in the permanent stopping of study drug defined in section 6.  
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition (clinical adverse event, laboratory 
abnormality or intercurrent illness) which renders the patient unacceptable for further 
treatment in the judgment of the investigator. 
• 
Clinical progression 
• 
Pregnancy: 

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31 
• 
All women of child bearing potential (WOCBP) should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. Institutional policy and local 
regulations should determine the frequency of on study pregnancy tests for WOCBP 
enrolled in the study. 
• 
The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor. 
 
5.4 
Duration of Follow Up 
 
Patients who discontinue treatment for any reason other than PD with evidence of SD, PR or CR 
will be followed for 1 year on a 3 monthly basis, until progression of disease or death, whichever 
occurs first. Subsequent therapy to Ipilimumab data will be collected for these patients for the 
duration of 1 year. 
 
Patients removed from study due to PD will be seen only once at 1 month after withdrawn from 
treatment.  
 
Any patient experiencing an adverse event will be given medical treatment as appropriate and 
followed monthly until resolution to a < grade 1 or until the adverse event remains stable at the 
same grade for at least 2 months and then every 3 months until progression of disease or death, 
whichever occurs first.  
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies. The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
Ipilimumab is expected to trigger immune-mediated responses, which require activation of the 
immune system prior to the observation of clinical responses.  Such immune activation may take 
weeks to months to be evident.  Some patients may have objective volume increase of tumor 
lesions or other disease parameters (based on study indication, i.e., hematologic malignancies) 
within (specific 12-24) weeks following the start of Ipilimumab dosing.  Such patients may not 
have had sufficient time to develop the required immune activation or, in some patients, tumor 
volume or other disease parameter increases may represent infiltration of lymphocytes into the 
original tumor or blood.  In conventional studies, such tumor volume or relevant laboratory 
parameter increases during the first 12 weeks of the study would constitute PD and lead to 
discontinuation of imaging to detect response, thus disregarding the potential for subsequent 
immune-mediated clinical response.  
 
Therefore, patients with tumor progression by RECIST imaging (≤ 30% uni-dimensional growth 
in measurable lesions, development of no more than two new lesions) or laboratory parameters at 
week12 and beyond without rapid clinical deterioration or change in ECOG who do not require 

NCI 9209 / PHL-085 
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32 
additional immediate therapy (are in stable condition), may continue to be treated with 
Ipilimumab. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and off treatment criteria for Ipilimumab associated immune/inflammatory events 
are provided below. 
 
No dose modifications are indicated as part of this protocol. Adverse effects as specified will 
warrant withholding of treatment dose until resolution as specified within the protocol. 
 
6.1 
Ipilimumab Administration Rule 
 
Decisions to administer an Ipilimumab dose must be made on specified safety criteria.  
Treatment with Ipilimumab will be discontinued if the subject experiences at least one adverse 
event, specified below, considered by the investigator to be “possibly,” probably,” or “definitely” 
related to Ipilimumab treatment.  
 
Each site should specify a procedure for reviewing all AEs that require holding drug treatment 
and or a regularly scheduled conference call with the PI and co-investigators.  
 
The investigator should contact the study PI to discuss any questions.  
 
 
It is necessary to avoid study drug dosing and initiate appropriate evaluation and/or treatment for 
the following adverse events: 
• 
Any ≥ grade 3 skin related adverse event regardless of causality. 
• 
Any ≥ grade 2 non-skin related adverse event (including immune-mediated adverse 
reactions), except for easily correctly laboratory abnormalities that do not reflect underlying 
organ pathology. 
• 
Any ≥ grade 3 laboratory abnormality. 
• 
Any adverse event, laboratory abnormality or intercurrent illness that, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued dosing. 
• 
It may be necessary to hold study drug to evaluate Grade 1 events that suggest ongoing or 
incipient autoimmune disease including GI toxicity, diarrhea, pancreatitis, hepatitis, 
pituitary insufficiency, early evidence of neurologic events, skin toxicity until it is first 
clinically safe to continue, in discussion with central office.  
 
➢ For the induction phase 
Ipilimumab may be restarted if/when the adverse event(s) resolve(s) to ≤ grade 1 or returns to 
baseline within 2 weeks of previous dose administration: 

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33 
 
If the adverse event has been determined not to be related to Ipilimumab or is not an 
autoimmune/inflammatory event: 
Plan to administer the total number of planned doses. If > 2-week delay is expected, the 
dosing schedule modifications must be discussed with the principal investigator prior to 
implementation.  
 
If the adverse event has been determined to be related to Ipilimumab or is an 
autoimmune/inflammatory event: 
• 
If the adverse event has resolved to ≤ grade 1, Ipilimumab dosing may be restarted at the 
next scheduled time point per protocol (±3 days).  Please follow guidelines for specific 
events. Please note that re-initiating treatment may be associated with recurrence or 
exacerbation of autoimmune or inflammatory events.  In some instances, clinical resolution 
of events such as colitis may be associated with residual pathologic changes and should 
require evaluation of complete resolution prior to restarting therapy.  
• 
If the adverse event has not resolved ≤ grade 1, the next scheduled dose will be delayed until 
resolution to grade ≤ 1. Please note that re-initiating treatment may be associated with 
recurrence or exacerbation of autoimmune or inflammatory events.   
• 
Events which require intervention with immunosuppressant therapy, steroids, surgery, or 
hormone replacement generally require permanently stopping study treatment.  Consult 
guidelines for exceptions and specific events.   
• 
Autoimmune/inflammatory events are presumably related to the mechanisms of action of 
Ipilimumab and potentially to a therapeutic effect.  The incidence and severity of these 
events may be dose related, but once initiated, there is no evidence that lowered doses can 
be administered without continued autoimmune activity and there has so far been no 
demonstrable benefit to continuing Ipilimumab after an autoimmune event during the initial 
treatment.  The significance and benefit of toxicity or continued treatment in the 
maintenance phase has not been determined.  Typically no dose modification is used for 
Ipilimumab. 
 
➢ For the maintenance phase 
Ipilimumab may be restarted if/when the adverse event(s) resolve(s) ≤ grade 1 or returns to 
baseline within 4 weeks of previous dose administration: 
 
 
If the adverse event has been determined not to be related to Ipilimumab or is not an 
autoimmune/inflammatory event: 
Plan to administer the total number of planned doses. If > 4 week delay is expected due to 
current events, the dosing schedule modifications must be discussed with the principal 
investigator prior to implementation.  
 
 
 
If the adverse event has been determined to be related to Ipilimumab or is an 
autoimmune/inflammatory event: 
• 
If the adverse event has resolved to ≤ grade 1, Ipilimumab dosing may be restarted at 
the next scheduled time point per protocol (±3 days).  Please follow guidelines for specific 
events. Please note that re-initiating treatment may be associated with recurrence or exacerbation 
of autoimmune or inflammatory events.  In some instances clinical resolution of events such as 
colitis may be associated with residual pathologic changes and should require evaluation of 

NCI 9209 / PHL-085 
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34 
complete resolution prior to restarting therapy.  
• 
If the adverse event has not resolved to ≤ grade 1, the next scheduled dose will be 
delayed until resolution to grade ≤ 1. 
• 
Events which require intervention with immunosuppressant therapy, steroids, surgery, 
or hormone replacement generally require permanently stopping study treatment.  Consult 
guidelines for exceptions and specific events.   
• 
Autoimmune/inflammatory events are presumably related to the mechanisms of 
action of Ipilimumab and potentially to a therapeutic effect.  The incidence and severity of these 
events may be dose related, but once initiated, there is no evidence that lowered doses can be 
administered without continued autoimmune activity and there has so far been no demonstrable 
benefit to continuing Ipilimumab after an autoimmune event during the initial treatment.  The 
significance and benefit of toxicity or continued treatment in the maintenance phase has not been 
determined.  Typically no dose modification is used for Ipilimumab. 
 
6.2 
Discontinuation of Study Therapy 
 
Subjects MUST be discontinued from study therapy AND withdrawn from the study for the 
reasons outlined in section 5.3. 
 
6.2.1 Permanent Discontinuation for Related Adverse Events 
 
Permanently discontinue Ipilimumab for any of the following: 
• 
Persistent adverse reactions that require holding more than 2 treatment doses.  
• 
Any grade 3 or higher non-dermatologic autoimmune breakthrough event considered to be 
secondary to treatment with Ipilimumab 
• 
Any event that requires immunosuppressive treatment or systemic steroids  
*Exception: Short term oral steroids to treat potentially reversible Grade 2 diarrhea and 
skin toxicities as per algorithm in appendix C 
• 
Severe or life-threatening adverse reactions, including any of the following: 
• Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency 
(7 or more over baseline), stool incontinence, need for IV hydration for more than 24 
hours, gastrointestinal hemorrhage, and gastrointestinal perforation 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper 
limit of normal or total bilirubin >3 times the upper limit of normal 
• Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full 
thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations 
• Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis 
• Severe immune-mediated reactions involving any organ system (e.g., nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis) 
• Immune-mediated ocular disease that is unresponsive to topical immunosuppressive 
therapy 
• Any adverse event, laboratory abnormality or intercurrent illness which, in the judgment 
of the investigator, presents organ specific injury and/or a substantial clinical risk to the 
patient with continued dosing.  
 

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35 
The following neurological adverse event requires permanent discontinuation of 
Ipilimumab and defines unacceptable neurotoxicity: 
• Any motor neurologic toxicity > grade 3 regardless of causality 
• Any > grade 3 treatment related sensory neurologic toxicity 
 
Please refer to Appendix C and the IB for specific treatment algorithms. 
 
6.2.2 Exceptions to Permanent Discontinuation 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 or to monitor clinical condition felt to be warranted 
due to minimal experience with Ipilimumab treatment. 
• Patients with the following conditions where in the investigator’s opinion continuing 
study drug administration is justified based on the potential for continued clinical benefit:  
• 
Patients treated with systemic steroids for less than 2 weeks without evidence of 
autoimmune disease requiring steroids treatment  
• 
Grade 2 skin rash treated with topical steroids for less than 4 weeks  
• 
Grade 2 Ocular toxicity that has completely responded to topical therapy .within 4 
weeks 
• 
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.  
 
6.2.3 Immune-Related Adverse Events (irAEs)Reactions and Immune-mediated Adverse 
Reactions: Definition, Monitoring, and Treatment  
 
For the purposes of this study, an immune-related adverse reaction is defined as an adverse 
reaction of unknown etiology associated with drug exposure and consistent with an immune 
phenomenon. Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other 
etiologic causes prior to labeling an event an irAEs.  Serologic, immunologic, and histologic 
(biopsy) data should be used to support the diagnosis of an immune-related toxicity. Suspected 
immune-related adverse reactions must be documented on an AE or SAE form. Another term for 
an irAE is an immune-mediate adverse reaction, as it is termed in the Ipilimumab US Prescribing 
Information. Both terms may be used in this protocol document.  
 
Patients should be informed of and carefully monitored for evidence of clinically significant 
systemic immune-mediated adverse reactions (e.g., systemic lupus erythematosus-like diseases) 
or organ-specific immune-mediated adverse reaction (e.g., rash, colitis, uveitis, hepatitis or 
thyroid disease). If an immune-mediated adverse reaction is noted, appropriate work-up 
(including biopsy if possible) should be performed, and steroid therapy may be considered if 
clinically necessary.   

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36 
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. 
 
Recommended guidelines for specific immune-mediated adverse reactions are included in 
section 6.2.4 below, in Appendix C, and the package insert.  These recommendations should be 
utilized as clinically appropriate for the treatment of individual patients.  Please contact the PI or 
drug monitor for any questions. 
 
6.2.4 Other Guidance 
 
The following guidance is provided for the management of Ipilimumab treatment related events.  
These recommendations, treatment algorithms in Appendix C, and further information in the IB, 
should be considered in the context of appropriate medical treatment for each patient.  Patients 
removed from study due to Ipilimumab related adverse events will receive medical treatment as 
appropriate to manage Ipilimumab related adverse effects until their resolution. 
 
6.2.4.1 
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 
except acetaminophen should be given unless indicated by previous experience in an individual 
patient. Reactions should be treated based upon the following recommendations.  
 
• For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, 
flushing, rash): 
• Decrease the rate of infusion until recovery from symptoms, remain at bedside 
and monitor patient. 
• Complete the Ipilimumab infusion at the initial planned rate. 
• Diphenhydramine 50 mg IV may be administered at the discretion of the treating 
physician and patients may receive additional doses with close monitoring. 
• 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. 

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37 
• 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 additional pre-medication (diphenhydramine) 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). 
 
6.2.4.2 
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 with continue and / or the 
addition of a 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. 
 
6.2.4.3 
Monitoring and Management of Immune-mediated Adverse Reactions 
 
Immune-mediated Enterocolitis 
The clinical presentation of GI immune-related AEs included diarrhea, increase in the frequency 
of bowel movements, abdominal pain, or hematochezia, with or without fever. However 
inflammation may occur in any part of the GI tract including esophagitis and gastritis.  Fatalities 
due to GI perforation have been reported in clinical trials of Ipilimumab. Patients should be 
carefully monitored for GI symptoms that may be indicative of immune-related colitis, diarrhea, 
or GI perforation.  Diarrhea or colitis occurring after initiation of Ipilimumab therapy should be 

NCI 9209 / PHL-085 
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38 
evaluated to exclude infectious or alternate etiologies. In clinical trials, immune-related colitis 
was associated with evidence of mucosal inflammation, with or without ulcerations, and 
lymphocytic infiltration. 
 
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, 
mucus or blood in stool, with or without fever) and bowel perforation (such as peritoneal signs 
and ileus).  In symptomatic patients, rule out infectious etiologies and consider endoscopic 
evaluation to establish etiology and for persistent or severe symptoms.  C.difficile toxin has been 
detected in several patients with colitis and may be an independent entity or may co-exist with 
Ipilimumab induced inflammatory colitis.   
 
Withhold Ipilimumab dosing for any patient with enterocolitis pending evaluation; administer 
anti-diarrheal treatment and, if persistent evaluate with colonoscopy and initiate systemic 
corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. 
 
Permanently discontinue Ipilimumab in patients with severe enterocolitis and initiate systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to 
grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In 
clinical trials, rapid corticosteroid tapering has resulted in recurrence or worsening symptoms of 
enterocolitis in some patients.  
 
Patients have been treated with anti-TNF agents for persistent colitis not responding to steroids.  
Please note autoimmune pancreatitis may cause abdominal pain and should be included in all 
evaluations. Enteritis may occur occasionally with other autoimmune events including hepatitis, 
pancreatitis, and endocrine insufficiency, which should be evaluated as clinically indicated.  
 
Immune-mediated Hepatitis and Pancreatitis  
Hepatic immune-related AEs were mostly clinically silent and manifested as transaminase or 
bilirubin laboratory abnormalities. Fatal hepatic failure has been reported in clinical trials of 
Ipilimumab.  Serum transaminase and bilirubin and lipase levels must be evaluated before each 
dose of Ipilimumab as early laboratory changes may be indicative of emerging immune-related 
hepatitis/ pancreatitis and elevations in liver function tests (LFTs) may develop in the absence of 
clinical symptoms. Increase in LFT or total bilirubin should be evaluated to exclude other causes 
of hepatic injury, including infections, disease progression, or other medications, and monitored 
until resolution.  Liver biopsies from patients who had immune-related hepatotoxicity showed 
evidence of acute inflammation (neutrophils, lymphocytes, and macrophages). 
 
Monitor liver function tests (hepatic transaminase and bilirubin levels, lipase) and assess patients 
for signs and symptoms of hepatotoxicity/ pancreatitis before each dose of Ipilimumab.  In 
patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of 
liver function test monitoring until resolution.  Withhold Ipilimumab in patients with grade 2 
hepatotoxicity.  
 
Permanently discontinue Ipilimumab in patients with grade 3–5 hepatotoxicity/pancreatitis and 
administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  
When liver function tests show sustained improvement or return to baseline, initiate 

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39 
corticosteroid tapering and continue to taper over 1 month. Across the clinical development 
program for Ipilimumab, mycophenolate treatment has been administered in patients who have 
persistent severe hepatitis despite high-dose corticosteroids.  
 
Immune-mediated Dermatitis 
Skin immune-related AEs presented mostly frequently as a rash and/or pruritus.  Some subjects 
reported vitiligo associated with Ipilimumab administration.  Fatal toxic epidermal necrolysis has 
been reported in clinical trials of Ipilimumab.  
 
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus.  Unless an 
alternate etiology has been identified, signs or symptoms of dermatitis should be considered 
immune-mediated.   
 
Permanently discontinue Ipilimumab in patients with Stevens-Johnson syndrome, toxic 
epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, 
bullous, or hemorrhagic manifestations.  Administer systemic corticosteroids at a dose of 1 to 2 
mg/kg/day of prednisone or equivalent.  When dermatitis is controlled, corticosteroid tapering 
should occur over a period of at least 1 month.  Withhold Ipilimumab dosing in patients with 
moderate to severe signs and symptoms.  
 
For mild to moderate dermatitis, such as grade 1 or 2 pruritus, treat symptomatically. For grade 1 
or 2 rash treat with topical corticosteroids (such as hydrocortisone or betamethasone). For 
persistent grade 2 (more than 7 days, despite treatment with topical steroids) or grade 3 or 
greater, oral steroids may be administered. 
 
Immune-related Neurological Events  
Fatal Guillain-Barré syndrome has been reported in clinical trials of Ipilimumab. Patients may 
present with muscle weakness and myasthenia gravis, cranial nerve palsy (n VII Bells palsy), and 
aseptic meninigits, encephalopathy.  Unexplained motor neuropathy, muscle weakness, or 
sensory neuropathy lasting more than 4 days should be evaluated and non-inflammatory causes 
such as disease progression, infections, metabolic syndromes, nerve entrapment, and medications 
should be excluded as causes.  
 
Withhold Ipilimumab dosing in patients with any evidence of neuropathy pending evaluation.   
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, 
sensory alterations, or paresthesia. Permanently discontinue Ipilimumab in patients with severe 
neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes.  Institute 
medical intervention as appropriate for management of neuropathy and other neurologic events.  
Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent for severe neuropathies.  
 
Immune-mediated Endocrinopathies 
Ipilimumab can cause inflammation of endocrine organs including thyroid (Hashimoto’s 
thryroiditis with positive antibodies) and adrenal glands, hypophysitis, hypopituitarism, and 
resulting thyroid and adrenal insufficiency, low ADH, prolactin, FSH, LH. Hyperthyroid with 
Graves’ disease and positive antibody has been reported. Patients may present with subtle and 

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40 
nonspecific symptoms.  The most common clinical presentation includes headache and fatigue.  
Symptoms may also include visual field defects, behavioral changes, and electrolyte disturbances 
including hyponatremia and hypotension.  Adrenal crisis as a cause of the patient’s symptoms 
should be excluded.  Based on the available data with known outcome, most of the subjects 
symptomatically improved with hormone replacement therapy.  Long-term hormone replacement 
therapy with HC and synthroid will typically be required for subjects developing 
hypophysitis/hypopituitarism after treatment with Ipilimumab.  Some patients have regained 
partial function following steroid treatment.  
 
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency 
(including adrenal crisis), and hyper or hypothyroidism.  Headache is often the first symptoms of 
hypophysitis.  Patients may present with fatigue, headache, mental status changes, loss of libido, 
abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may 
resemble other causes such as brain metastasis or underlying disease.  Unless an alternate 
etiology has been identified, signs or symptoms of endocrinopathies should be considered 
immune-mediated and drug withheld pending evaluation.  Patients may demonstrate both central 
(hypophysitis) and peripheral adrenal and thyroid insufficiency.  Evaluation of hypophysitis 
should include pituitary MRI.  
 
Monitor thyroid function tests and clinical chemistries at the start of treatment and hold blood for 
possible evaluation should clinical events require determining baseline function and anti-thyroid 
antibodies.  A plan for evaluating endocrine function at each visit either by history or monitoring 
TSH should be included in the protocol with further evaluation as clinically indicated. In a 
limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement 
of the pituitary gland.  Withhold Ipilimumab dosing in symptomatic patients. Initiate systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate 
hormone replacement therapy.  
 
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations  
Ocular inflammation, manifested as grade 2 or grade 3 episcleritis or uveitis, was associated with 
concomitant diarrhea in a few subjects (<1%) and occasionally occurred in the absence of 
clinically apparent GI symptoms.  Other presumed immune-related AEs reported include, but 
were not limited to, arthritis/arthralgias, pneumonitis, pancreatitis, autoimmune (aseptic) 
meningitis, autoimmune nephritis, pure red cell aplasia, noninfective myocarditis, polymyositis, 
and myasthenia gravis, of which were individually reported for <1% of subjects.  
 
The following clinically significant immune-mediated adverse reactions were seen in less than 
1% of Ipilimumab-treated patients in Study 1: nephritis, pneumonitis, pulmonary granuloma 
resembling sarcoidosis, meningitis, pericarditis, uveitis, iritis, ITP, neutropenia and hemolytic 
anemia. 
 
Across the clinical development program for Ipilimumab, the following likely immune-mediated 
adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, 
temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, 
scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and 
autoimmune thyroiditis.   

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41 
Permanently discontinue Ipilimumab for clinically significant or severe immune-mediated 
adverse reactions.  Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent for severe immune-mediated adverse reactions. 
 
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis.  
Permanently discontinue Ipilimumab for immune-mediated ocular disease that is unresponsive to 
local immunosuppressive therapy. 
 
Overall, immune-related AEs commonly started within 3 to 10 weeks from first dose, were 
successfully managed in most instances by omitting doses, discontinuing dosing, and/or through 
administering symptomatic or immunosuppressive therapy, including corticosteroids, as 
mentioned above and detailed in Section 7.  Immune-related AEs generally resolved within days 
to weeks in the majority of subjects. 
 
6.2.4.4 
Prohibited and Restricted Therapies 
 
Patients may not receive standard non-oncology vaccines for the prevention of infectious 
diseases for up to 4 weeks before or 4 weeks after any dose of Ipilimumab with the exceptions of 
amantadine and flumadine. 
 
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 CTLA-4 inhibitors or agonists 
• 
CD137 or other immunologic activation agonists 
• 
Immunosuppressive agents 
• 
Chronic systemic corticosteroids 
 
6.2.4.5 
Precautions 
 
Combination therapy may result in unexpected toxicity especially in novel combinations with 
other immune modifying agents.  A striking example in macaques is presented in Vaccari, et al. 
2012. 
 
Please note that while unproven, there is a suggestion that autoimmune events, including 
hepatitis, may occur more frequently at sites of metastases or prior injury.  
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.  The management 
guidelines for general inflammatory AEs and Ipilimumab-related GI toxicities, hepatotoxicity, 
endocrinopathy, and neuropathy (Investigator Brochure, 2011) are provided in Appendix C. 
 

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42 
Patients who have received Ipilimumab may potentially develop autoimmune disease with 
subsequent therapy including the appearance of colitis, hypophysitis or adrenal insufficiency. 
 
6.2.4.6 
Study Procedures by Visit and Treatment Cycle 
 
Note that results of all safety laboratory tests (that is, all chemistry and all hematology results) 
must be obtained and reviewed before Ipilimumab administration, as applicable before 
administration of Ipilimumab. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting.     
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
7.1.1 CAEPRs for CTEP IND Agent 
 
7.1.1.1 
CAEPR for Ipilimumab  
 
Below is the CAEPR for Ipilimumab (MDX-010).  Frequency is provided based on 2678 
patients. 
 
 
Version 2.6, July 8, 20141 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 4.0 Term) 
[n= 2678] 
 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 

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43 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
 
Blood and lymphatic system 
disorders - Other (acquired 
hemophilia) 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Myocarditis2 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(hypopituitarism/hypophysitis)2 
 
  
 
Endocrine disorders - Other 
(testosterone deficiency)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
Eye disorders - Other (episcleritis)2 
 
  
 
Uveitis2 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
 Colitis (Gr 3) 
 
 
Colonic perforation3 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Enterocolitis 
 
  
 
Esophagitis 
 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis2 
 
  
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Infusion related reaction 
 
  
 
 
Multi-organ failure 
  
HEPATOBILIARY DISORDERS 
 
 
 
Hepatobiliary disorders – Other 
(hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder2 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infections and infestations - Other 
(aseptic meningitis)2 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased 
 
  
 
Aspartate aminotransferase increased  
  
 
Neutrophil count decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  

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44 
 
 Adverse Events with Possible  
 Relationship to Ipilimumab (MDX-010) 
 (CTCAE 4.0 Term) 
[n= 2678] 
 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Hyperglycemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Arthritis 
 
  
 
Musculoskeletal and connective tissue 
disorder -  Other (polymyositis)2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Facial nerve disorder 
 
  
 
Headache 
 
  
 
Nervous system disorders - Other   
(Guillain-Barre syndrome)2 
 
  
 
Nervous system disorders - Other 
(myasthenia gravis)2 
 
  
 
Trigeminal nerve disorder 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - Other 
(granulomatous tubulointerstitial 
nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular  
 
 Rash maculo-papular (Gr 3)  
 
Skin and subcutaneous disorders – 
Other (Sweet’s Syndrome) 
 
  
 
 
Stevens-Johnson syndrome   
 
 
Toxic epidermal necrolysis 
  
 
Urticaria 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
  
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-cell 
activation and proliferation.  These can include (but are not limited to) autoimmune hemolytic anemia, 
acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune hepatitis, 
autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic 
colitis, endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, and adrenal insufficiency), ocular manifestations (e.g., uveitis, iritis, 
conjunctivitis, blepharitis, and episcleritis), sarcoid granuloma, myasthenia gravis, polymyositis, and 
Guillain-Barre syndrome.  The majority of these reactions manifested early during treatment; however, a 
minority occurred weeks to months after discontinuation of ipilimumab especially with the initiation of 
additional treatments. 
 

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45 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with 
subsequent IL-2 therapy. 
 
4In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
 
5Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC 
 
6Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Non-serious adverse events also reported on ipilimumab (MDX-010) trials but with the relationship 
to ipilimumab (MDX-010) still undetermined due to low frequency (i.e., <3%): 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - 
Other (pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis4; Eye disorders - Other (retinal pigment changes) 
GASTROINTESTINAL DISORDERS - Dyspepsia; Dysphagia; Gastrointestinal hemorrhage5 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection6 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase increased; 
Platelet count decreased; Serum amylase increased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Metabolism and nutrition disorders - Other 
(exacerbation of pre-existing diabetes mellitus) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint range of motion 
decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; Dyspnea; 
Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal arteritis) 
 
Note: Ipilimumab (MDX-010) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.2 
Adverse Event Characteristics  
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting until March 31, 2018 for AE reporting.  CTCAE 
version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  A copy of the 

NCI 9209 / PHL-085 
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46 
CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.    
 
• 
For expedited reporting purposes only:   
o 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the SPEER 
column, Section 7.1.1) should be reported through CTEP-AERS only if the grade is above the 
grade provided in the SPEER. 
o 
Other AEs for the protocol that do not require expedited reporting are outlined in section 7.3.4. 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event  
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The reporting 
procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse Event 
Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be 
downloaded from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly 
outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
 
7.3.2 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal Investigator, and 
the local treating physician. Each site will submit the electronic version of the CTEP-AERS 
report to the PMH Phase II Consortium Central Office.  Once review by the lead group 
coordinator has taken place the report will be forwarded to NCI.  CTEP-AERS provides a copy 
feature for other e-mail recipients. 
 
7.3.3 Expedited Reporting Guidelines 
 
Note:  A death on study requires both routine and expedited reporting regardless of causality, unless as noted 
below.  Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as grade 5 “Neoplasms benign, malignant 
and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system 
organ class (SOC) of the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 

NCI 9209 / PHL-085 
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47 
registration on all reports. 
 
In order to ensure the timely fulfillment of both US and Canadian IND regulatory reporting 
requirements, all CTEP-AERS reports must be sent to the PMH Phase II Consortium Central 
Office within 3 working days from the date the event was known to the investigator. 
 
• 
In the unlikely event that an adverse event occurs that does not meet the reporting 
requirements for CTEP-AERS, but does meet the definition of a Serious Adverse 
Event, an CTEP-AERS report must still be completed and sent to the Central Office 
within 3 working days of the event being known to the investigator.  The event must 
be telephoned or e-mailed to Central Office within 1 working day.   
 
• 
The PMH Phase II Consortium Central Office will be responsible for reporting to 
Canadian regulatory authorities all Serious Adverse Events that are both unexpected 
and related to study drug.  The Central Office will notify all Investigators of all 
Serious Adverse Events that are reportable to regulatory authorities in Canada from 
this trial or from other clinical trials as reported to the Central Office by the NCI U.S. 
 
Investigators must notify their local Research Ethics Boards (REB/IRBs), according to their guidelines, of all SAE 
reports from their centre and file the report in their regulatory study binder.   In addition, all reports sent out to 
centres by the PMH Phase II Consortium Central Office must be sent to local REB/IRBs, according to their 
guidelines.  Documentation from the REB/IRB of receipt of these reportable events must be kept on file in each 
institution's regulatory binder.  
 
Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that Occur 
on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 

NCI 9209 / PHL-085 
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48 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported viaCTEP-AERS. Three options are available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 

NCI 9209 / PHL-085 
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49 
8.1.1 Ipilimumab (NSC 732442) 
 
Chemical Name or Amino Acid Sequence: 4 polypeptide chains, 2 identical heavy chains with 
447 amino acids and 2 identical light chains consisting of 215 amino acids. 
 
Other Names: Anti-CTLA-4 monoclonal antibody, MDX-010 
 
Classification: Human monoclonal antibody 
 
M.W.: 147,991 Daltons 
 
Mode of Action: Ipilimumab is specific for the CTLA-4 antigen expressed on a subset of 
activated T-cells. CTLA-4 interaction with the B7 molecule, one of its ligands expressed on 
professional antigen presenting cells, can down-regulate T-cell response.  Ipilimumab is, thought 
to act by blocking the interaction of CTLA-4 with the B7 ligand, resulting in a blockade of the 
inhibitory effect of T-cell activation.  The CTLA-4/B7 creates the interaction.  
 
Description: Ipilimumab is a fully human immunoglobulin (IgG1) with two manufacturing 
processes – ongoing trials have been using substances manufactured using Process B.  New 
clinical trials will be using Ipilimumab that is manufactured by Process C. The Process C has 
been developed using a higher producing sub-clone of the current Master Cell Bank, and 
modified cell culture and purification steps.  
  
How Supplied: Bristol-Myers-Squibb (BMS) supplies Ipilimumab to the DCTD/NCI.  Ipilimumab 
is available as a 50 mg/10 mL (5 mg/ mL) and a 200 mg /40 mL (5 mg/mL) single-use vial.  The 
vial is a clear, colorless, sterile, isotonic aqueous solution (pH of 7) that may contains particles.  
 
Each vial is a Type I flint glass vial with gray butyl stoppers and sealed with aluminum seals. 
 
 
Process B 
Process C 
Component 
50 mg/ viala 
200 mg/ 
vialb 
50 mg/ viala 
200 mg/ vialb 
Ipilimumab 
53.5 mg 
213 mg 
53.5 mg 
213 mg 
Sodium Chloride, USP  
62.6 mg 
249 mg 
62.6 mg 
249 mg 
TRIS-hydrochloride 
33.7 mg 
134.3 mg 
33.7 mg 
134.3 mg 
Diethylenetriamine pentacetic acid 
0.42 mg 
1.67 mg 
0.42 mg 
1.67 mg 
Mannitol, USP 
107 mg 
426 mg 
107 mg 
426 mg 
Polysorbate 80 (plant-derived) 
1.07 mg 
4.26 mg 
1.18 mg 
4.69 mg 
Sodium Hydroxide 
QS to pH 7 
Hydrochloric acid 
QS to pH 7 
Water for Injection 
QS: 10.7 
mL 
QS: 42.6 
mL 
QS: 10.7 mL 
QS: 42.6 mL 
Nitrogenc 
Processing agent 
aIncludes 0.7 overfill;  bIncludes 2.6 mL overfill. 
cNitrogen is used to transfer the bulk solution through the pre-filled and sterilizing filters into the 
aseptic area. 

NCI 9209 / PHL-085 
31Jan2018 
 
50 
 
Preparation:  Ipilimumab is given undiluted or further diluted in 0.9% NaCl Injection, USP or 5% 
Dextrose Injection, USP in concentrations between 1 mg/mL and 4 mg/mL.  Ipilimumab is stable in 
a polyvinyl chloride (PVC), non-PVC/non DEHP (di-(2-ethylhexyl) phthalate) IV bag or glass 
container up to 24 hours refrigerated at (20 to 80 C) or at room temperature/ room light.  
 
Storage: Store intact vials refrigerated at (20 to 80 C), protected from light.  Do not freeze. 
 
Stability: Shelf-life surveillance of the intact vials is ongoing. 
Solution as described above is stable up to 24 hours refrigerated at (20 to 80 C) or at room 
temperature/ room light.  
 
CAUTION:  Ipilimumab does not contain antibacterial preservatives.  
Use prepared IV solution immediately. Discard partially used vials.  
 
Route(s) of Administration: IV.  Do not administer Ipilimumab as an IV push or bolus injection. 
 
Method of Administration:  Can use a volumetric pump to infuse Ipilimumab at the protocol-
specific dose(s) and rate(s) via a PVC IV infusion set with an in-line, sterile, non-pyrogenic, low-
protein-binding filter (0.2 micron to 1.2 micron). 
 
Patient Care Implications:  Monitor patients for immune-related adverse events, e.g., rash/vitiligo, 
diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism.  If you suspect toxicity, refer to 
the protocol guidelines for ruling out other causes. 
 
Availability:  Ipilimumab is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  Ipilimumab is provided to the NCI under a 
Collaborative Agreement between the Bristol-Myers-Squibb and the DCTD, NCI (see Section 
12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated.  PMB does 
not permit the transfer of agents between institutions (unless prior approval from PMB is obtained).  
The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 

NCI 9209 / PHL-085 
31Jan2018 
 
51 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a 
“current” password.  For questions about drug orders, transfers, returns, or accountability, call 
(301) 496-5725 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents received 
from DCTD using the NCI Drug Accountability Record Form (DARF).  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Immune assessment studies will be performed using peripheral blood obtained from study 
subjects prior to and following ipilimumab therapy.  These studies are exploratory and are 
designed to identify immune biomarkers that may be associated with ipilimumab treatment 
and/or clinical response.  These studies will be used in the design of future larger studies.  
 
Previous studies have investigated potential biomarkers in patients treated with anti-CTLA-4 
monoclonal antibodies (mAbs).  Monitoring peripheral blood T cells has shown that T cell 
activation markers such as HLA-DR and ICOS are increased following treatment.  Studies 
evaluating more specific biomarkers have not yielded consistent results, including those 
evaluating T cells specific for tumor antigens or negative regulatory T cell populations (Phan et 
al., 2003; Maker et al., 2005; O'Mahony et al., 2007; Reuben et al., 2006; Yuan et al., 2008; 
Liakou et al., 2008).  Evaluation of tumor tissues suggests that anti-CTLA-4 treatment may 
increase the number of tumor infiltrating lymphocytes (TIL) and increase the ratio of effector T 
cells to regulatory T cells (Hodi et al., 2003; Hodi et al., 2008).  In bladder cancer patients, 
ipilimumab treatment resulted in increases in ICOShigh CD4+ TIL, which produce the pro-
inflammatory cytokine IFN-  (Liakou et al., 2008).  In a small study that included biopsies from 
four melanoma patients before and after anti-CTLA-4 therapy with tremelimumab, 
immunohistochemical (IHC) staining suggested that clinical responders tended to show increased 
CD8+ TIL following treatment (Ribas et al., 2009).  Another study that examined pre- and post-
ipilimumab treatment biopsies was reported in abstract form.  This study found that clinical 
activity correlated with higher levels of FOXP3 and IDO staining at baseline and with an 
increase in TIL post-treatment (Hamid et al., 2009). 
 
9.1 
Biomarker Studies 
 
9.1.1 Peripheral Blood Immune Assessment – Laboratory Correlative Study #1 
 
Peripheral blood cells, plasma, and serum will be isolated from phlebotomy specimens.  These 
samples will be used fresh or stored for future analysis and will undergo immunologic 
assessment using established protocols (Butler et al., 2007; Butler et al., 2011, Crome et al. 2010; 
Nguyen et al. 2010).  We anticipate that the samples will undergo the following analysis, 

NCI 9209 / PHL-085 
31Jan2018 
 
52 
however, samples may also undergo additional studies in the future as part of exploratory 
studies.  Peripheral blood mononuclear cells (PBMC) will be analyzed phenotypically by flow 
cytometry using mAbs specific for molecules such as CD4, CD8, CD3, CD16, CD19, CD56, 
CD11c and CD11b to delineate immune populations present. Furthermore, markers will be used 
to characterize the function of immune populations.  
 
These include molecules upregulated with activation (ie CD25, CD69, HLA-DR), molecules that 
indicate stimulatory versus inhibitory immune responses (CD28, CD80, CD86, CTLA-4, PD-1, 
PDL-1, ICOS), markers of central versus effector memory T cells (CD62L, CCR7) and 
molecules which are differentially expressed between CD4+ T helper subsets (CD161, CXCR3, 
CCR6, CCR4, GARP and FOXP3).  In parallel, circulating lymphocytes will be analyzed for 
cytotoxicity and the ability to secret cytokines such as interferon-gamma, tumor necrosis factor 
alpha, Interleukin (IL)-2, IL-4, IL-6, IL-9, IL-10, IL-17 and IL-22.  Antigen-specific responses 
may be analyzed using overlapping peptides spanning the HPV-derived proteins, E6 and E7, to 
assess immune reactivity to these tumor associated antigens antigens.  Samples may also undergo 
HLA serotyping and/or genotyping. 
 
9.1.1.1 
Collection of Specimens 
Immune study bloods include nine 6ml tubes for heparinized blood, and one 5 ml tubes for sera 
(SST tube).  Blood will be obtained at the following study visits: Pre-study, Wk 1 (prior to 
ipilimumab infusion), Wk 2, Wk 4, Wk7, and Wk 10.  Immune study bloods will also be 
obtained during the maintenance phase of the study on days that ipilimumab is infused (ie Wk 
24, 36, 48, 60 and every 3 months thereafter.).  After the end of the maintenance phase of 
treatment immune study blood samples will be obtained at the time of follow-up appointments 
(every 3 months).  A final immune study blood sample will be obtained on the follow-up visit 
one month after withdrawal from study. 
 
9.1.1.2 
Shipping of Specimens 
Heparinized blood must be kept at room temperature after collection.  Blood for sera should be 
kept upright at room temperature and clot for 30-60 minutes. Centrifuge blood at 1500g for 15 
minutes. Divide serum evenly into two aliquots. Freeze samples at -70o C and store until 
shipping. 
Refer to the study-specific Laboratory Manual for detailed collection and processing procedures. 
 
9.1.1.3 
Handling of Specimens 
Blood specimens will be transferred by overnight shipment to the Correlative Studies Program 
(PMH). 
Correlative Studies Program 
Princess Margaret Hospital 
610 University Avenue 9-718 
Toronto, Ontario M5G 2M9 
Tel:  (416) 946-4501 ext 5047 
Fax: (416) 946-4431 
Email: CCRUcorrelativestudies@uhn.ca 
 

NCI 9209 / PHL-085 
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53 
9.1.1.4 
Site Performing Correlative Study 
PMH will be the site for performing correlative studies for peripheral blood. 
 
9.1.2 Tumor Biopsy Assessment 
 
We will perform immunohistochemistry on archived tumour tissue and fresh tumour tissue 
(within 14 days prior to registration and within the first week of cycle 2 onset) to assess the 
density of tumor infiltrating lymphocytes using validated markers for CD3, CD4, and CD8 
which are in routine clinical use.  Exploratory analysis will be performed to assess for markers 
associated with immune suppression such as Foxp3 and IDO.  When sufficient tumor tissue is 
available, enzymatic dissociation will be performed and tumor infiltrating lymphocytes will be 
expanded.  Exploratory analysis by flow cytometry will be performed to phenotypically assess 
expanded cells using monoclonal antibodies such as CD4, CD8, CD3, CD16, CD19, CD56, 
CD11c, CD11b, CD25, CD69, HLA-DR, CD28, CD80, CD86, CTLA-4, PD-1, PD-L1, CCR7, 
CD62L, and Foxp3. 
 
9.1.2.1 
Collection of Specimens 
 
Archival slides and tumor biopsies will be obtained.  Refer to the study-specific Laboratory 
Manual for detailed collection and processing procedures. 
 
9.1.2.2 
Handling of Specimens 
Refer to the study-specific Laboratory Manual for detailed collection and processing procedures. 
 
9.1.2.3 
Shipping of Specimens 
 
Correlative Studies Program 
Princess Margaret Hospital 
610 University Avenue 9-718 
Toronto, Ontario M5G 2M9 
Tel:  (416) 946-4501 ext 5047 
Fax: (416) 946-4431 
Email: CCRUcorrelativestudies@uhn.ca 
 
9.1.2.4 
Site Performing Correlative Study 
PMH will be the site for performing correlative studies for archival tissue. 
Statistical Considerations  
Clinical response to treatment as defined by the main drug treatment clinical protocol will be 
compiled and results of biomarker analysis from “responders” and “non-responders” will be 
compared.  These correlative studies are exploratory in nature and will be used in the design of 
future larger studies. 
9.2 
Special Studies 
N/A 
 

NCI 9209 / PHL-085 
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54 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy unless 
stated otherwise.  Scans and x-rays must be done <3 weeks prior to the start of therapy.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. If pre-study blood work, vitals and 
weight were done within 7 days of treatment initiation, they do not need to be repeated for cycle 
1 day 1.  If pre-study physical exam and performance status were done within 3 days prior to 
treatment initiation, they do not need to be repeated for cycle 1 day 1.  For subsequent cycles 
(2+), day 1 assessments can be completed up to 48hrs prior to day 1; however blood samples can 
be collected and analyzed up to 72hrs prior to dosing.    A cycle is 21 days long for phase I and 
II. 
 
 
 
C1 
C2 
C3 
C4 
Post C4 Treatment 
 
Pre-study 
D1 
W2 
D1 
D1 
D1 
W3 
Wk 
16 
Wk 
18 
Wk 
20 
Ipilimumab 
 
A 
 
A 
A 
A 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Physical exam 
X 
X 
 
X d 
X d 
X d 
X d 
X d 
 
X d 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
X 
 
X 
 
X 
ECOG assessment 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
CBC w/diff, plts g 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Serum chemistrya, g 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
TSH, T3, T4 g 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
LFT’s (AST, ALT, total bilirubin, lipase)e,g 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
EKG (as indicated) c 
X 
 
 
 
 
 
 
 
 
 
CRP 
X 
X 
 
 
 
 
X 
 
 
 
Adverse event evaluationd 
 
X-----------------------------------------------------------X 
Tumor measurements 
X 
 
 
 
 
X 
 
X 
 
Radiologic evaluation 
X 
 
 
 
 
 
X f 
 
X 
 
B-HCG (serum)b 
X 
X 
 
X 
X 
X 
 
 
 
 
Archival tissue (if available) 
X 
 
 
 
 
 
 
 
 
 
Pre and Post treatment biopsy  
X  
(pre)h 
 
 
X 
(post) i 
 
 
 
 
 
 
Peripheral blood immune assessment 
X 
X1,j 
Xj 
X2,j 
X3,j X4,j 
 
 
 
 
1. Prior to Ipilimumab infusion 
2. To be performed during week 4 of the study, preferably day 1 
3. To be performed during week 7 of the study, preferably day 1 
4. To be performed during week 10 of the study, preferably day 1 
a. Sodium, potassium, chloride, albumin, creatinine, magnesium, phosphate 
b. To be performed on women of childbearing potential 

NCI 9209 / PHL-085 
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55 
c. As clinically indicated beyond screening 
d. Review for autoimmune events 
e. LFT results must be reviewed by the principal investigator (or designee) to meet dosing criteria. The 
subject should be evaluated and managed referring to the IB, management section, and algorithm in 
Appendix C, as clinically appropriate  
f. 
Cycle 4 week 3 (week 12) radiological assessment can be performed +/- 1 week 
g. Any change from baseline levels within the first 4 cycles which may be related to known immune events 
are to be followed on a weekly basis until the event is no longer related or returns to baseline levels. 
h. Pre-treatment biopsy must be done within 14 days prior to registration 
i. 
Post treatment biopsy to be completed within the first week of cycle 2 onset 
j. 
Can be done up to 24hrs prior to Ipilimumab infusion 
 
 
Maintenance Phase 
Off  
Study a,g 
 
C5 
C6 
C7 
C8 
 
 
W24 
W30 W36 W42 W48 W54 
W60 
 
Ipilimumab        
A 
 
A 
 
A 
 
A 
 
Informed Consent 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam c 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG assessment 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry e 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, T3, T4 
X 
X 
X 
X 
X 
X 
X 
X 
LFT’s (AST, ALT, total 
bilirubin, lipase) d 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (as indicated) b 
 
 
 
 
 
 
 
 
CRP 
X 
 
X 
 
X 
 
X 
 
Adverse event 
evaluation c 
X-----------------------------------------------------------------X 
Tumor measurements 
Xi 
 
Xi 
 
Xi 
 
Xi 
Xh 
Radiologic evaluation 
Xi 
 
Xi 
 
Xi 
 
Xi 
Xh 
Β-HCG (serum) 
X 
 
X 
 
X 
 
X 
 
Peripheral blood 
immune assessment 
X 
 
X 
 
X 
 
X 
X f 
Subsequent therapy 
received post 
Ipilimumab 
 
 
 
 
 
 
 
X 
 
a. Off study follow-up appointments should occur every 3 months in individuals with PR, CR or SD at the end of 
treatment for a maximum period of 1 year or until progression of disease or death whichever occurs sooner.  
Individuals withdrawn from study due to PD will have only one follow-up visit after withdrawal from treatment 
and will not be followed for a year.  Individuals withdrawn from study due to Ipilimumab related adverse 
effects will be given medical treatment as appropriate and followed up on a monthly basis until resolution of the 
adverse event and then every 3 months for 1 year or until progression or death whichever occurs sooner. 

NCI 9209 / PHL-085 
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56 
b. As clinically indicated beyond screening 
c. Review for autoimmune events 
d.  LFT results must be reviewed by the principal investigator (or designee) to meet dosing criteria If, during the 
course of treatment abnormal LFT values are detected, Ipilimumab should not be administered.  The subject 
should be evaluated and managed referring to the IB, management section, and algorithm in Appendix C, as 
clinically appropriate  
e. Sodium, potassium, chloride, albumin, creatinine, magnesium, phosphate 
f.  Obtained every 3 months during the follow-up visit. 
g. Patients that are not going on to the maintenance cycle will complete their off study on week 24 or when they 
stop receiving treatment as applicable 
h.  Radiological  assessment only necessary for individuals demonstrating PR, CR or SD at completion of  
treatment. 
i. Radiological evaluations in maintenance phase can be done up to 1 week prior to Ipilimumab dosing for week 24 
and onwards (-1 week) 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be evaluated for response as stipulated on the study 
calendar.   
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 
1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with Ipilimumab.  
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.   
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray or as >10 mm 

NCI 9209 / PHL-085 
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57 
with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). Tumor lesions situated in a previously 
irradiated field are considered measurable if they have previously been demonstrated to progress 
as per RECIST 1.1 criteria on radiologic imaging prior to enrollment on study.  
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 

NCI 9209 / PHL-085 
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58 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 

NCI 9209 / PHL-085 
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59 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when 
the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response 
or stable disease (an effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate 
the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' 
disease).  New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new 
lesion. 
b. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-PET at follow-up 
is not confirmed as a new site of disease on CT, additional follow-up CT  scans are needed to determine 
if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of FDG-PET in 
this circumstance should be prospectively described in the protocol and supported by disease-specific 
medical literature for the indication.  However, it must be acknowledged that both approaches may lead 
to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 

NCI 9209 / PHL-085 
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60 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD) modified:(to be used at week 12 and beyond  of study) 
 
 
 
 
 
Clinically stable patients with no change in ECOG status and not requiring any additional 
medical interventions who demonstrate an increase of ≤30% in the sum of diameters of target 
lesions, taking as reference the smallest sum on study. In addition, the sum must also 
demonstrate an absolute increase of at least 5mm. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 

NCI 9209 / PHL-085 
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61 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 

NCI 9209 / PHL-085 
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62 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Progression free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first.  If such event is not observed after 1 year of 
follow up, patients are censored. 
 
11.1.7 Response Review 
 
All responses will be reviewed by an expert(s) independent of the study at the study’s 
completion by simultaneous review of patient files and radiologic images. 
 
11.2 
Other Response Parameters 
 
Tumors will be assessed for response as per suggested immune related response criteria (irRC). 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are due 
January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS 
can be found on the CTEP Web site  (http://ctep.cancer.gov/reporting/cdus.html).  
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.  If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 

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63 
Study participants are responsible for entering their data into the Medidata Rave system and 
submitting copies of their source notes to the Central Office / Coordinating Centre within 3 
weeks of the end of cycle.  Please refer to Appendix G, Data Management Guidelines, for further 
details regarding data submission requirements. 
 
The Central Office / Coordinating Centre is responsible for compiling and submitting CDUS 
data to CTEP for all participants and for providing the data to the Principal Investigator for 
review. 
12.2 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
12.3 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement.  A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 

NCI 9209 / PHL-085 
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64 
use of data by each Collaborator shall be as follows (data pertaining to such combination 
use shall hereinafter be referred to as "Multi-Party Data”): 
 
a.  
NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b.  
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c.  
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential 
and proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) 
for courtesy review as soon as possible and preferably at least three (3) days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the 
proceedings.  Press releases and other media presentations must also be forwarded to CTEP 
prior to release.  Copies of any manuscript, abstract and/or press release/ media presentation 
should be sent to: 

NCI 9209 / PHL-085 
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65 
 
Email:  ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
The run in phase of this study is to assess the safety of Ipilimumab in eligible cervical cancer 
patients. Six patients will be enrolled in this phase of the study and followed for a period of 12 
weeks. If 3 patients experience toxicity considered to be dose-limiting the safety cohort will be 
expanded to include an additional 6 individuals. In the event that the phase I cohort is expanded, 
should >4 patients experience a dose limiting toxicity, as defined earlier, the trial will be halted 
at this point. 
Should minimum safety criteria be fulfilled we will proceed to the second phase of the trial 
which will be a single-arm, non-randomized, open-label multi-center two-stage phase II study to 
evaluate the antitumor activity of Ipilimumab as measured by the primary endpoint of objective 
response rate using RECIST. 
 
In phase II of the trial a safety assessment will be conducted after 12 patients have been treated. 
If >4 have DLT by same definition as Phase I run in, the study will be put on hold and discussed 
with CTEP.  
 
Sample size calculations are based on the two stage design according to Simon (Simon, 1989). 
The design will allow the study to terminate after enrollment of 18 evaluable patients if no 
objective response is observed. If the stopping rule is not met, a further 14 evaluable patients will 
be enrolled for a total of 32 patients. If the total number of patients responding is 4 or more, the 
drug is accepted. 
                   
The null hypothesis is that the response rate is less than 5% and the alternative is that   
the response rate is more than 20%. The design has alpha error 10% and power of                  
90%. 
 
13.2 
Sample Size/Accrual Rate 
 
6-44 
 
13.3 
Stratification Factors 
 
N/A 
 
13.4 
Analysis of Secondary Endpoints 
 

NCI 9209 / PHL-085 
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66 
Secondary Endpoints: 
• 
To assess the antitumor activity of Ipilimumab through secondary endpoints including 
of disease stabilization and PFS. 
• 
Assessment of antitumor activity of Ipilimumab using immune-related response 
criteria (irRC) 
• 
Assessment of the predictive value of baseline C-reactive protein  
• 
Assess the biologic responses of exposure to Ipilimumab via correlative studies 
involving analysis of lymphocyte subsets and assessment of cervical cancer-antigen 
specific T cells anti-tumor response.  
• 
Evaluation of archival tissue with regard to markers of immune population in 
correlation with clinical stage and response to treatment   
 
 
 
 
Summary statistics, such as mean, median, counts and proportion, will be used to summarize the 
patients.  Survival estimates will be computed using the Kaplan-Meier method. Potential 
association between variables will be measured using Pearson correlation coefficients, chi-square 
tests, one- or two-sample t-tests or logistic regression analyses as appropriate. Non-parametric 
tests such as Spearman correlation coefficients, Fisher’s exact tests and Wilcoxon rank sum test 
may be substituted if necessary. Ninety-five percent confidence intervals will be constructed and 
selected results will be illustrated using figures and plots. 
                 
Frequency and severity of adverse events will be tabulated using counts and proportions 
detailing frequently occurring, serious and severe events of interest. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with Ipilimumab. 
 
13.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 8) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 8 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-7 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate  
 

NCI 9209 / PHL-085 
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67 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided. 
 
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. 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 

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APPENDIX B 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 

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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 

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APPENDIX C 
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS, 
DIARRHEA, HEPATOTOXICITY, ENDOCRINOPATHY, AND NEUROPATHY* 
 
General recommendations for management of suspected inflammatory events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Investigator Brochure (2011) 
Caution: With the appearance of any 
generalized rash, discontinue and avoid 
any concomitant medications 
(e.g. antibiotics, anticonvulsants, or proton 
pump inhibitors) that may be associated 
with severe skin reactions 
+ Definition: irAEs are associated with 
ipilimumab exposure and are consistent with 
immune phenomenon 
 
Examples of possible irAEs (common and 
rare): rash, pruritus, diarrhea/colitis, 
hepatitis/elevated liver function tests, 
hypopituitarism, hypo/hyperthyroidism, 
uveitis, pneumonitis, nephritis, pancreatitis, 
aseptic meningitis, toxic epidermal 
necrolysis, myopathy/myositis or 
neuromuscular disorder (e.g. Myasthenia 
gravis, Guillain-Barre Syndrome)  
Suspicion of an 
immune related 
adverse event 
(irAE)+ 
Rule-out non-immune related causes 
If symptoms have a GI, Liver, or Endocrine etiology, then refer 
To ‘Diarrhea”, “Hepatotoxicity”, or “Endocrinopathy” Management 
Low grade 
(Grade 1 or 2) 
What is the severity 
of the adverse 
event? (NCI 
CTCAE grading) 
High grade 
 
- Increase monitoring 
- Symptomatic treatment  
- Consider skipping next dose until 
event resolves 
- Consider oral steroid therapy* for 
persistent or recurring Grade 2 irAEs 
- If symptoms worsen or do not 
improve with treatment after 1-2 weeks 
then consider managing as a high 
grade event 
 
- Increase monitoring 
- Strongly consider high dose steroid therapy* 
- Hold further dosing until adverse event resolves 
- Consider specialist consult 
- If steroid therapy is initiated and symptoms 
improve, then consider a gradual steroid taper 
over 4 weeks 
- If symptoms do not respond within 5-7 days of 
intervention, then consider alternative 
immunosuppression therapy (eg. mycophenolate 
mofetil, tacrolimus, infliximab) 
 
* Based on clinical experience to date, systemic steroids for 
treatment of irAEs do not appear to impact the development or 
maintenance of ipilimumab clinical activity in advanced melanoma.  

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Diarrhea Management Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea 
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  activities of daily living (ADL) 
GRADE 3 
Increase of ≥7 stools per day over 
baseline; incontinence; IV fluids ≥24 hrs; 
hospitalization; 
severe increase in ostomy output 
compared to baseline; interfering with 
ADL 
GRADE 4 
Life-threatening 
consequences 
(e.g., 
hemodynamic 
collapse) 
GRADE 5 
Death 
Rule out 
clear non-
irAE causes 
Caution: 
 
• The use of narcotics for abdominal 
pain in the setting of suspected 
immune related diarrhea/colitis may 
mask symptoms of perforation and 
peritonitis 
 
• Infliximab should not be used if 
perforation or sepsis are present 
Patient complains 
of diarrhea or 
blood in stool 
Yes 
No 
Specific 
treatment 
for non-irAE 
cause 
Grade of 
diarrhea  
Continue 
ipilimumab 
as per protocol 
Treat 
symptomatically 
without steroids 
Treat 
symptomatically 
without steroids 
Stool WBC, 
Stool 
calprotectin, 
Consider 
endoscopy  
Continue 
ipilimumab 
as per protocol 
Resolved to 
≤ grade 1?  
1 
2 
3-4 
No 
Yes 
Likely 
Colitis?  
No 
Yes 
Grade of 
diarrhea  
Treat with high 
dose steroids 
and taper for at 
least 1 month 
Treat with oral 
budesonide or 
other moderate 
dose steroid 
Treat with high 
dose steroids 
and taper for at 
least 1 month 
If no response in 
1 week, consider 
a 5 mg/kg dose 
of infliximab 
Resolved to 
≤ grade 1?  
Yes 
No longer eligible 
for further 
ipilimumab 
treatment 
2 
3-4 
No 
Resolved to ≤ 
grade 1?  
No 
Yes 

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79 
 
Hepatoxicity Management Algorithm 
 
Situation: rising liver function tests (LFTs) >8X ULN or suspected immune-mediated 
hepatitis 
1) 
Admit subject to hospital for evaluation and close monitoring 
2) 
Stop further Ipilimumab dosing until hepatotoxicity is resolved. Consider permanent 
discontinuation of Ipilimumab per protocol  
3) 
Start at least 120 mg methylprednisolone sodium succinate per day, given IV as a 
single or divided dose 
4) 
Check liver laboratory test values (LFTs, T-bilirubin) daily until stable or showing 
signs of improvement for at least 3 consecutive days 
5) 
If no decrease in LFTs after 3 days or rebound hepatitis occurs despite treatment with 
corticosteroids, then add mycophenolate mofetil 1g BID per institutional guidelines 
for immunosuppression of liver transplants (supportive treatment as required, 
including prophylaxis for opportunistic infections per institutional guidelines) 
6) 
If no improvement after 5 to 7 days, consider adding 0.10 to 0.15 mg/kg/day of 
tacrolimus (trough level 5-20 ng/mL) 
7) 
If target trough level is achieved with tacrolimus but no improvement is observed 
after 5 to 7 days, consider infliximab, 5 mg/kg, once 
8) 
Continue to check LFTs daily for at least 2 weeks to monitor sustained response to 
treatment 
 
A flow chart of the algorithm is depicted on the following page. 

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Hepatoxicity Management Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
LFTs >8x ULN? 
and/or 
 T Bili >5x ULN? 
Monitor Course: 
1. 
Hold further ipilimumab per  
Treatment Modification criteria 
2. 
Repeat LFTs within 24 hrs 
LFTs still rising 
over 24-48 hrs? 
and/or 
suspected irAE 
Trigger Point #2 
Consult with Medical Monitor 
and consider therapeutic 
intervention 
Monitor Course: 
Check labs q3 days until stable or 
decreasing, then once per week  
Monitor Course: 
Check labs q3 days until stable or 
decreasing, then once per week  
No 
No 
No 
Yes 
No
Yes
Determine  
Baseline LFT’s, T Bili at 
screening 
Baseline 
LFTs, T Bili 
NORMAL 
Baseline 
LFTs, T Bili 
Grade 1or2 
Routine monitoring of 
LFTs, T Bili per 
protocol 
Routine monitoring of 
LFTs, T Bili per 
protocol 
LFTs and/or T 
Bili ≥GRADE 
2?** 
LFTs and/or T Bili 
≥2x BASELINE 
VALUES?* 
 
Trigger Point #1 
Intensified monitoring 
Work-up for Autoimmunity: 
1. 
 Clinical Signs 
2. 
Labs: ANA, SMA, LFTs, TBili, 
Creat, other 
3. 
Check LFTs, TBili q3 days 
Work-up to r/o non-irAE causes: 
monitoring of LFTs, T Bili per protocol 
1. Imaging to r/o mets 
2. Consider liver biopsy if suggestion of 
autoimmune etiology 
No
Yes
No
*Consider Permanent Discontinuation of ipilimumab per 
protocol 
 
References: 
1.Maddrey W.C. Clinicopathological Patterns of Drug-
Induced Liver Disease, In:Kaplowitz N. Drug-induced liver 
disease. 2nd ed. 2007 
2.Temple, FDA slide presentation 

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Endocrinopathy Management Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote 
For numbered footnotes (1,2,3,4), please refer to further explanation and text found in the corresponding dotted line boxes to the right 
side of the algorithm 
Suspect endocrinopathy 
(based on clinical signs and 
symptoms)1 
Long term follow-up 
 
1. Taper high dose steroids4 
2. Continue hormone replacement 
as needed 
3. Monitor endocrine labs as 
appropriate 
4. Repeat MRI as clinically 
indicated 
Suspect adrenal crisis 
1. Rule out sepsis 
2. If strong suspicion of adrenal crisis (e.g. exhibits 
signs of severe dehydration, hypotension, or 
shock out of proportion to severity of current 
illness) then start stress dose IV steroids (with 
mineralocorticoid activity), fluids, consult 
endocrinologist 
3. If symptoms suggestive of endocrinopathy but 
patient is not in crisis then it may be appropriate to 
wait for lab results before starting steroid therapy 
4Prolonged replacement steroid therapy: 
a) Patients may require chronic 
hydrocortisone replacement to maintain 
homeostatic levels 
b) Beware of complete discontinuation of 
steroids due to prolonged adrenal 
suppression 
1Clinical signs and symptoms that may be 
indicative of underlying endocrinopathy 
 
headache, visual field defects, fatigue, 
weakness, asthenia, failure to thrive, 
anorexia, nausea and vomiting, lethargy, 
impotence, amenorrhea, fever, coma, new 
onset atrial fibrillation, hypotension, 
hypoglycemia, hyponatremia, eosinophilia 
2 Suggested endocrine labwork: 
1. TSH, free T4, T3 
2. ACTH, AM serum cortisol => if 
abnormal, co-syntropin stimulation test 
3. LH, FSH, testosterone, prolactin 
3Ipilimumab dosing: 
a) Upon resolution of adequate 
treatment for endocrinopathy, patients 
may continue ipilimumab dosing with 
appropriate hormone replacement 
unless limited by protocol. 
b) The risk of having a recurrence of 
endocrinopathy with subsequent 
ipilimumab dosing after experiencing 
initial inflammatory events is currently 
unknown. 
1. Initiate short course of high dose 
steroid treatment to reverse 
inflammation 
2. Initiate appropriate hormone 
replacement to reverse 
endocrinopathy 
3. Consult endocrinologist as needed 
4. Review ipilimumab dose 
modification criteria per protocol3 
1. Rule-out other etiologies for 
patient symptoms 
2. Initiate more frequent patient 
follow-up 
3. Repeat endocrine labs in 1-3 wks 
If lab and radiologic results are 
negative but symptoms persist: 
 
1. consult Endocrinologist 
2. consider repeating head MRI in 
1 month 
1. Check endocrine labs2 (draw before 
giving steroids) 
2. MRI head with pituitary cuts, 
Visual field testing if appropriate 
3. Consult medical monitor 
4. Consider endocrinologist consult 
Suspect adrenal crisis 
Endocrine labs abnormal 
OR 
Head MRI abnormal 
Yes 
No 
Condition stabilized 
No 
Yes 

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Neuropathy Management Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3/4 
Assessment of neuropathy 
Sensory 
- Symptoms constant and 
persistent for ≥5 days 
Diagnostic testing 
- Rule out non-inflammatory causes (e.g. infection, 
metabolic, other medications) 
- Neurology consult, electromyogram and nerve 
conduction studies to fully characterize the 
neurological syndrome and establish a baseline to 
assess evolution 
- Consult with a medical monitor 
CTCAE Grade Severity 
Grade 1 
Grade 2 
Continue 
Ipilimumab 
Skip 
Ipilimumab 
(if related) 
Sensory 
Motor 
Stop 
Ipilimumab 
(if related) 
Stop 
Ipilimumab 
(regardless of 
causality) 
Clinically 
stable? 
-Treat symptoms per local PI/Neuro recs 
-Complete diagnostic testing 
-If symptoms related to ipilimumab, consider IV 
steroids for Grade 3/4 AE 
-If atypical presentation or progressive 
symptoms, consider hospitalization, then start 
IV steroids 
-consider IV Ig or other immunosuppressive 
therapies 
Motor 
- confirm on exam 
Yes 
No 

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APPENDIX D 
IMMUNE RELATED RESPONSE CRITERIA (IRRC)* 
*Note that the proposed irRC may be incorporated as secondary end points to compare to standard criteria 
and evaluate alternative patterns of response in various disease setting and treatment regimens. 
 
Immune Related Response Criteria 
Definition of Tumor Response Using irRC 
The sum of the products of diameters (SPD) at tumor assessment using the immune-related response 
criteria (irRC) for progressive disease incorporates the contribution of new measurable lesions.  Each 
net Percentage Change in Tumor Burden per assessment using irRC criteria accounts for the size and 
growth kinetics of both old and new lesions as they appear. 
 
Definition of Index Lesions Response Using irRC 
• 
irComplete Response (irCR): Complete disappearance of all index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• 
irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the 
products of the two largest perpendicular diameters of all index and all new measurable lesions 
(i.e., Percentage Change in Tumor Burden). Note: the appearance of new measurable lesions is 
factored into the overall tumor burden, but does not automatically qualify as progressive disease 
until the SPD increases by ≥25% when compared to SPD at nadir. 
• 
irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive 
disease. 
• 
irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden (i.e., 
taking sum of the products of all index lesions and any new lesions) when compared to SPD at 
nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
• 
irComplete Response (irCR): Complete disappearance of all non-index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• 
irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not considered in 
the definition of PR, these terms do not apply. 
• 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden increases by 
25% (i.e., the SPD at nadir of the index lesions increases by the required amount). 
 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However their contribution 
to total tumor burden is included in the SPD which in turn feeds into the irRC criteria for tumor 
response. Therefore, new non-measurable lesions will not discontinue any subject from the study. 
 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
• 
Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions 
(index and nonindex together with no new measurable/unmeasurable lesions) for at least 4 weeks 
from the date of documentation of complete response.  
• 
Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD baseline. At 
each subsequent tumor assessment, the sum of the products of the two largest perpendicular 
diameters of all index lesions and of new measurable lesions are added together to provide the 
Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline of the 

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84 
irSPD compared to the previous SPD baseline, of 50% or greater is considered an immune Partial 
Response (irPR).  
• 
Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive disease.  
• 
Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to confirm 
PD by serial imaging. Any of the following will constitute progressive disease: 
o At least 25% increase in the sum of the products of all index lesions over baseline SPD 
calculated for the index lesions. 
o At least a 25% increase in the sum of the products of all index lesions and new measurable 
lesions (irSPD) over the baseline SPD calculated for the index lesions. 
 
Table: 
Immune-Related Response Criteria Definitions 
Index 
Lesion 
Definition 
Non-Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Percent change in 
tumor burden 
(including measurable 
new lesions when 
present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
> -50% 
irPR 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
>+25% 
irPD 
 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between the date 
of first dose until the last tumor assessment before subsequent therapy (except for local palliative 
radiotherapy for painful bone lesions) for the individual subject in the study. For the assessment of 
irBOR, all available assessments per subject are considered. 
 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks after the 
criteria for response are first met. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX E 
DATA MANAGEMENT GUIDELINES 
 
Case Report Form Submission Schedule 
 
Data required for the study will be collected in Case Report Forms provided by the PMH Phase 2 
Consortium Central Office.  The site will be required to complete a paper Eligibility Checklist 
case report form (CRF) at the time of patient registration.  All other data will be collected on 
electronic case report forms (eCRFs) in the Medidata Rave system.  Site staff access to Medidata 
Rave will be initiated at the time of site activation.  The form submission schedule is outlined 
below. 
 
Case Report Form 
Submission Schedule 
Eligibility Checklist 
At the time of registration 
Baseline eCRFs 
Within 3 weeks of on study date 
On Treatment (Cycle) eCRFs 
Within 3 weeks of the end of each 
cycle of treatment 
Off Treatment eCRFs 
Within 3 weeks of the patient coming 
off-study 
Short Follow-up eCRFs 
Within 3 weeks of the patient coming 
to clinic.   
Final eCRFs 
Within 3 weeks from the follow-up 
period being complete or of the 
patient's death being known to the 
investigator unless this constitutes a 
reportable adverse event when it 
should be reported according to 
CTEP-AERS guidelines 
 
Case Report Form Completion 
 
The paper Eligibility Checklist CRF must be completed using black ink.  Any errors must be 
crossed out so that the original entry is still visible, the correction clearly indicated and then 
initialed and dated by the individual making the correction. 
 
eCRFs will be completed according to the schedule noted above and all relevant supporting 
documentation such as scans, progress notes, nursing notes, blood work, pathology reports, etc., 
will be submitted to the PMHC Phase 2 Consortium Central Office for review.  All patient 
names or other identifying information will be removed prior to being sent to the Central Office 
and the documents labeled with patient initials, study number and the protocol number.   
 
eCRF completion guidelines are available for all sites. 
 
Monitoring 
 
Central data monitoring will take place throughout the trial at the Central Office.  On-site 
monitoring will be performed once a year at participating sites during which a subset of PMHC 

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studies will be picked for on-site monitoring.  
 
Data in the Medidata Rave eCRFs will be monitored on a regular basis and quality assurance 
measures will be performed.  Electronic data queries as well as paper query letters may be issued 
to the site prior to the quarterly submission of data to CDUS. 
 
Patient Registration 
 
• Refer to section 4 of the protocol 
 
Data Safety 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study to see if there are unexpected or more serious side 
effects than described in the consent. 
 
 
Regulatory Requirements 
 
 
• Please submit all required documents to the PMH Phase 2 Consortium Central Office. 
• Canadian Principal Investigators must submit a completed Qualified Investigator 
Undertaking. 
• All investigators must have a current NCI investigator number on file with the PMH Phase 2 
Consortium Central Office. 
• All investigators must have an up-to-date CV (signed within 2 years) on file with the PMH 
Phase 2 Consortium Central Office. 
• Laboratory certification/accreditation and normal ranges are required 
• Confirmation of all investigators having undergone training in the Protection of Human 
Research Subjects is required.  It is preferred that other staff involved in the trial also 
undergoes such training. 
• Investigators and site staff are required to complete Medidata eCRF training modules 
depending on delegated tasks  
• OPRR assurance numbers for each institution are required 
• Consent forms must be reviewed by the Central Office before submission to the local ethics 
regulatory board (REB/IRB) and must include a statement that 1) information will be sent to 
and 2) medical records will be reviewed by the PMH Phase 2 Consortium Central Office. 
• A Membership list of the local ethics board is required. 
• A copy of the initial approval letter from the ethics board must be submitted to the PMH 
Phase 2 Consortium Central Office. 
• A completed Site Participant List/Training Log is required and must be submitted to PMHC 
Continuing approval will be obtained at least yearly until follow-up on patients is completed