A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in Combination With High Dose Interferon-Alpha in Advanced Melanoma
Phase: PHASE2
Conditions: Recurrent Melanoma, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

i 
 
 
Operations Office – Boston  
 
 
 
 
March 2, 2016 
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office 
Quality Assurance Section 
CTEP, DCT, NCI 
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD   20892 
Dear Ms. Kruhm: 
Enclosed is Addendum #5 to E3611, A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 
10 mg/kg Alone or in Combination with High Dose Interferon-α in Advanced Melanoma.  
This amendment is in response to Drs. Howard Streicher, James Zwiebel, and Meg Mooney’s 
Request for Rapid Amendment on March 1, 2016.  
The following revisions to E3611 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover page 
Updated version date 
2. 
Section 5.3 
Replaced ipilimumab CAEPR with updated Version 2.7, June 28, 2015 
The following revisions to E3611 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Cover page 
Updated version date 
2. 
“Non immune-based 
Risks Associated 
with Ipilimumab” 
Removed instructional text titled “Please note the following in reviewing 
these risks” and replaced condensed risk list with updated Version 2.7, 
June 28, 2015 
If you have any questions regarding this addendum, please contact li.amy@jimmy.harvard.edu 
or 617-632-3610. 
We request review and approval of this addendum to E3611 so ECOG-ACRIN may activate it 
promptly.   
Thank you.  
900 Commonwealth Avenue, Boston, MA 02215 
p: 617.632.3610 
f: 617.632.2990 
ecog-acrin.org 

ii 
Sincerely, 
 
Pamela Cogliano 
Protocol Development Manager 
Enclosure 
CC: Ahmad Tarhini, MD, PhD 
Sandra Lee, ScD 
Uma Rao, MD 
John Kirkwood, MD 
Ross Goldberg 
Sarah Archambault 
Donna Marinucci 
Lauren Lambert 
Lam Le 
 
Carol Chami, R.N. 
Melinda Flood 
Bruce Giantonio, M.D. 
Robert L. Comis, M.D 
Kerry Higgins 
Mary Steele 
Jean MacDonald 
James Corkery 
Amy Li 
 
 

E3611 
 
1 
 
 
A Randomized Phase II Study of Ipilimumab at  
3 mg/kg or 10 mg/kg Alone or in Combination with 
High Dose Interferon-α in Advanced Melanoma 
STUDY CHAIR: 
Ahmad A. Tarhini MD, PhD 
STUDY CO-CHAIR: 
John M Kirkwood, MD 
STUDY STATISTICIAN: 
Sandra Lee, ScD 
PATHOLOGY CO-CHAIR: 
Uma Rao, MD 
MELANOMA COMMITTEE CHAIR: 
John M Kirkwood, MD 
Version Date: March 2, 2016 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
US Sites Only 
 
December 27, 2012 
 
 
Addendum #1 – Incorporated prior to activation 
 
 
Addendum #2 – 5/14 
 
 
Addendum #3 - 10/14 
 
 
Addendum #4 - 4/15 
 
 
 
Addendum #5 – 3/16 
 
 
 
 
 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
Ipilimumab 
10200 
732442 
NCI Supplied 
Interferon 
 
377523 
Commercial 
 

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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Management of Metastatic Melanoma and the Role of CTLA4 Blockade 7 
1.2 IFN-2b and the Role of High-Dose IFN-α2b (HDI) as Adjuvant Therapy 
for High-risk Resected Melanoma ............................................................. 8 
1.3 CTLA-4 and T Cell Activation ..................................................................... 9 
1.4 Summary of Results of Investigational Program of Ipilimumab ............. 10 
1.5 Overall Risk/Benefit Assessment of Ipilimumab Studies ........................ 27 
1.6 A phase II study of tremelimumab combined with HDI for metastatic 
melanoma ............................................................................................... 28 
1.7 Study Rationale ....................................................................................... 34 
2. Objectives ......................................................................................................... 37 
2.1 Primary Endpoints ................................................................................... 37 
2.2 Secondary Endpoints............................................................................... 37 
3. Selection of Patients ......................................................................................... 38 
3.1 Eligibility Criteria ..................................................................................... 38 
4. Registration Procedures.................................................................................... 42 
4.1 Protocol Number ..................................................................................... 44 
4.2 Investigator Identification ....................................................................... 44 
4.3 Patient Identification .............................................................................. 44 
4.4 Eligibility Verification .............................................................................. 44 
4.5 Stratification Factors ............................................................................... 44 
4.6 Additional Requirements ........................................................................ 44 
4.7 Instructions for Patients who Do Not Start Assigned Protocol Treatment45 
5. Treatment Plan ................................................................................................. 46 
5.1 Administration Schedule ......................................................................... 46 
5.2 Adverse Event Reporting Requirements ................................................. 48 
5.3 Comprehensive Adverse Events and Potential Risks List ........................ 56 
5.4 Dose Modifications ................................................................................. 60 
5.5 Supportive Care and Prohibited Therapies ............................................. 80 
5.6 Duration of Therapy ................................................................................ 81 
5.7 Duration of Follow-up ............................................................................. 81 
6. Measurement of Effect ..................................................................................... 82 
6.1 Antitumor Effect – RECIST ....................................................................... 82 
6.2 Definition of Tumor Response Using irRC ............................................... 90 
7. Study Parameters .............................................................................................. 93 
7.1 Therapeutic Parameters.......................................................................... 93 
7.2 Arms A and C: Patients Treated with HDI and Ipilimumab at 10 mg/kg 
(Arm A) or 3 mg/kg (Arm C) .................................................................... 94 
7.3 Arms B and D: Patients Treated with Ipilimumab alone at 10 mg/kg (Arm 
B) or 3 mg/kg (Arm D) ............................................................................. 97 

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7.4 Biological Sample Submissions ............................................................. 100 
8. Drug Formulation and Procurement ............................................................... 101 
8.1 Ipilimumab ............................................................................................ 101 
8.2 Alfa Interferon ....................................................................................... 105 
9. Statistical Considerations ................................................................................ 110 
9.1 Endpoints and Sample Size ................................................................... 110 
9.2 Stratification .......................................................................................... 111 
9.3 Gender and Ethnicity ............................................................................ 112 
10. Pathology Review ............................................................................................ 113 
10.1 Pathology Materials Required For This Protocol .................................. 113 
10.2 Shipping Procedures ............................................................................. 114 
10.3 ECOG-ACRIN Sample Tracking System .................................................. 115 
11. Submission of Samples ................................................................................... 116 
11.1 Sample Submission Schedule ................................................................ 116 
11.2 Sample Preparation Guidelines ............................................................. 116 
11.3 Shipping Kits .......................................................................................... 117 
11.4 Shipping Procedures ............................................................................. 117 
11.5 Use of Specimens in Research .............................................................. 118 
11.6 Sample Inventory Submission Guidelines ............................................. 118 
12. Electronic Data Capture .................................................................................. 119 
12.1 Records Retention ................................................................................. 119 

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13. Patient Consent and Peer Judgment .............................................................. 120 
14. References ...................................................................................................... 120 
Appendix I  Pathology Submission Guidelines ...................................................... 125 
Appendix II  Patient Thank You Letter ................................................................... 131 
Appendix III  Patient Interferon Diary ................................................................... 132 
Appendix IV  E3611 Cooperative Research and Development Agreement (CRADA)134 
Appendix V  ECOG Performance Status ................................................................ 136 
Appendix VI  Shipping Kit Request Facsimile Form ............................................... 137 
Appendix VII  Specimen Shipment Requisition Form ............................................ 138 
Appendix VIII  Administration of Interferon (Directions for Administration of 
Subcutaneous Doses) ...................................................................................... 140 
Appendix IX  TNM Staging for Melanoma ............................................................. 143 
Appendix X  General Recommendations for immune-related Adverse Events 
(IrAEs) .............................................................................................................. 145 
Appendix XI  Suggested Work-up and Treatment for Immune-Related Adverse 
Events (irAEs) .................................................................................................. 146 
Appendix XII  Diarrhea Management Algorithm ................................................... 149 
Appendix XIII Hepatotoxicity Management Algorithm ......................................... 150 
Appendix XIV Endocrinopathy Management Algorithm ....................................... 151 
Appendix XV Neuropathy Management Algorithm .............................................. 152 
Appendix XVI Skin Toxicity Management Algorithm ............................................. 153 
Appendix XVII  Instructions for Reporting Pregnancies on a Clinical Trial ............ 154 
 

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STUDY CHAIR 
Ahmad A. Tarhini, MD, PhD 
University of Pittsburgh Cancer Institute 
UPMC Cancer Pavilion 
5150 Centre Avenue, 5th Floor 
Pittsburgh, PA 15232 
Tel: (412) 648-6578 
Fax: (412) 648-6579 
E-mail: tarhiniaa@upmc.edu 
 
STUDY CO-CHAIR 
John Kirkwood, M.D 
University of Pittsburgh Cancer Institute 
Hillman Cancer Research Pavilion Suite 1.32 
5117 Centre Avenue 
Pittsburgh, PA 15213 
Tel: (412)623-7707 
Fax: (412)623-7704 
E-mail: KirkwoodJM@upmc.edu 
 
STUDY CHAIR LIAISON (SCL) 
Amy Rose, RN OCN 
University of Pittsburgh Cancer Institute 
UPMC Cancer Pavilion 
5150 Centre Avenue, 3rd Floor 
Pittsburgh, PA 15232 
Phone: (412) 647-8587 
Fax: (412) 647-3768 
E-mail: kennaj@upmc.edu 
 

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Schema 
Induction Phase
· Ipilimumab: 10 mg/kg I.V. infusion every 3 weeks for 4 doses
GIVEN CONCURRENTLY WITH
· Interferon Alfa-2b, 20 MU/m²/d I.V. x 5 consecutive days out of 
7 (e.g. M-F) every week for 4 wks, followed by 10 MU/m²/d 
Subcutaneous every other day (e.g. M,W,F) 3times each week 
for 8 wks
Induction Phase
· Ipilimumab: 3 mg/kg  I.V. infusion every 3 weeks for 4 doses
GIVEN CONCURRENTLY WITH
· Interferon Alfa-2b, 20 MU/m²/d I.V. x 5 consecutive days out of 
7 (e.g. M-F) every week for 4 wks, followed by 10 MU/m²/d 
Subcutaneous every other day (e.g. M,W,F) 3times each week 
for 8 wks
Induction Phase
·  Ipilimumab: 10 mg/kg I.V. infusion every 3 weeks for 4 doses
Arm A
Arm B
Arm C
R
A
N
D
O
M
I
Z
E
Accrual Goal: 88
F
O
L
L
O
W
-
U
  P1
Induction Phase
· Ipilimumab: 3 mg/kg I.V. infusion every 3 weeks for 4 doses
Arm D
1Long term follow up until disease progression
Stratification 
Factors:
Stage: 
· III/M1a
· M1b
· M1c
Maintenance Phase
· Ipilimumab: 10 mg/kg I.V. infusion every 12 weeks (3 months), 
beginning at week 24, for a max of 4 doses (wk 24, 36, 48, 60)
GIVEN CONCURRENTLY WITH
· Interferon Alfa-2b10 MU/m²/d Subcutaneous every other day 
(e.g. M,W,F) 3times each week for 48 wks
Maintenance Phase
· Ipilimumab: 3 mg/kg  I.V. infusion every 12 weeks (3 months), 
beginning at week 24, for a max of 4 doses (wk 24, 36, 48, 60)
GIVEN CONCURRENTLY WITH
 
· Interferon Alfa-2b10 MU/m²/d Subcutaneous every other day 
(e.g. M,W,F) 3times each week for 48 wks
Maintenance Phase
· Ipilimumab: 10 mg/kg infusion every 12 weeks (3 months), 
beginning at week 24, for a max of 4 doses (wk 24, 36, 48, 60)
Maintenance Phase
· Ipilimumab: 3 mg/kg I.V. infusion every 12 weeks (3 months), 
beginning at week 24, for a max of 4 doses (wk 24, 36, 48, 60)
 

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1. 
Introduction 
1.1 
Management of Metastatic Melanoma and the Role of CTLA4 Blockade 
Advances in the preceding few years have brought deepening and exciting 
understanding to the molecular biology of melanoma and the immune regulatory 
mechanisms that play an important role in the oncogenesis of this  disease and 
the host immune tolerance conducive to disease progression. As a result, 
therapeutic options against melanoma has expanded to include several 
promising agents that exploit various targets that the melanoma cell is dependent 
upon for survival. Recent trials involving the CTLA-4 blocking antibody 
ipilimumab and the BRAF inhibitor vemurafenib have produced exciting results 
leading to regulatory approval of both agents as standard of care treatment 
options in the metastatic setting, while their use in the adjuvant setting is a topic 
of ongoing investigation. Therapeutic options outside of clinical trials for 
melanoma have had limited benefits and no known survival advantage until the 
approval of ipilimumab and vemurafenib in 2011.(1, 2) Immunotherapy utilizing 
interleukin-2 (IL-2) (for metastatic melanoma) and interferon (IFN)-α (for resected 
high risk melanoma) have produced the most promising and durable results, 
albeit in subgroups of patients only.(3) 
By the time melanoma has become clinically detectable, the theory of 
immunoediting holds that the tumor has already evolved mechanisms to evade 
the host immune response. Anti-CTLA4 therapy has a novel mechanism of 
action, unlocking the immune response by disrupting the CTLA4 checkpoint, a 
key regulator of T-cell activity that appears to play an important role in 
maintaining tolerance.(4) CTLA4 blocking antibodies (ipilimumab and 
tremelimumab) have shown promising and durable activity as monotherapy in a 
fraction of patients.(5) The ipilimumab-Gp100, MDX-1020, phase III study that 
lead to the recent FDA approval of ipilimumab at 3 mg/kg for advanced 
inoperable melanoma demonstrated significant OS prolongation in favor of 
ipilimumab.(6)  More recently, the MDX-024 phase III trial showed that 
ipilimumab at 10 mg/kg plus dacarbazine has significant survival benefit over 
dacarbazine alone as first-line treatment in metastatic melanoma.(7) 
Tremelimumab has shown promising clinical activity in earlier trials testing this 
anti-CTLA4 blocking antibody in pretreated advanced melanoma (A3671008) and 
in phase III clinical trial (A3671009) that enrolled 655 patients with treatment-
naive advanced melanoma and compared tremelimumab to  dacarbazine or 
temozolomide.(8) Although this study was halted for futility, the majority of 
responses to tremelimumab were durable and median survival was12 months. 
These efforts utilizing CTLA4 blockade to harness the immune system to target 
melanoma have had tremendous potential and have lead to significant progress, 
but also face daunting challenges reflected by the limited clinical benefits seen 
with monotherapy, overall and where there is room for major improvements in the 
magnitude of benefits derived and their durability. Although very promising, the 
benefits of ipilimumab monotherapy have been limited and it has become 
obvious that the future of melanoma therapy resides in rational combinations that 
build upon the promise of single agent activity with such agents as IFN-α that 
currently hold the most durable adjuvant immunotherapeutic survival benefits. 

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1.2 
IFN-2b and the Role of High-Dose IFN-α2b (HDI) as Adjuvant Therapy for High-
risk Resected Melanoma 
IFN-2b, a type-I IFN, has potent immunoregulatory, antiproliferative, 
differentiation-inducing, apoptotic, and anti-angiogenic properties in a variety of 
malignancies.(9) IFN-α at high dosage (HDI) has been shown to play a critical 
role in interrupting tumor immune tolerance both improving tumor immunogenicity 
and increasing dendritic cell (DC) activation and survival.(9, 10) IFN-α 
upregulates major histocompatibility complex (MHC) antigen processing and 
costimulatory molecules leading to more efficient antigen presentation that may 
elicit previously low-affinity autoreactive T-cells.(9, 10)  IFN-α has been reported 
to affect almost all stages of myeloid DC generation, maturation, differentiation 
and function(11) increase activation and survival of DCs, which in turn promote 
maturation of effector CD8 T cells.(9, 10)  Therefore, IFN-α has a potentially 
significant impact on tumor and antigen-presenting cells (APCs) by making the 
tumor more immunogenic and enhancing antigen cross presentation, jointly 
leading to better anti-tumor immunization. Moreover, in their immature state, IFN-
treated DCs induce a ‘polarized’ Th1 cytokine microenvironment.(12) Similarly, 
IFNs polarize lymphocytes towards the pro-inflammatory Th1 phenotype.(13-15) 
This may promote a significant impact of  type-I IFNs in the cytotoxic T cell 
compartment, inducing potent antitumor cell-mediated cytotoxicity(16), and 
promoting natural killer (NK) cell-mediated proliferation and cytotoxicity.(17) 
Type-I IFNs have been shown to activate APCs to produce chemokines that 
differentiate naïve CD4 T-cells, expand non-polarized antigen-primed Th1 T-
cells, and cooperate with NK cells to induce anti-tumor CD8 T-cells to create a 
polarized Th1-biased tumor micro-environment in which host effector response 
against melanoma is possible.(18) This IFN-induced Th1 bias can be detected in 
melanoma patient circulation as an upregulation of the pro-inflammatory cytokine 
response (Th1 polarization) as demonstrated in the adjuvant E1694 trial.(19) In 
addition, locally produced type-I IFNs induce the expression of integrins and 
chemokine receptors and recruitment of natural killer cells and macrophages 
leading to Th1 rather than Th2 lymphocyte traffic to the tumor site.(18) This has 
been demonstrated clinically where responding patients had significantly greater 
increases in intra-tumor CD11c+ DCs and CD3+ T-cells in a neoadjuvant 
melanoma study of HDI.(20) Therefore, IFN-α induces a Th1 shift in immunity, 
promotes antitumor cell-mediated cytotoxicity and attracts Th1 lymphocyte traffic 
to the tumor, while increasing cellular expression of MHC, making tumor cells 
better targets for cell-mediated immune attack. 
Clinically, three national cooperative group studies have evaluated the benefit of 
HDI as adjuvant therapy for resectable cutaneous melanoma that is at high-risk 
for recurrence and death. These included patients with regional lymph node 
metastases (T1-4, N1, M0) and primary localized deep melanomas (T4, N0, M0) that 
have a 5-year post-surgical relapse rate of more than 40-50%. The HDI 
treatment regimen is comprised of daily intravenous IFN-α2b at 20 MU/m² given 
for 5/7days for 4 weeks followed by a self-administered subcutaneous phase of 
10 MU/m² TIW for 48 weeks. The first and third of these studies both 
demonstrated significant relapse free as well as overall survival prolongation, 
compared to observation (E1684) and compared to a vaccine (GMK) that was 
selected as the optimal vaccine candidate at the time (E1694). The second trial, 
E1690, conducted in part before and in part after the approval of HDI, was 
associated with systematic crossover of patients from the observation-assigned 

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arm to treatment at nodal relapse with HDI.  This trial showed significant 
differences in terms of relapse-free but not overall survival.(21-23) The most 
recently reported intergroup adjuvant trial, E1694, tested HDI in relation to the 
GMK vaccine, for which outcome results appeared nearly identical to the prior 
E1690 observation arm, which was unblinded and reported when mortality and 
relapse frequencies observed with GMK proved to be significantly higher (RFS 
HR = 1.49; OS HR = 1.38) than with HDI.  Thus, the published literature contains 
three RCT reports of relapse-free survival benefit and two RCT reports of overall 
survival benefit of HDI that have yet to be equaled by any other therapy available 
for high-risk melanoma. The advantage for patients treated with HDI amounts to 
a relapse frequency reduction of 24-38% and mortality reduction of 22-32% 
based upon the hazard ratios for patients treated with HDI or observation, or the 
vaccine (GMK). 
1.3 
CTLA-4 and T Cell Activation 
Figure 1 
Mechanism of Action 
 
Advances in the understanding of the mechanisms that regulate T cell activation 
have allowed the rational design of new strategies for immunotherapy of tumors, 
including melanoma. It has been known for some time that engagement of the T 
cell antigen receptor by itself is not sufficient for full T cell activation; a second 
co-stimulatory signal is required for induction of IL-2 production, proliferation and 
differentiation to effector function of naive T cells. Abundant data now indicate 
that the primary source of this costimulation is mediated by engagement of CD28 
on the T cell surface by members of the B7 family on the antigen-presenting cell 
(APC).(24) (Figure 1.) 
Expression of B7 has been shown to be limited to “professional” antigen 
presenting cells; that is, specialized cells of the hematopoietic lineage, including 
dendritic cells, activated macrophages, and activated B cells. It has been 
suggested that this sharply-defined restriction of B7 expression is a fail-safe 
mechanism for maintenance of peripheral T cell tolerance, insuring that T cell 
activation can only be stimulated by appropriate APCs.(25) The fact that tumor 
cells do not express B7 contributes to their poor capacity to elicit immune 
responses.(26, 27) The demonstration that induction of expression of B7 on 
many tumor cells by transfection, transduction, or other mechanisms can 
heighten tumor immunogenicity led to great interest in pursuing this as an 
approach to tumor immunotherapy. As demonstrated in vivo in murine tumor 
models, the utility of B7 expression as a vaccination approach is limited by the 
following factors: (1) B7-expressing tumor cell vaccines are only effective when 
the tumor cells have a high degree of inherent immunogenicity; (2) while B7-

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expressing vaccines have been shown in many cases to be effective in inducing 
protective immune responses, they have demonstrated only limited utility in 
inducing responses to established tumors; and (3) inactivation of tumor cells by 
radiation has been shown to destroy the immuno-enhancing activity of the B7 
gene product.(28, 29) In the past few years it has become apparent that co-
stimulation is even more complex than originally thought. After activation, T cells 
express CTLA-4, a close homologue to CD28. CTLA-4 binds members of the B7 
family with a much higher affinity than CD28.(30) Although there was initially 
some controversy as to the role of CTLA-4 in regulating T cell activation, it has 
become clear that CTLA-4 down-regulates T cell responses.(31) This was initially 
suggested by the following in vitro observations: (1) blockade of CTLA-4/B7 
interactions with antibody enhanced T cell responses; (2) cross-linking of CTLA-4 
with CD3 and CD28 inhibited T cell responses; and (3) administration of 
antibodies to CTLA-4 in vivo enhanced the immune response to peptide antigens 
or superantigens in mice.(32-35) Blocking CTLA-4-B7 interaction while 
preserving signaling via CD28 resulted in enhanced T cell responses in vitro.(33) 
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-
4 came from examination of mice with a null mutation.(36-38) CTLA-4 knockout 
mice appear to have spontaneously activated T cells evident at approximately 1 
week after birth, followed by rampant lymphoproliferation and lymphadenopathy. 
These mice die at approximately 3 weeks of age, either as a result of polyclonal 
T cell expansion and tissue destruction or as a result of toxic shock resulting from 
lymphokine production by the T cells. Since thymocyte differentiation and 
selection proceed normally in CTLA-4-deficient mice, the rampant T cell 
expansion that occurs in the mice indicates that CTLA-4 plays a critical role in 
down-regulating T cell responses in the periphery.(35) 
1.4 
Summary of Results of Investigational Program of Ipilimumab 
1.4.1 
Pharmacology of Ipilimumab 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 
monoclonal antibody (mAb). In vitro studies were performed with 
ipilimumab to demonstrate that it is specific for CTLA-4, actively 
inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any 
cross-reactivity with human B7.1, B7.2 negative cell lines, and stains 
the appropriate cells without non-specific cross-reactivity in normal 
human tissues, as demonstrated by immunohistochemistry. 
Ipilimumab does cross-react with CTLA-4 in non-human primates 
including cynomolgus monkeys. 
1.4.2 
Animal Toxicology of Ipilimumab 
The effects of ipilimumab on prenatal and postnatal development in 
monkeys have not been fully investigated. Preliminary results are 
available from an ongoing study 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 

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incidences of infant mortality in a dose-related manner compared to 
controls. Genetically engineered mice heterozygous for CTLA-4 
(CTLA-4+/-), the target for ipilimumab, 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-/-). The CTLA-4-/- homozygous 
negative offspring appeared healthy at birth, exhibited signs of 
multiorgan lymphoproliferative disease by 2 weeks of age, and all died 
by 3–4 weeks of age with massive lymphoproliferation and multiorgan 
tissue destruction. 
Complete information on the pre-clinical toxicology studies can be 
found in the Ipilimumab Investigator Brochure (IB). Non-clinical toxicity 
assessments included in vitro evaluation for the potential of 
ipilimumab to mediate complement-dependent cellular cytotoxicity 
(CDCC) or antibody-dependent cellular cytotoxicity (ADCC), and 
toxicology assessments in cynomolgus monkeys alone and in the 
presence of vaccines. The in vitro studies demonstrated that 
ipilimumab did not mediate CDCC of PHA- or (CD)3-activated human 
T cells. However, low to moderate ADCC activity was noted at 
concentrations up to 50 ug/mL. These data are consistent with the 
requirement of high levels of antigen expression on the surface of 
target cells for efficient ADCC or CDCC. Since ipilimumab is a human 
IgG1, an isotype generally capable of mediating CDCC and ADCC, 
the lack of these activities is likely due to a very low expression of 
CTLA-4 on activated T cells. Therefore, these data suggest that 
ipilimumab treatment would not result in depletion of activated T cells 
in vivo. Indeed, no depletion of T cells or T cell subsets were noted in 
toxicology studies in cynomolgus monkeys. 
No mortality or signs of toxicity were observed in three independent 
14-day intravenous toxicology studies in cynomolgus monkeys at 
multiple doses up to 30 mg/kg/dose. Furthermore, ipilimumab was 
evaluated in sub-chronic and chronic toxicology studies in 
cynomolgus monkeys with and without Hepatitis B (HepB) Vaccine 
and Melanoma Vaccine. Ipilimumab was well tolerated alone or in 
combination in all studies. There were no significant changes in 
clinical signs, body weight values, clinical pathology values or T cell 
activation markers. In addition, there were no significant 
histopathology changes in the stomach or colon. 
1.4.3 
Clinical Pharmacology of Ipilimumab 
1.4.3.1 
Mechanism of Action of Ipilimumab 
CTLA-4 is a negative regulator of T-cell activation. 
Ipilimumab binds to CTLA-4 and blocks the interaction of 
CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 
has been shown to augment T-cell activation and 
proliferation. The mechanism of action of ipilimumab’s 
effect in patients with melanoma is indirect, possibly 
through T-cell mediated anti-tumor immune responses. 

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1.4.3.2 
Pharmacokinetics of Ipilimumab 
The pharmacokinetics 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 for four doses. Peak concentration (C max), 
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 every 3 weeks, 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 
pharmacokinetic 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 pharmacokinetics were assessed in population 
pharmacokinetic 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 
pharmacokinetics 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 pharmacokinetics in patients with various 
degrees of hepatic impairment. 

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Pharmacokinetic (PK) profiles for ipilimumab have been 
analyzed. The primary objective of Protocol MDX010-015 
was to determine the safety and PK profile of single and 
multiple doses of ipilimumab derived from a transfectoma 
or hybridoma cell line. Mean plasma concentrations of 
ipilimumab administered at doses of 3 mg/kg (hybridoma-
derived drug product); 2.8 mg/kg, 5 mg/kg, 7.5 mg/kg, 
10 mg/kg, 15 mg/kg, and 20 mg/kg (transfectoma-derived 
drug product) demonstrated approximate dose 
proportionality. Equimolar doses of hybridoma-derived and 
transfectoma-derived drug product had comparable PK 
profiles. The range of mean volume of distribution at 
steady state (Vss) across cohorts 2.8, 3, 5, 7.5, 10, 15, and 
20 mg/kg, was 57.3 to 82.6 mL/kg, indicating drug 
distribution was mostly limited to the intravascular space. 
The clearance was low (range 0.11 to 0.29 mL/h/kg) and 
reflective of the half-life (range 297 to 414 h), which is 
consistent with the long terminal disposition phase of 
ipilimumab. There was moderate variability in the PK 
parameters among subjects, with CV of 11% to 48% in 
AUC(0-21d), 20% to 59% in CL, and 17% to 46% in Vss. 
Ipilimumab was originally produced and purified from a 
hybridoma clone. Ipilimumab drug substance is currently 
manufactured using Process B. A new drug substance 
manufacturing process (Process C) has been developed 
utilizing a higher producing sub-clone of the current Master 
Cell Bank, and modified cell culture and purification steps. 
The new drug substance manufacturing process is 
intended to replace the current drug substance 
manufacturing process. The biocomparability of Process C 
relative to Process B was assessed in Study CA184087. 
PK in Phase 1 Study CA184087 (Process B and 
Process C): The PK of ipilimumab was assessed when 
manufactured by a newer process C relative to current 
process B as an IV infusion (1.5-hr), in subjects with 
advanced melanoma (CA184087). Upon meeting eligibility 
criteria, subjects were randomized (1:1) to receive either 
ipilimumab Process B (Arm A, reference) or ipilimumab 
Process C (Arm B, test) at a dose of 10 mg/kg IV 
administered over 90 minutes every 3 weeks on Days 1, 
22, 43, and 64 (Weeks 1, 4, 7, and 10) during induction 
therapy. Randomization was stratified by baseline body 
weight (BW) and LDH values since both were identified as 
potential covariates in a population PK assessment. The 
primary endpoint of PK data at week 4 demonstrated that 
the PK of Process B and Process C are biocomparable as 
the 90% CIs for the ratio of geometric means of 
AUC(0-21d) and Cmax - both adjusted or not adjusted for 
covariates - were entirely contained with the pre-specified 
equivalence interval (80 - 125%). 

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Population Pharmacokinetics: The population 
pharmacokinetics (PPK) of ipilimumab was developed with 
420 subjects (1767 serum concentrations) with advanced 
melanoma in phase 2 studies (CA184007, CA184008, and 
CA184022). Subsequently, the final PPK model was 
evaluated by an external model validation dataset from 
CA184004 (79 subjects with 328 serum concentration 
data). The PPK analysis demonstrated that PK of 
ipilimumab is linear and exposures are dose proportional 
across the tested dose range of 0.3 to 10 mg/kg, and the 
model parameters are time-invariant. The ipilimumab CL of 
15.3 mL/h from PPK analysis is consistent with that 
determined by PK analysis as assessed in MDX010-15 as 
12.8 mL/h for a dose of 2.8 mg/kg and 15.7 mL/h for a 
dose of 10 mg/kg. The terminal half-life and Vss of 
ipilimumab calculated from the model were 14.7 days, and 
7.21 L, which are consistent with that determined by non-
compartmental analysis (NCA). Volume of central and 
peripheral compartment were found to be 4.16 and 3.22 L, 
respectively, suggesting that ipilimumab first distributes 
into plasma volume and subsequently into extracellular 
fluid space. Clearance of ipilimumab was found to increase 
with increase in body weight, supporting dosing of 
ipilimumab based on a weight normalized regimen. Other 
covariates had effects that were either not statistically 
significant or were of minimal clinical relevance. 
1.4.4 
Clinical Safety with Ipilimumab 
1.4.4.1 
Overview of Clinical Trials Experience with Ipilimumab 
The clinical development program excluded patients with 
active autoimmune disease or those receiving systemic 
immunosuppression for organ transplantation. Exposure to 
ipilimumab 3 mg/kg for four doses given by intravenous 
infusion in previously treated patients with unresectable or 
metastatic melanoma was assessed in a randomized, 
double-blind clinical study (MDX010-20). One hundred 
thirty-one patients (median age 57 years, 60% male) 
received ipilimumab as a single agent, 380 patients 
(median age 56 years, 61% male) received ipilimumab with 
an investigational gp100 peptide vaccine (gp100), and 132 
patients (median age 57 years, 54% male) received gp100 
peptide vaccine alone. Patients in the study received a 
median of 4 doses (range 1 to 4 doses). Ipilimumab was 
discontinued for adverse reactions in 10% of patients. The 
most common adverse reactions (≥5%) in patients who 
received ipilimumab at 3 mg/kg were fatigue, diarrhea, 
pruritus, rash, and colitis. Table 1 presents selected 
adverse reactions from MDX010-20, which occurred in at 
least 5% of patients in the ipilimumab-containing arms and 
with at least 5% increased incidence over the control 

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gp100 arm for all-grade events and at least 1% incidence 
over the control group for Grade 3–5 events. 
 
Table 1: 
Selected Adverse Reactions in MDX010-20 
 
Percentage (%) of Patientsa 
 
YERVOY 3 mg/kg 
n = 131 
YERVOY 3mg/kg  
+ gp100  
n = 380 
gp100 
n = 132 
System Organ 
Class/Preferred Term 
Any Grade 
Grade 3-5 
Any Grade 
Grade 3-5 
Any Grade 
Grade 3-5 
Gastrointestinal 
Disorders 
 
 
 
 
 
 
Diarrhea 
32 
5 
37 
4 
20 
1 
Colitis 
8 
5 
5 
3 
2 
0 
Skin and 
Subcutaneous Tissue 
Disorders 
 
 
 
 
 
 
Pruritus 
31 
0 
21 
<1 
11 
0 
Rash 
29 
2 
25 
2 
8 
0 
General Disorders 
and Administration 
Site Conditions  
 
 
 
 
 
 
Fatigue 
41 
7 
34 
5 
31 
3 
a Incidences presented in this table are based on reports of adverse events regardless of causality. 
Source: Yervoy Prescribing Information, Bristol-Myers Squibb, March 2011. 
Table 2 presents the per-patient incidence of severe, life-
threatening, or fatal immune-mediated adverse reactions 
from MDX010-20. 
Table 2: 
Severe to Fatal Immune-mediated Adverse Reactions in MDX010-20 
 
Percentage (%) of Patients 
 
YERVOY 3 mg/kg 
n = 131 
YERVOY 3 mg/kg + gp100  
n = 380 
Any Immune-mediated Adverse Reaction  
15 
12 
Entercolitis a,b 
7 
7 
Hepatotoxicity a 
1 
2 
Dermatitis a 
2 
3 
Neuropathy a 
1 
< 1 
Endocrinopathy 
4 
1 
Hypopituitarism 
4 
1 
Adrenal insufficiency 
0 
1 
Other 
 
 
Pneumonitis 
0 
< 1 
Meningitis 
0 
< 1 
Nephritis 
1 
0 
Eosinophilia c 
1 
0 
Pericarditis a,c 
0 
< 1 
a Including fatal outcome 
b Including intestinal perforation 
c Underlying etiology not established 
Source: Yervoy Prescribing Information, Bristol-Myers Squibb, March 2011. 
CA184024 evaluated the addition of 10 mg/kg ipilimumab 
to dacarbazine in patients with previously untreated, 

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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 predominately 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. Select adverse events 
associated with the mechanism of action of ipilimumab, 
regardless of attribution by the investigator) are shown in 
Table 3. 
 
Table 3: 
CA184024 Select Adverse Events 
 
Ipilimumab + DTIC 
n = 247 
Placebo + DTIC 
n = 251 
Total 
Grade 3 - 4 
Total 
Grade 3 - 4 
% Patients 
Dermatologic 
 
 
 
 
 
Pruritis 
29.6 
2.0 
8.8 
0 
 
Rash 
24.7 
1.2 
6.8 
0 
Gastrointestinal (GI) 
 
 
 
 
 
Diarrhea 
36.4 
4.0 
24.7 
0 
 
Colitis 
4.5 
2.0 
0.4 
0 
 
GI perforation 
0 
0 
0 
0 
Hepatic 
 
 
 
 
 
Increased ALT 
33.2 
21.9 
5.6 
0.8 
 
Increased AST 
29.1 
18.2 
5.6 
1.2 
Endocrine 
 
 
 
 
 
Hypothyroidism 
1.6 
0 
0.4 
0 
 
Autoimmune thyroiditis 
0.8 
0 
0 
0 
 
Hyperthyroidism 
0.4 
0 
0.4 
0 
 
Hypophysitisa 
0 
0 
0 
0 
a 
1 (0.4%) hypophysitis was reported on Day 364. 

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Safety Profile of Ipilimumab at a Dose of 10 mg/kg 
(Phase 2 data) 
The safety profile of ipilimumab at a dose of 10 mg/kg was 
characterized in a total of 325 subjects who received 
multiple doses of 10 mg/kg ipilimumab as monotherapy in 
the 4 completed melanoma studies (CA184004, -007, -
008, and -022). 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 are displayed in Table 4. 
 
Table 4: 
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 (eg, rash, pruritus) 
52.0 
49.2 
2.8 
6.14 
GI (eg, colitis, diarrhea) 
37.2 
24.9 
12.3 
2.29 
Liver (eg, LFT elevations) 
8.0 
0.9 
6.8 
4.0 
Endocrine (eg, hypophysitis, 
hypothyroid) 
6.2 
3.7 
2.5 
20.1 
Overall, the 10 mg/kg had an acceptable safety regimen, 
while being the most active dose. The study drug related 
deaths across the program are in Section 5 of the 
investigators brochure. Across clinical studies that utilized 
ipilimumab doses ranging from 0.3 to 10 mg/kg, the 
following adverse reactions were also reported (incidence 
less than 1% unless otherwise noted): urticaria (2%), large 
intestinal ulcer, esophagitis, acute respiratory distress 
syndrome, renal failure, and infusion reaction. Based on 
the experience in the entire clinical program for melanoma, 
the incidence and severity of enterocolitis and hepatitis 
appear to be dose dependent. 
Updated data provided by BMS from a pooled analysis of 
phase II studies of ipilimumab 10 mg/kg, multiple doses, 
including studies CA184004, CA184007, CA184008, 
CA184022 and CA184042, reviewed AEs from 353 
patients treated with ipilimumab 10 mg/kg. A total of 10 
related deaths were reported and at least 7 were 
considered irAE. These cases included colon perforation, 
multiorgan failure/disease progression, Grade 3 
hypophysitis/disease progression, acute myeloid leukemia, 
acute glomerulonephritis, hypovolemic shock, liver 
dysfunction, Grade 3 AST increase/unknown cause of 
death, Grade 2 enterocolitis/disease progression, Grade 4 
septic shock/Disease. In 3 cases, it was determined that 
the AE management algorithms were not followed: 
- Colon perforation (patient treated with pulse steroids; no 
high dose steroids and no taper). 
Rev. 5/14 

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- Liver dysfunction (patient received ipilimumab in the 
setting of severe liver dysfunction). 
- Gr2 enterocolitis (treated with prednisone and rapid taper. 
Patient died of disease progression but the enterocolitis 
was still ongoing at that time). 
1.4.4.2 
Immunogenicity of Ipilimumab 
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. Immunogenicity assay results are highly 
dependent on several factors including assay sensitivity 
and specificity, assay methodology, sample handling, 
timing of sample collection, concomitant medications, and 
underlying disease. For these reasons, comparison of 
incidence of antibodies to ipilimumab with the incidences of 
antibodies to other products may be misleading. 
1.4.4.3 
Pregnancy Outcomes After Exposure to Ipilimumab 
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 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. 
1.4.4.4 
Immune-mediated Adverse Reactions with Ipilimumab 
Ipilimumab can result in severe and fatal immune-mediated 
reactions due to T-cell activation and proliferation. 

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Immune-related Gastrointestinal Events 
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. 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 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. 
Immune-related Hepatotoxicity 
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 levels must be evaluated before each dose of 
ipilimumab as early laboratory changes may be indicative 
of emerging immune-related hepatitis. 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 medications, 
and monitored until resolution. Liver biopsies from patients 
who had immune-related hepatotoxicity showed evidence 
of acute inflammation (neutrophils, lymphocytes, and 
macrophages). 
Immune-related Skin Toxicity 
Skin immune-related AEs presented mostly 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. 
Immune-related Endocrinopathy 
Ipilimumab can cause inflammation of the endocrine 
system organs, specifically hypophysitis, hypopituitarism, 
and adrenal insufficiency and patients may present with 
nonspecific symptoms, which may resemble other causes 
such as brain metastasis or underlying disease. The most 
common clinical presentation includes headache and 
fatigue. Symptoms may also include visual field defects, 
behavioral changes, electrolyte disturbances, 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. It is possible that long term hormone replacement 

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therapy will be required for subjects developing 
hypophysitis/hypopituitarism after treatment with 
ipilimumab. 
Immune-related Neurological Events 
Neurological manifestations included muscle weakness 
and sensory neuropathy. Fatal Guillain-Barré syndrome 
has been reported in clinical trials of ipilimumab. Patients 
may present with muscle weakness. Sensory neuropathy 
may also occur. 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, and 
medications should be excluded. 
Other Immune-related AEs 
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.  
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. 
1.4.5 
Clinical Efficacy of Ipilimumab in Melanoma 
The clinical efficacy of ipilimumab as a single agent at a dose of 3 
mg/kg administered every 3 weeks 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 for the treatment of unresectable or metastatic melanoma. 
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 and was feasible with an acceptable 
safety profile. 
1.4.5.1 
MDX010-20 (Phase 3, 3 mg/kg, previously treated 
melanoma) 
MDX010-20, a randomized (3:1:1), double-blind, double-
dummy study included 676 randomized subjects with 

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unresectable or metastatic melanoma previously treated 
with one or more of the following: aldesleukin, 
dacarbazine, temozolomide, fotemustine, or carboplatin. Of 
these 676 subjects, 403 were randomized to receive 
ipilimumab at 3 mg/kg in combination with an 
investigational peptide vaccine with incomplete Freund’s 
adjuvant (gp100), 137 were randomized to receive 
ipilimumab at 3 mg/kg, and 136 were randomized to 
receive gp100 alone. The study enrolled only subjects with 
HLA A2*0201 genotype; this HLA genotype facilitates the 
immune presentation of the investigational peptide 
vaccine. The study excluded subjects with active 
autoimmune disease or those receiving systemic 
immunosuppression for organ transplantation. 
Ipilimumab/placebo was administered at 3 mg/kg as an 
intravenous infusion every 3 weeks for 4 doses. 
Gp100/placebo was administered at a dose of 2 mg 
peptide by deep subcutaneous injection every 3 weeks for 
four doses. Assessment of tumor response was conducted 
at Weeks 12 and 24, and every 3 months thereafter. 
Subjects with evidence of objective tumor response at 12 
or 24 weeks had assessment for confirmation of durability 
of response at 16 or 28 weeks, respectively. 
The major efficacy outcome measure was overall survival 
(OS) in the ipilimumab + gp100 arm compared to that in 
the gp100 arm. Secondary efficacy outcome measures 
were OS in the ipilimumab + gp100 arm compared to the 
ipilimumab arm, OS in the ipilimumab arm compared to the 
gp100 arm, best overall response rate (BORR) at Week 24 
between each of the study arms, and duration of response. 
Of the randomized subjects, 61%, 59%, and 54% in the 
ipilimumab + gp100, ipilimumab, and gp100 arms, 
respectively, were men. Twenty-nine (29%) percent were  
65 years of age, the median age was 57 years, 71% had 
M1c stage, 12% had a history of previously treated brain 
metastasis, 98% had ECOG performance status of 0 and 
1, 23% had received aldesleukin and 38% had elevated 
LDH level. Sixty-one (61%) percent of subjects randomized 
to either ipilimumab -containing arm received all 4 planned 
doses. The median duration of follow-up was 8.9 months. 
The OS results are shown in Table 5 and Figure 2. 
 

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Table 5: 
MDX010-20 Overall Survival Results 
 
Ipilimumab 
n = 137 
Ipilimumab + 
gp100 
n = 403 
gp100 
n = 136 
Hazard Ratio (vs gp100) 
 
(95% CI) 
0.66 
(0.51, 0.87) 
0.68 
(0.55, 0.85) 
 
 
p-value 
p = 0.0026a 
p = 0.0004 
 
Hazard Ratio (vs ipilimumab) 
 
(95% CI) 
 
1.04 
(0.83, 1.30) 
 
Median (months) 
 
(95% CI) 
10 
(8.0, 13.8) 
10 
(8.5, 11.5) 
6 
(5.5, 8.7) 
a 
Not adjusted for multiple comparisons 
Figure 2: MDX010-20 - Overall Survival by Treatment (ITT 
Population) 
 
The best overall response rate (BORR) as assessed by the 
investigator was 5.7% (95% CI: 3.7%, 8.4%) in the 
ipilimumab + gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in 
the ipilimumab arm, and 1.5% (95% CI: 0.2%, 5.2%) in the 
gp100 arm. The median duration of response was 11.5 
months in the ipilimumab + gp100 arm and has not been 
reached in the ipilimumab or gp100 arm. 
1.4.5.2 
CA184024 (Phase 3, previously untreated melanoma, 10 
mg/kg) 
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/kg or placebo 
cycles 1-4, and as maintenance after completion of 
chemotherapy. The two arms were well balanced 
regarding most baseline characteristics, as shown in Table 
6. 

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Table 6: 
CA184024 Baseline Characteristics 
 
Ipilimumab + DTIC 
n = 250 
Placebo + DTIC 
n = 252 
Age (years) 
 
 
 
Mean 
57.5 
56.4 
Gender (%) 
 
 
 
Male 
60.8 
59.1 
 
Female 
39.2 
40.9 
M Stage (%) 
 
 
 
M0 
2.4 
3.2 
 
M1a 
14.8 
17.1 
 
M1b 
25.6 
24.6 
 
M1c 
57.2 
55.2 
ECOG PS (%) 
 
 
 
0 
70.8 
71.0 
 
1 
29.2 
29.0 
LDH (%) 
 
 
 
 ULN  
62.8 
55.6 
 
> ULN  
37.2 
43.7 
 
 2x ULN 
86.4 
85.3 
Patients on the ipilimumab arm received a median of 3 
ipilimumab induction doses, versus 4 placebo induction 
doses on the placebo arm. A total of 17.4% and 21.1% of 
patients continued to receive maintenance ipilimumab or 
placebo, for a median of 4 and 2 doses, respectively. The 
number of patients who received all 8 dacarbazine doses 
was 12.2% in the ipilimumab arm, and 21.5% in the 
placebo arm. The study met its primary end-point of 
prolonging overall survival in patients treated with 
ipilimumab (HR 0.72 (95% CI, 0.59 – 0.87), median OS 
11.2 vs 9.1 months, p = 0.0009). The OS Kaplan-Meier 
curve is presented in Figure 3. 
Figure 3: CA184024 Kaplan-Meier Plot of Overall 
Survival - All Randomized Subjects 
 
PROPORTION ALIVE
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Ipilimumab + DTIC 
Placebo + DTIC 
Months 

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One, two and three year survival rates were 47.3%, 28.5% 
and 20.8% in the ipilimumab arm, and 36.3%, 17.9% and 
12.2% in the placebo arm. PFS, a secondary end-point, 
was also prolonged by the addition ipilimumab, HR 
0.76 (95% CI, 0.63 - 0.93). The median PFS was 2.8 
months in the ipilimumab and vs 2.6 months in the placebo 
arm, p = 0.006. BORR was increased from 10.3% in the 
placebo arm to 15.2% in the ipilimumab arm (Table 7). 
More importantly, duration of response was more than 
twice as long in the ipilimumab arm (19.3 months) than in 
the placebo arm (8.1 months). 
Table 7: 
CA184024 Tumor Response 
 
Ipilimumab + DTIC 
n = 250 
Placebo + DTIC 
n = 252 
Disease Control Rate, n (%) 
83 (33.2) 
76 (30.2) 
BORR (CR + PR), n (%) 
38 (15.2) 
26 (10.3) 
 
Complete response 
4 (1.6) 
2 (0.8) 
 
Partial response 
34 (13.6) 
24 (9.5) 
 
Stable disease 
45 (18.0) 
50 (19.8) 
 
Progressive disease 
111 (44.4) 
131 (52.0) 
Duration of response, months 
19.3 
8.1 
1.4.5.3 
10 mg/kg Dosing with Ipilimumab 
In melanoma, Phase 3 studies show improved survival at 
both 3 mg/kg (study MDX010 20) as well as with 10 mg/kg 
(study CA184024). Several additional conducted 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 is necessary to ensure a blockade 
of the CTLA-4 pathway: in vitro a concentration of  
20 g/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 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 

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as CR, PR, or prolonged SD (ie, 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 during the induction 
period had the highest response, disease control rates, 
median OS as well as 1-year and 2-year survival rates 
compared to other doses. The CA184022 data are 
summarized in Table 8. 
Table 8: Summary of Phase 2 Response Data in Melanoma (CA184022) 
 
10 mg/kg 
(n = 72) 
3 mg/kg 
(n = 72) 
0.3 mg/kg 
(n = 73) 
BORR (mWHO) – % 
(95% CI) 
11.1 
(4.9 - 20.7) 
4.2 
(0.9 - 11.7) 
0 
(0.0 - 4.9) 
DCR (mWHO) – % 
(95% CI) 
29.2 
(19.0 - 41.1) 
26.4 
(16.7 - 38.1) 
13.7 
(6.8 - 23.8) 
Survival rate at 1 year - % 
%, 95% CI 
48.64 
(36.84, 60.36) 
39.32 
(27.97, 50.87) 
39.58 
(28.20, 51.19) 
Survival rate at 2 year - % 
%, 95% CI 
29.81 
(19.13, 41.14) 
24.20 
(14.42, 34.75) 
18.43 
(9.62, 28.22) 
Overall median survival 
95%CI (months) 
11.43 
(6.90, 16.10) 
8.74 
(6.87, 12.12) 
8.57 
(7.69, 12.71) 
Finally, the dose and schedule in study CA184156 is the 
one that was evaluated in the signal finding study 
CA184041, with an acceptable safety profile and 
improvement of irPFS and OS. Treatment with ipilimumab 
has demonstrated clinically important and durable tumor 
responses in several malignancies including melanoma, 
prostate cancer, and renal cell carcinoma. 
1.4.5.4 
Advanced Melanoma 
Ipilimumab prolonged survival in subjects with pre-treated 
advanced melanoma are based on results from MDX010-
20 (Phase 3) supported by data from Phase 2 studies; the 
primary efficacy and safety studies are summarized in 
Table 9. The primary endpoint in MDX010 20 was OS, 
which was also a key secondary endpoint in Phase 2 
studies. 

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Table 9: 
Studies Supporting the Efficacy and Safety of Ipilimumab in Subjects with Advanced 
Melanoma 
 
 
 
 
# Randomized or 
Enrolled/Treated 
Study No. 
(Phase) 
Populations 
Primary 
Efficacy 
Endpoint 
Doses Studies 
3  
mg/kg 
10 
mg/kg 
Total 
MDX010-20 
(Phase 3) 
HLA-A2*0201-
positive, 
previously treated, 
unresectable 
Stage III or IV 
melanoma 
OS 
3 mg/kg q3 wk x 4  
gp100 (induction) 
followed by re-
induction 
540/512 
--/-- 
676/643a 
CA184022  
(Phase 2)  
Previously treated, 
unresectable 
Stage III or IV 
melanoma  
BORR 
0.3, 3, or 10 mg/kg q3 
wk x 4 (induction) 
followed by 
maintenance dosing 
q12 wk 
72/71 
72/71 
217/214 
CA184004  
(Phase 2) 
Biomarker 
Study 
Unresectable 
Stage III or IV 
melanoma  
BORR 
3 or 10 mg/kg q3 wk x 
4 (induction) followed 
by maintenance 
dosing q12 wk 
40/40 
42/42 
82/82 
CA184008  
(Phase 2) 
Previously treated 
unresectable State 
III or IV melanoma 
BORR 
10 mg/kg q3 wk x 4 
(induction) followed by 
maintenance dosing 
q12 wk 
--/-- 
155/155 155/155 
CA184007 
Unresectable 
Stage III or IV 
melanoma 
BORR 
10 mg/kg q3 wk x 4  
budesonide (induction) 
followed by 
maintenance dosing 
q12 wk 
--/-- 
115/115 115/115 
Additional Studies  
 
 
 
 
 
MDX010-08 
(Phase 2) 
Chemotherapy-
naive advanced 
melanoma 
ORR 
3 mg/kg q4 wk x 4  
DTIC (induction) 
78/74 
--/-- 
78/74 
CA184042  
(Phase 2) 
Stage IV 
melanoma with 
brain metastases 
DCR 
10 mg/kg q3 wk x 4 
(induction) followed by 
maintenance dosing 
q12 wk 
--/-- 
28/28b 
28/28b 
MDX010-28 
(Phase 
2) 
Survival 
Follow-up 
Study 
Subjects enrolled 
in earlier Medarex 
studies, including 
MDX010-08 and 
MDX010-15c 
OS 
N/A 
--/N/A 
--/N/A 
--/N/A 
BORR = best overall response rate; DCR = disease control rate; DTIC = dacarbazine; N/A = not 
applicable; ORR = overall response rate; OS = overall survival; PK = pharmacokinetics. 
a Total includes 136 randomized/131 treated subjects in the gp100 treatment group. 
b Information is presented only for subjects enrolled in MDX010-20, Arm A. 
c MDX010-15 was primarily a PK study that evaluated ipilimumab at single and multiple doses.  
Source:  Reference 16-23 

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1.5 
Overall Risk/Benefit Assessment of Ipilimumab Studies 
Ipilimumab is the first drug to demonstrate prolonged survival in subjects with 
pre-treated advanced melanoma, based on a large, multinational, double-blind, 
pivotal, Phase 3 study supported by a comprehensive Phase 2 program. The 
unique immune-based mechanism of action is reflected in the clinical patterns of 
anti-cancer activity in some patients. Ipilimumab impacts 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, inflammation may not be noted by radiological examination and 
objective response is observed with the first tumor assessment in a manner seen 
in patients receiving other types of anti-cancer treatments. In other 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 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. 
In summary, ipilimumab offers clinically meaningful and statistically significant 
survival benefit to patients with pre-treated advanced melanoma and evidence of 
clinical activity in randomized studies in other tumor types. These findings, 
together with evidence of a safety profile that is manageable with careful 
monitoring and appropriate intervention for treatment of immune-mediated 
toxicities, suggest an acceptable benefit to risk ratio. 

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1.6 
A phase II study of tremelimumab combined with HDI for metastatic melanoma 
A phase II study testing the combination the anti-CTLA4 blocking monoclonal 
antibody tremelimumab and HDI was conducted in metastatic melanoma.(39) 
Tremelimumab was given at 15 mg/kg IV/course q12 wks. HDI was given 
concurrently including IV induction at 20 MU/m2 IV, 5 d/wk x 4 wks followed by 
maintenance at 10 MU/m2 SC TIW, for 8 wks/course. From course 2 onward, HDI 
maintenance was given SC. Dose delays were allowed for tremelimumab, and if 
HDI was tolerable with dose modification patients continued HDI even if 
tremelimumab was discontinued. A 2-stage design was adopted. 
At the completion of stage 1 accrual, 16 patients were enrolled. All had AJCC 
stage IV melanoma (4 M1a, 2 M1b, 10 M1c) and all had previously received 
therapy for metastatic disease (range 1-5 prior regimens). Two patients had 
previously treated stable brain metastases. A total of 24 courses have been 
administered (median of 1 course per patient; 6 patients continue on therapy). 
The frequency of grade 3/4 toxicities did not exceed experience with the FDA-
approved HDI regimen alone. Grade 3/4 toxicities included neutropenia (3 
patients; 19%), hepatic enzyme elevations >5 fold ULN (2; 13%), fatigue (6; 
38%), anxiety (2; 13%). One patient had grade 4 autoimmune colitis leading to 
treatment discontinuation, but recovered completely following steroid therapy. 
The overall response rate was 19% (3 partial responses lasting 2+ - 4+ months). 
Responses were seen in both M1a (1) and M1c (2) disease. Two of the PRs 
were associated with autoimmune manifestations (autoimmune colitis and 
marked vitiligo). Six patients have stable disease lasting 1+ - 4.5 months and 3 
have had progression.(40, 41) 
The study completed accrual (stages I and II) with 37 patients enrolled, median 
age 58 (28-76). All subjects had AJCC stage IV (9 M1a, 6 M1b, 22 M1c) and 
most had previously received therapy (0-5 regimens). Two patients had prior 
treated brain metastases. Seventy two courses of tremelimumab have been 
administered as of the data cut-off date (average 2/pt).  Grade 3/4 toxicities 
included neutropenia (6 pts; 17%), diarrhea/colitis (4; 11%), liver enzyme 
elevation (4; 11%), rash (4; 11%), fatigue (15; 40%), anxiety/depression (5; 
14%). Autoimmune toxicities due to tremelimumab were successfully managed 
with steroids.  Table 10 summarizes the adverse event profile. 
Response data were available for 35 patients. Best OR rate (RECIST) was 26% 
(90%CI=0.14-0.38) (4CR and 5PR lasting 6, 6, 12+, 14+, 18+, 20, 28+, 30, 37+ 
months). By intent to treat (N=37), the response rate was 24% (90%CI=13%-
36%). Fourteen patients (38%) had SD lasting up to 21 months. Among these 9 
responders, 4 had prior adjuvant IFN-α. Seven patients had prior high dose IL-2, 
but none of these patients had a response on this study. Tables 11 and 12 
summarize tumor response data and the durability of the responses. 
Median PFS was 6.4 months (95%CI = 3.3-12.1 months). Median OS was 21 
months (95%CI=9.5,-). Conducting an exploratory analysis utilizing the model 
proposed by Korn et. al., the predicted 1-year OS rate was 21% while the 
observed rate was 62% (95% CI = 46%, 78%); p <.0001.(42) Please see Figures 
4 and 5 and Table 13. 
There was significant association between therapy-induced autoimmunity and 
clinical benefit (CR/PR/SD;P=0.0059).  Lower baseline C-reactive protein (CRP ≤ 
2.7ULN) was associated with clinical benefit (p=0.0494) and improved probability 

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of survival (p=0.0032). Higher absolute lymphocyte count at baseline was 
associated with response (CR/PR;p=0.0183) and clinical benefit 
(CR/PR/SD;p=0.0255). However, biomarker associations were not significant 
(P>.05) after adjusting for multiple comparisons. 
These results compare favorably to monotherapy with HDI,  tremelimumab(43) or 
ipilimumab.(6) IFN-α was the first recombinant cytokine to be investigated for the 
therapy of metastatic melanoma yielding response rates of about 16%. However, 
the median duration of response was only about 4 months. The ipilimumab-
Gp100 phase III study that lead to recent FDA approval of ipilimumab for 
metastatic melanoma randomized 676 pretreated patients. The RR was 5.7% 
(ipilimumab+gp100), 10.9% (ipilimumab+placebo), 1.5% (gp100+placebo). 
Median OS was 10.0 months (ipilimumab+gp100), 10.1 months 
(ipilimumab+placebo), 6.4 months (gp100+placebo). The 1-year survival rates 
were 44% (ipilimumab+gp100), 46% (ipilimumab+placebo), 25% (gp100 + 
placebo).(6)  Our data in this study also compare favorably to the MDX-024 
phase III trial where ipilimumab plus dacarbazine had a significant survival 
benefit over dacarbazine alone as first-line treatment in metastatic melanoma 
(median OS 11.2 vs. 9.1 months, median PFS 2.8 vs. 2.6 months, RR 15% vs. 
10%).(7) Tremelimumab at 15 mg/kg every 90 days (up to 4 cycles) was tested in 
a second line phase II study (A3671008) in inoperable, AJCC stage III/IV 
melanoma (N=246).(44) The objective RR was 7%, median OS 10.1 months and 
the one-year survival rate was 41%.(44) In a subsequent phase III trial 
(A3671009) in treatment-naive advanced melanoma comparing tremelimumab to  
dacarbazine/temozolomide, median OS was 11.8 months.(8) In terms of safety, 
the results of this study that tested the combination of HDI and tremelimumab at 
15 mg/kg are comparable to other studies testing anti-CTLA4 monoclonal 
antibody therapy, as summarized in Table 14. 
Therefore, this study has met the phase II criteria for safety and efficacy. The 
combination of HDI and tremelimumab had tolerable and manageable toxicity in 
relation to the therapeutic benefit observed. Testing in a randomized setting is 
therefore now warranted. Given the interval FDA approval of ipilimumab for 
therapy of advanced melanoma, this study would by extension argue for 
evaluation of ipilimumab in combination with IFN- in a randomized phase II 
study. 

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Figure 4. Kaplan – Meier plot of the probability of progression-free survival (N=37). The 
estimated median is 6.4 months (95% Confidence Interval = 3.3, 12.1). 
 
 
Figure 5. Kaplan – Meier plot of the probability of overall survival (N=37). The estimated 
median is 21 months (95% Confidence Interval = 9.5 months, -). 
 
 

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Table 10. Adverse events considered possibly, probably or definitely related to the study 
regimen (CTCAE v.3) 
Type  
All Grades 
Grade 3 
Grade 4 
 
No. 
Patients 
% 
No. 
Patients 
% 
No. 
Patients 
% 
Immune mediated  
 
 
 
 
 
 
Diarrhea/Colitis 
21 
57.0 
3 
8.0 
1 
2.7 
Hyper/pothyroidism 
2 
5.4 
0 
0 
0 
0 
Hypogonadism 
1 
2.7 
0 
0 
0 
0 
Hepatitis-Increased 
AST/ALT/AP/GGT 
8 
21.6 
3 
8.0 
1 
(GGT) 
2.7 
Skin rash 
23 
62.0 
4 
11.0 
0 
0 
Constitutional  
 
 
 
 
 
 
Fatigue 
37 
100 
15 
40.5 
0 
0 
Gastrointestinal 
 
 
 
 
 
 
Nausea 
27 
73.0 
1 
2.7 
0 
0 
Vomiting 
17 
46.0 
1 
2.7 
0 
0 
Hematologic  
 
 
 
 
 
 
Neutropenia 
19 
51.4 
5 
13.5 
1 
2.7 
Neuro-Psychiatric  
 
 
 
 
 
 
Depression/Anxiety 
9 
24.3 
4 
11.0 
0 
0 
Renal  
 
 
 
 
 
 
Increased 
Creatinine/dehydration 
2 
5.4 
1 
2.7 
0 
0 
Respiratory  
 
 
 
 
 
 
Bronchospasm 
1 
2.7 
1 
2.7 
0 
0 
Other  
 
 
 
 
 
 
Cardiac arrhythmia  
(atrial fibrillation) 
1 
2.7 
1 
2.7 
0 
0 
Increased CPK 
9 
24.3 
2 
5.4 
1 
2.7 
 

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Table 11. 
Efficacy Summary (Stage I + II): Best response based on 37 patients enrolled 
(Intent To Treat) 
  
No. Pts 
Duration 
(month) 
Primary  
No. Pts (%) 
Classification 
No. Pts (%)  
Cutaneous 
Ocular 
Unknown 
M1a 
M1b 
M1c 
RR 
Overall 
9* 
 
8/9 
(89) 
1/9 (11) 
0 
5/9 
(56) 
2/9 
(22) 
3/9 
(33) 
CR 
4/9 
14+ – 30 
3/4 
(75) 
1/4 
(25) 
0 
1/4 
(25) 
1/4 
(25) 
2/4 
(50) 
PR* 
5/9 
 
3 – 37+ 
5/5 
(100) 
0 
0 
3/5 
(60) 
1/5 
(20) 
1/5 
(20) 
SD 
14 
1.5 – 21 
7/14 
(50) 
4/14 
(29) 
2/14 
(14) 
5/14 
(21) 
5/14 
(21) 
7/14 
(50) 
PD 
12 
 
8/12 
(67) 
3/12 
(25) 
0 
1/12 
(8) 
1/12 
(8) 
9/12 
(75) 
No 
response 
data 
2 
2 (1cutaneous, M1c and 1unknown, M1c) unknown response 
* One additional responder was not confirmed per RECIST, had PD and rendered surgically NED 
with no progression at 16+ months. This patient has been designated SD.  
PR: partial response; CR: complete response; SD: stable disease; NED: no evidence of disease. 
 
Table 12.  Durability of responses and stable disease (3 month duration or longer).  
Responders 
Primary  
Classification  
Duration  
(Months)  
Comment  
1. Cutaneous  
M1a 
37+ 
PR  surgical CR (NED) 
2. Cutaneous  
M1c 
30 
CR 
3. Ocular  
M1c 
28+ 
CR 
4. Cutaneous  
M1c 
20 
PRPD  Surgical NED 4+ months 
5. Cutaneous  
M1a 
18+ 
CR  
6. Cutaneous  
M1b 
12+ 
PR (likely CR; residual 4 mm lung nodule) 
7. Cutaneous  
M1a 
6 
PR 
8. Cutaneous  
M1a 
6 
PR 
9. Cutaneous  
M1b 
14+ 
CR 

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Durable Stable Disease (≥3 months) 
 
1. Unknown  
M1a 
4 
 
2. Cutaneous  
M1c 
9 
 
3. Ocular  
M1c 
4.5 
 
4. Ocular  
M1c 
13 
 
5. Cutaneous  
M1b 
21 
 
6. Cutaneous  
M1b 
4 
 
7. Ocular  
M1c 
7 
 
8. Cutaneous  
M1b 
4.5 
 
9. Cutaneous  
M1a 
10.5 
 
10. Unknown  
M1c 
4  
 surgical NED for 5 months 
11. Cutaneous  
M1a 
3 
Unconfirmed PR PD  Surgical NED 16+ 
months 
PR: partial response; CR: complete response; SD: stable disease; NED: no evidence of disease 
 
37 Patients Analyzed 
- 23 Alive at one year
-14 Dead at one year
Observed 1 Year Survival Rate = 62%
95% Confidence Interval = 46% - 78%
One tailed hypothesis test: observed
rate better than predicted (21%) -> p  <.0001
Table 13. One Year Survival Rate Observed vs Predicted (Korn Model)
As of 2/16/2011
One Year Survival Rate
Predicted by Korn
Model 
= 21%
Korn, et,al, JCO Feb 1, 2008
* Predicted rates assume the study was open to patients with brain metastasis
Gender
PS
Visceral
Disease
Total
# Alive
@ 1 year
Observed
Rate
Predicted
Rate
Male
0
N
3
2
67%
35%
Male
0
Y
11
9
82%
22%
Male
1
N
3
3
100%
17%
Male
1
Y
6
2
33%
10%
Female
0
N
0
0
---
49%
Female
0
Y
4
2
50%
33%
Female
1
N
3
2
76%
27%
Female
1
Y
7
3
43%
16%
 

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Table 14.  
Summary of the frequency of observed/reported irAEs across different studies 
testing anti-CTLA4 monoclonal antibody therapy 
Study 
Agent, dose 
Total (%) 
Grade 
3/4/5 (%) 
Comment 
Phase II CA184-022, IDB 
Ipilimumab, 3 mg/kg 
65 
7 
No grade 5 
Phase II CA184-022, IDB 
Ipilimumab, 10 mg/kg 
70 
25 
No grade 5 
Hodi, NEJM, 2010, PhIII 
Ipilimumab, 3 mg/kg 
61 
16 
 
Studies (CA184-008, 022, 004, or 007), N=325, IDB  
Ipilimumab, 10 mg/kg 
72.3 
25.2 
 
Tarhini, ASCO 2011, AACR 2012 (preliminary data); neoadjuvant 
Ipilimumab, 10 mg/kg 
80 
30 
No grade 4 
or 5 
Tarhini, JCO 2011 (N=37) 
Treme 15 mg/kg + HDI 
65 
24 
No grade 5 
 
Diarrhea/Colitis 
57.0 
10.7 
1 grade 4 
Hyper/pothyroidism 
5.4 
0 
 
Hypogonadism 
2.7 
0 
 
Hepatitis-Increased     AST/ALT/AP/GGT 
21.6 
10.7 
1 grade 4 
(GGT) 
Skin rash 
62.0 
11.0 
 
1.7 
Study Rationale 
Patients with advanced metastatic melanoma derive limited survival benefit from 
currently approved therapeutic options. There is an urgent and unmet need to 
improve the clinical outcomes of this patient population. Ipilimumab is active in 
patients with advanced stage melanoma, with an overall survival benefit, durable 
objective responses and important disease control rates reported mainly across 2 
dose levels (3 mg/kg and 10 mg/kg). However, response rates continue to be 
modest and appear to benefit only a subgroup a patients. Our data from the 
phase II study combining the anti-CTLA4 monoclonal antibody tremelimumab 
and HDI have shown the combination to be safe and with promising efficacy 
results when compared to reported single agent activity of tremelimumab in 
phase II and III studies and phase II data of IFN-α in metastatic melanoma.(8, 45) 
Clinically, both IFN-α and ipilimumab have been demonstrated to have significant 
clinical activity in melanoma, and activity that appears to be associated with the 
induction of autoimmunity. This autoimmunity is correlated with clinical benefits 
and a sign of altered immunologic tolerance.(46-60) 
Immunologically, both have been demonstrated to up-regulate the pro-
inflammatory cytokine response (Th1 polarization) in patients with melanoma,(19, 
61) and to be associated with increased T-cell and dendritic cell (DC) infiltration 
in tumor in clinical responders.(20, 62, 63) Moreover, the impact of IFNα on DCs 
is well established, affecting almost all stages of myeloid DC generation, 

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maturation, differentiation and function (11). In addition, in their immature state, 
IFN-treated DCs induce a ‘polarized’ Th1 cytokine microenvironment (12). Similar 
to myeloid DCs, IFNs polarize lymphocytes toward a pro-inflammatory Th1 
phenotype (13-15). In the cytotoxic T cell compartment, type I IFNs induce potent 
antitumor cell-mediated cytotoxicity (16), and promote natural killer (NK) cell-
mediated proliferation and cytotoxicity (17). This Th1 shift in immunity induced by 
IFN-α may, however, still be countered by other mechanisms (e.g. CTLA-4) 
explaining more limited activity observed with IFN-α as monotherapy in 
metastatic melanoma. Combination with CTLA-4 blockade may, however, alter 
this balance by downregulating the CTLA4 suppressive regulatory elements and 
possibly releasing inhibitory influences on activated CD25-expressing CD4 and 
CD8 effector cells,  increasing the antitumor response. 
We hypothesize that this combination of ipilimumab and HDI will prove superior 
to single agent ipilimumab in terms of efficacy and with acceptable toxicity as has 
been demonstrated with the tremelimumab-HDI combination. 
1.7.1 
Rationale for evaluating 3 mg/kg and 10 mg/kg dose levels of 
ipilimumab 
Some data suggest a dose dependant effect of ipilimumab from 0.3 
mg/kg to 10 mg/kg (CA184-022, a randomized phase II trial of 
ipilimumab at 0.3 mg/kg, 3 mg/kg and 10 mg/kg), where 10 mg/kg 
appears to have the greatest efficacy.  However the 10 mg/kg 
ipilimumab dose level also appears to have the greatest frequency of 
Grade 3-4 adverse events based on CA 184-022, and thus a different 
safety/efficacy profile compared to 3 mg/kg is possible.(64)  In 
addition, the magnitude of survival benefit for ipilimumab 10 mg/kg 
given with dacarbazine in untreated melanoma (CA 184-024) was 
comparable to the magnitude of survival benefit for ipilimumab 3 
mg/kg given with vaccine in pretreated melanoma by cross-study 
comparison (CA184-024: HR 0.72 (p = 0.0009), median OS 11.2 vs. 
9.1 months; MDX010-20: HR 0.68 (p < 0.0001), median OS 6.4 vs. 
10.0 months). Given that the risk/benefit ratio may differ at the 3 
mg/kg and 10 mg/kg dose levels, there is increasing need to further 
understand the safety/efficacy profile of both 3 mg/kg and 10 mg/kg 
dosages of ipilimumab in the treatment of melanoma.  The following 
points are relevant to the consideration of testing both 3mg/kg and 10 
mg/kg dose levels of ipilimumab in this study: 
· 
The CA184-022 trial in advanced inoperable melanoma patients 
suggested a dose-dependent effect of ipilimumab with the highest 
activity observed in the 10 m/kg dose group (BORR 11.1%, 4.2% 
and 0% for the 10, 3, and 0.3 mg/kg dose groups, respectively). 
· 
In addition, the CA184-022 trial suggested that the frequency of 
grade 3-4 irAEs was different between the 3 mg/kg and 10 mg/kg 
ipilimumab doses. 
· 
Immunologically, IFN-α is known to mount a potent pro-
inflammatory (Th1 polarized) immune response that may be 
suppressed by host immune suppressor elements where CTLA4 
plays a significant role. Blocking CTLA-4 may release host 
inhibition of antitumor immunity but it is not known whether a 
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synergistic effect. On the other hand, pharmacokinetically, data 
from CA 184-022 suggest that 10 mg/kg may be the optimal dose 
where the CminSS (minimum plasma concentration at steady-state) 
of 20 g/ml ipilimumab needed to fully abrogate binding of CTLA-4 
to B7.1 & B7.2 (near complete receptor saturation) is exceeded in 
95% patients at 10 mg/kg versus 30% patients at 3 mg/kg.(64) 
That study also suggested potentially greater efficacy, but at the 
expense of potentially greater toxicity.  
· 
The magnitude of survival benefit for ipilimumab 10 mg/kg given 
with dacarbazine in untreated melanoma (CA 184-024) was 
similar to the magnitude of survival benefit for ipilimumab 3 mg/kg 
given with vaccine in pretreated melanoma by cross-study 
comparison (CA184-024: HR 0.72 (p = 0.0009), median OS 11.2 
vs. 9.1 months; MDX010-20: HR 0.68 (p < 0.0001), median OS 
6.4 vs. 10.0 months). Therefore, an evaluation of a more optimal 
safety/efficacy ratio by testing both dose levels is important. 
· 
We therefore, propose a randomized phase II trial to test the 
combination of ipilimumab (recently approved by the FDA for 
metastatic melanoma) at both 3 mg/kg and 10 mg/kg dose levels 
alone or in combination with IFN-α. 

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2. 
Objectives 
2.1 
Primary Endpoints 
2.1.1 
Test the hypothesis that the combination of ipilimumab and HDI will 
improve PFS of patients with advanced metastatic melanoma as 
compared to ipilimumab alone (across ipilimumab treatment status).  
2.2 
Secondary Endpoints 
2.2.1 
Test the hypothesis that the combination of ipilimumab and HDI will 
prove to be safe and tolerable. 
Adverse events will be assessed across all treated cases and 
specifically comparing predefined regimen limiting serious adverse 
events (RLE) in patients without HDI versus with HDI (at the 2 
ipilimumab dose levels and across ipilimumab treatment status).  
Also, by comparing the RLE rate with ipilimumab 10 mg/kg versus 
ipilimumab 3 mg/kg (across HDI treatment status). 
Within the constraints of the sample size, attempt to test the 
hypotheses that (1) ipilimumab 10mg/kg will lead to improved PFS in 
comparison to ipilimumab 3mg/kg (across HDI treatment status); (2) 
the combination of ipilimumab and HDI will improve OS of patients 
with advanced metastatic melanoma as compared to ipilimumab 
alone (across ipilimumab treatment status) and (3) ipilimumab 
10mg/kg will lead to improved OS in comparison to ipilimumab 
3mg/kg (across HDI treatment status).” 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. _____________________________________ 
Patient’s Initials (L, F) ________________________________ 
Physician Signature and Date ____________________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria 
3.1.1 
Age ≥ 18 years. 
3.1.2 
Patients must have unresectable stage III or stage IV melanoma, 
either initial presentation or recurrent, that is of cutaneous origin or 
unknown primary origin and that is histologically diagnosed.   
3.1.3 
No more than one prior systemic therapeutic regimen for unresectable 
stage III or stage IV melanoma. This includes chemotherapy, biologic 
therapy, biochemotherapy, or investigational treatment. This does not 
include any therapies given in the adjuvant setting. However, patients 
are excluded if they have a history of prior treatment for melanoma 
(either adjuvant or metastatic disease) with ipilimumab or other CTLA-
4 inhibitor,  or prior interferon-α treatment for metastatic disease 
(history of adjuvant interferon-α is allowed). There should be a 4-week 
washout period between last treatment administration and initiation of 
study therapy. 
3.1.4 
Patients must have ECOG performance status of 0-1. 
3.1.5 
Patients must not have other significant medical, surgical, or 
psychiatric conditions or require any medication or treatment that in 
the opinion of the investigator may interfere with compliance, make 
the administration of Ipilimumab or HDI hazardous or obscure the 
interpretation of AEs, such as a condition associated with frequent 
diarrhea. Patients must not have an active infection requiring current 
treatment with parenteral antibiotics. 
3.1.6 
Patients must not have a history of inflammatory bowel disease or 
diverticulitis (history of diverticulosis is allowed). 
3.1.7 
Patients who have other current malignancies are not eligible. 
Patients with other malignancies are eligible if they have been 
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continuously disease free for > 5 years prior to the time of 
randomization. One exception are patients treated with a curative 
intent and are continuously disease free for > 3 years. These patients 
would be considered eligible. 
Patients with prior history at any time of any in situ cancer, lobular 
carcinoma of the breast in situ, cervical cancer in situ, atypical 
melanocytic hyperplasia or Clark I melanoma in situ are eligible.  
Patients with prior history of basal or squamous skin cancer are 
eligible. 
3.1.8 
Patients must not have autoimmune disorders or conditions of 
immunosuppression that require current ongoing treatment with 
systemic corticosteroids (or other systemic immunosuppressants), 
including oral steroids (e.g., prednisone, dexamethasone) or 
continuous use of topical steroid creams or ointments or 
ophthalmologic steroids. A history of occasional (but not continuous) 
use of steroid inhalers is allowed. Replacement doses of steroids for 
patients with adrenal insufficiency are allowed. Patients who 
discontinue use of these classes of medication for at least 2 weeks 
prior to randomization are eligible if, in the judgment of the treating 
physician investigator, the patient is not likely to require resumption of 
treatment with these classes of drugs during the study. 
Exclusion from this study also includes patients with a history of 
symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic 
progressive sclerosis [scleroderma], systemic lupus erythematosus, 
Sjögren's syndrome, autoimmune vasculitis [e.g., Wegener’s 
Granulomatosis]); motor neuropathy considered of autoimmune origin 
(e.g., Guillain-Barre Syndrome and Myasthenia Gravis); other CNS 
autoimmune disease (e.g., poliomyelitis, Multiple sclerosis). 
Patients with autoimmune hypothyroid disease or type I diabetes on 
replacement treatment are eligible. 
3.1.9 
Due to the possible effect of treatment with ipilimumab on the 
immunologic response to infectious disease vaccines, patients must 
not have had any infectious disease vaccination (e.g, standard 
influenza, H1N1 influenza, pneumococcal, meningococcal, tetanus 
toxoid) within 4 weeks prior to randomization. 
3.1.10 
Women must not be pregnant or breast-feeding due to the unknown 
effects of ipilimumab and the combination with HDI on conception and 
the fetus. All females of childbearing potential must have a blood test 
or urine study during screening to rule out pregnancy. Please see 
Section 7 for required pregnancy testing prior to and during treatment. 
Female? ____ (Yes or No) Date of blood test or urine study: _______  
NOTE: 
A woman of childbearing potential (WOCBP) is any 
woman, regardless of sexual orientation or whether they 
have undergone tubal ligation, who meets the following 
criteria: 
1. has not undergone a hysterectomy or bilateral 
oophorectomy; or  

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2. has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time 
in the preceding 24 consecutive months). 
For the purposes of this study, post-menopause is defined as: 
· 
Amenorrhea ≥ 24 consecutive months without another cause, 
or 
· 
For women with irregular menstrual periods and taking 
hormone replacement therapy (HRT), a documented serum 
follicle stimulating hormone (FSH) level ≥ 35 mIU/mL. 
Women who are using oral contraceptives, other hormonal 
contraceptives (vaginal products, skin patches, or implanted or 
injectable products), or mechanical products such as an intrauterine 
device or barrier methods (diaphragm, condoms, spermicides) to 
prevent pregnancy, or are practicing abstinence or where their partner 
is sterile (e.g., vasectomy) should be considered to be of childbearing 
potential. 
Men of fathering potential and WOCBP must be using an adequate 
method of contraception or must abstain from sexual intercourse to 
avoid conception/pregnancy throughout the study and for up to 26 
weeks after the last dose of ipilimumab or HDI in such a manner that 
the risk of pregnancy is minimized. Men or WOCBP who are unwilling 
or unable to strictly follow this requirement are not eligible. 
3.1.11 
Patients must have the following required values for initial laboratory 
tests obtained within 4 weeks prior to randomization (ULN: 
institutional upper limit of normal): 
· 
WBC ≥ 3000/uL  
 
 
· 
ANC ≥ 1500/uL 
 
 
· 
Platelets ≥ 100 x 103/uL 
 
 
· 
Hemoglobin ≥10 g/dL  
· 
Serum creatinine ≤ 1.8 mg/dl    
 
· 
AST/ALT ≤ 2.5 x ULN for patients with liver metastases and ≤ 2.0 
x ULN for patients without liver metastases.  
 
 
· 
Serum bilirubin < 2 x ULN for patients with liver metastases and ≤ 
1.5 x ULN for patients without liver metastases, (except patients 
with Gilbert’s Syndrome, who must have a total bilirubin < 3.0 
mg/dL) 
3.1.12 
No active or chronic infection with HIV, hepatitis B, or hepatitis C due 
to the unknown effects of ipilimumab or the combination with HDI. 

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3.1.13 
Patients must be free of brain metastasis by contrast-enhanced 
CT/MRI scans within 4 weeks prior to enrollment. If known to have 
prior brain metastases, must not have evidence of active brain 
disease after definitive therapy (surgery, radiation therapy or 
stereotactic radiosurgery) on two successive MRI evaluations at least 
3 months apart (one of which is ≤ 4 weeks prior to starting the study 
drugs).  
3.1.14 
All sites of disease must be evaluated within 4 weeks prior to 
randomization. Patients must have measurable disease as defined by 
RECIST v1.1 (see Section 6) 
 
 
 
 
 
 
Physician Signature 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to use 
the eligibility checklist as source documentation. 

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4. 
Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group. Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet (FDA Form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature, and 
Financial Disclosure Form with original signature) to the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI. These forms are available on the CTSU Web site (enter 
credentials at https://www.ctsu.org; then click on the Register tab) or by calling the PMB 
at 240-276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
Requirements for E3611 site registration: 
· 
CTSU IRB Certification 
· 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Before an ECOG-ACRIN Institution may enter patients, protocol specific 
regulatory documents must be submitted to the CTSU Regulatory Office at the 
following address:   
 
CTSU Regulatory Office 
 
Coalition of National Cancer Cooperative Groups 
 
1818 Market Street, Suite 1100 
 
Philadelphia, PA 19103 
 
FAX: (215) 569-0206 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
3. 
A. CTSU IRB Certification Form. 
 
Or 
B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  
IRB Approval Letter 
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NOTE: 
The above submissions must include the following details: 
· 
Indicate all sites approved for the protocol under an assurance 
number. 
· 
OHRP assurance number of reviewing IRB 
· 
Full protocol title and number 
· 
Version Date 
· 
Type of review (full board vs. expedited) 
· 
Date of review. 
· 
Signature of IRB official 
The CTSU encourages you to link to the following RSS2.0 webpage so that more 
information on RSS2.0 as well as the submission forms can be accessed. Log in 
to http://www.ctsu.org and click on the Regulatory tab to access the RSS web 
page. If you have questions regarding regulatory document submission, please 
telephone the CTSU Help Desk at 1-888-823-5923 or E-mail 
CTSUContact@westat.com. 
Patients must not start protocol treatment prior to registration. 
Treatment should start within seven working days after registration. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study.  
OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
· 
All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
to verify eligibility. 
· 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
Access requirements for OPEN: 
· 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for the CTSU 
members' web site. 
· 
To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group or CTSU roster. 
· 
To perform registrations on protocols for which you are a member of the Lead Group, 
you must have an equivalent 'Registrar' role on the Lead Group roster.  Role 
assignments are handled through the Groups in which you are a member  
· 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead 
Group registrations) you must have the role of Registrar on the CTSU roster. Site 
and/or Data Administrators can manage CTSU roster roles via the new Site Roles 
maintenance feature under RSS on the CTSU members' web site. This will allow 
them to assign staff the "Registrar" role. 
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NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
The following information will be requested: 
4.1 
Protocol Number  
4.2 
Investigator Identification  
4.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2 
Investigator’s name (NCI number) 
4.2.3 
Cooperative Group Credit 
4.2.4 
Credit Investigator 
4.2.5 
Protocol specific contact information 
4.3 
Patient Identification  
4.3.1 
Patient’s initials (first and last) 
4.3.2 
Patient’s Hospital ID and/or Social Security number 
4.3.3 
Patient demographics 
4.3.3.1 
Gender 
4.3.3.2 
Birth date 
4.3.3.3 
Race 
4.3.3.4 
Ethnicity 
4.3.3.5 
Nine-digit ZIP code 
4.3.3.6 
Method of payment 
4.3.3.7 
Country of residence 
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
4.5 
Stratification Factors 
Stage: III/M1a, M1b, M1c 
4.6 
Additional Requirements  
4.6.1 
Patients must provide a signed and dated, written informed consent 
form. 
4.6.2 
Pathological tissue materials are to be submitted as indicated in 
Section 10 for central review (mandatory) and for future laboratory 
studies (per patient consent). 

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4.6.3 
Blood samples are to be submitted per patient consent as indicated in 
Section 11. for future markers related to this study. 
NOTE: 
ECOG-ACRIN requires that biological samples submitted 
from patients participating in E3611 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking 
System (STS). See Section 10.3. 
NOTE: 
Institutions outside of the United States and Canada must 
confer with the receiving laboratory and the ECOG-ACRIN 
Operations Office - Boston regarding logistics for 
submission of fresh samples. 
4.6.4 
Data collection for this study will be done exclusively in Medidata 
Rave. Prior to beginning data entry in Rave, study staff must be 
registered in Medidata and complete the required training modules. 
Study staff will receive an invitation to join the study in Rave after 
evidence of IRB approval is submitted to RSS. 
4.6.5 
Additional Registration Training Requirement 
Mandatory Investigator Training Course 
ECOG-ACRIN has developed a training course to provide additional 
information to enrolling investigators on the toxicity profile of 
ipilimumab.  Each investigator is required to review the slide deck 
titled: Ipilimumab Immune Related Adverse Events: Summary and 
Recommended Management, prior to their first patient enrollment by 
accessing the following URL: 
http://coccg.mindflash.com/PublicCoursePage.aspx?CourseId=55554
2873  
Patient enrollments will be blocked via the OPEN system if the 
enrolling investigator has not completed the required training.  If your 
site has a patient waiting and the enrolling INV completed the training 
after the hours of 9am – 5:30pm ET Monday through Friday, please 
email the ECOG Ipi Education Team at ECOGIpi@ecogchair.org for 
after hours assistance.   
NOTE:  
If enrolling investigator has already taken the mandatory 
training course for E1608 or E1609, the course does not 
need to be repeated for this study. 
4.7 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the E3611 Forms Completion Guidelines. 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
Patients will be randomized to either Arm A (ipilimumab 10 mg/kg + HDI), Arm B 
(ipilimumab 10 mg/kg alone), Arm C (ipilimumab 3 mg/kg + HDI) or Arm D 
(ipilimumab 3 mg/kg alone). 
Patients must receive their first induction dose within 7 days of randomization. 
Use actual weight when calculating the dose. 
5.1.1 
ARM A (ipilimumab 10 mg/kg + HDI) 
Induction Phase 
· 
Ipilimumab10 mg/kg I.V. infusion every 3 weeks for 4 doses 
· 
Interferon Alfa-2b, 20 MU/m²/day I.V. x 5 consecutive days out of 
7 (e.g., M-F) every week for 4 weeks, followed by10 MU/m²/day 
subcutaneous every other day (e.g., M,W,F) 3 times each week 
for 8 weeks 
Maintenance Phase 
· 
Ipilimumab10 mg/kg I.V. infusion every 12 weeks, beginning at 
week 24, for a maximum of 4 doses (wk 24, 36, 48, 60) 
· 
Interferon Alfa-2b10 MU/m²/day subcutaneous every other day 
(e.g., M,W,F) 3 times each week for 48 weeks 
5.1.2 
ARM B (ipilimumab 10 mg/kg alone) 
Induction Phase 
· 
Ipilimumab10 mg/kg I.V. infusion every 3 weeks for 4 doses 
Maintenance Phase 
· 
Ipilimumab10 mg/kg I.V. infusion every 12 weeks, beginning at 
week 24, for a maximum of 4 doses (wk 24, 36, 48, 60) 
5.1.3 
Arm C (ipilimumab 3 mg/kg + HDI) 
Induction Phase 
· 
Ipilimumab 3 mg/kg I.V. infusion every 3 weeks for 4 doses  
 
· 
Interferon Alfa-2b, 20 MU/m²/day I.V. x 5 consecutive days out of 
7 (e.g., M-F) every week for 4 weeks, followed by10 MU/m²/day 
subcutaneous every other day (e.g., M,W,F) 3 times each week 
for 8 weeks 
Maintenance Phase 
· 
Ipilimumab3 mg/kg I.V. infusion every 12 weeks, beginning at 
week 24, for a maximum of 4 doses (wk 24, 36, 48, 60) 
· 
Interferon Alfa-2b10 MU/m²/day subcutaneous every other day 
(e.g., M,W,F) 3 times each week for 48 weeks 

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5.1.4 
Arm D (ipilimumab 3 mg/kg alone) 
Induction Phase 
· 
Ipilimumab 3 mg/kg I.V. infusion every 3 weeks for 4 doses 
Maintenance Phase 
· 
Ipilimumab 3 mg/kg I.V. infusion every 12 weeks, beginning at 
week 24, for a maximum of 4 doses (wk 24, 36, 48, 60) 
5.1.5 
Ipilimumab Dose Calculations: 
The total dose must be calculated using the most recent subject 
weight (obtained within 3 days of the dosing visit, and prior to the 
infusion). Dose delays are allowed as per the dosing criteria described 
later in this section. Infusions should be given over 90 minutes (not 
bolus or IV push). 
Calculate Total Dose as follows: 
Patient body weight in kg x [10 mg or 3 mg/kg] = total dose in mg 
Calculate Total Infusion Volume as follows:  
Total dose in mg ÷ 5 mg/mL = infusion volume in mL 
Calculate Rate of Infusion as follows: 
Infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min. 
For example, a patient on Arm A (ipilimumab 10 mg/kg) weighing 114 
kg (250 lb) would be administered 1140 mg of ipilimumab (114 kg x 
10 mg/kg = 1140 mg) with an infusion volume of 228 mL (1140 mg ÷ 5 
mg/mL = 228 mL) at a rate of approximately 2.5 mL/min (228 mL ÷ 90 
minutes) in 90 minutes. 
5.1.6 
Interferon Alfa - 2b Dose Calculations and Special Considerations: 
Induction Phase: Interferon Alfa - 2b, 20 MU/m²/day (rounded to the 
nearest 1.0 million unit) administered I.V.  x 5 consecutive days out of 
7 (e.g., M-F) every week x 4 weeks. Then, 10 MU/m²/day (rounded to 
the nearest 1.0 million unit) subcutaneous every other day (e.g., 
M,W,F) three times each week x 8 weeks. 
Maintenance Phase: Interferon Alfa - 2b, 10 MU/m²/day (rounded to 
the nearest 1.0 million unit) subcutaneous every other day (e.g., 
M,W,F) three times each week x 48 weeks. 
Days 2-5 of interferon (IFN) Alfa - 2b administration for weeks 1-4 
may be administered at an institution other than the registering 
institution provided that the registering physician still retains primary 
oversight responsibility for the patient’s treatment. Day 1 of each of 
the first 4 weeks should be administered at the registering institution.  
Documentation concerning all drugs administered, side effects and 
tests performed must be forwarded to the registering institution. The 
registering institution must document any care given at an outside 
institution.  
Self Administration of Subcutaneous Doses:  Patients who are 
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doses of IFN Alfa - 2b may do so following the first 4 weeks of 
treatment. Interferon Alfa-2b should be prescribed in 10 million unit 
vials (other standard vial strengths are acceptable) with instructions to 
reconstitute with 1 ml of diluent to reach a final concentration of 10:1. 
See Appendix VIII for directions and patient IFN information guide. 
Patients must complete the E3611 Patient Diary -Interferon (Appendix 
III). 
NOTE:  
Patients randomized to the combination arms (Arm A or 
Arm C), the protocol does not mandate a specific 
sequence for the ipilimumab or IFN Alfa intravenous 
infusions on days when both of these agents are given. 
One suggested sequence is as follows: 
- Start with the ipilimumab infusion given over 90 minutes. 
- While the patient is in the 60 minutes observation period that follows 
the completion of the ipilimumab infusion, provide 500 ml normal 
saline intravenous hydration prior to IFN Alfa.   
- This is followed by IFN Alfa intravenous infusion over 20 minutes. 
5.2 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents. 
· 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave. 
· 
Expedited reporting:  In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
5.2.2 
Terminology 
· 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
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· 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
· 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports. 
· 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term. 
· 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours. 
· 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred. 
· 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes: 
· 
Death  
· 
A life-threatening adverse event  
· 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
· 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
· 
A congenital anomaly/birth defect.  
· 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a 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. 
· 
SPEER (Specific Protocol Exceptions to Expedited Reporting):  A 
subset of AEs within the CAEPR that contains list of events that 
are protocol specific exceptions to expedited reporting.  If an AE 
meets the reporting requirements of the protocol, and it is listed on 
the SPEER, it should ONLY be reported via CTEP-AERS if the 
grade being reported exceeds the grade listed in the parentheses 
next to the event. 
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5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to: 
· 
the NCI (301-897-7497) and  
· 
the AE Team at ECOG-ACRIN (617-632-3610) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours.  In addition, supporting or follow 
up documentation must be faxed to the NCI (301- 230-0159) in the 
same timeframe. 
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including: 
· 
the phase (0, 1, 2, or 3) of the trial  
· 
whether the patient has received an investigational or commercial 
agent or both 
· 
the seriousness of the event 
· 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
· 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
· 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
· 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E3611 and outline 
the specific expedited adverse event reporting requirements for 
study E3611. 
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5.2.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner 
5.2.5.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the investigational agent(s). 
 
 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the table 
below in section 5.2.6 
Yes 
No 
Identify the type and 
grade of the event using 
CTCAE v4.0 
Determine if the patient 
was hospitalized for ≥ 24 
hours for the event 
With this information, 
review the chart in 
section 5.2.6 to determine 
if event is reportable via 
CTEP-AERS 
Refer to section 5.2.7 to 
determine if the event meets 
the protocol specific reporting 
requirements for this study. If 
so, report the event via 
CTEP-AERS 
Refer to section 5.2.7 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study.  If so, report the event 
via CTEP-AERS 
Is the event 
reportable? 
No 
Yes 
Rev. 5/14 
Refer to section 5.2.7 to determine 
if the event meets the criteria as an 
exception to reporting on this 
protocol.  If it does not, report the 
event via CTEP-AERS. 

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5.2.5.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.6, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
· 
All Grade 4 and Grade 5 AEs 
NOTE:  Any death occurring greater than 30 days after the 
last dose of investigational agent with an 
attribution of possible, probable or definite must be 
reported via CTEP-AERS even if the patient is off 
study. 
Expedited 10 calendar day reports for: 
· 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
· 
Grade 3 adverse events 
5.2.6 
Expedited Reporting Requirements for Arms A, B, C, and D on 
protocol E3611 
Investigational Agent:  Ipilimumab 
Commercial Agent: Interferon Alfa-2b 
When an investigational agent(s) is used in combination with a 
commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events follow the 
guidelines for investigational agents.   
Late Phase 2 and Phase 3 Studies:  
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND/ within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE:   Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration of 
investigational agent/intervention. 
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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 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
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. 
1 Serious 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 4 and Grade 5 AEs 
Expedited 10 calendar day reports for: 
· 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
· 
Grade 3 adverse events 
 

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5.2.7 
Additional instructions, requirements and exceptions for protocol 
E3611 
Additional Instructions: 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD 
Medical Help Desk at 301-897-7497 or aemd@tech-res.com.  This 
will need to be discussed on a case by case basis. 
E3611 specific expedited reporting requirements: 
· Immune Related Adverse Events:  Any grade 2 or higher 
immune related adverse event (see section 5.4.1.3 and 5.4.1.4 
for definitions), excluding grade 2 or 3 skin reactions, must be 
reported via CTEP-AERS within 10 calendar days of learning of 
the event regardless of the attribution and designation as 
expected or unexpected.  Please submit any supporting data as 
well (ie: autoimmune serology tests or biopsy reports).  
· Bowel Perforation: Any grade 3 or higher bowel perforation must 
be reported via CTEP-AERS within 10 calendar days of learning 
of the event. 
· Pregnancy 
Pregnancies and suspected pregnancies (including a 
positive/inconclusive pregnancy test regardless of age or 
disease state) occurring while the subject is on Ipilimumab or 
Interferon Alfa, or within 28 days of the subject’s last dose of 
Ipilimumab or Interferon Alfa, are considered immediately 
reportable events. The pregnancy, suspected pregnancy, or 
positive/inconclusive pregnancy test must be reported via 
CTEP-AERS within 24 hours of the Investigator’s 
knowledge. Please refer to Appendix XVII for detailed 
instructions on how to report the occurrence of a pregnancy as 
well as the outcome of all pregnancies. 
E3611 specific expedited reporting exceptions: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the 
parentheses next to the event. 
5.2.8 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
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5.2.9 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave: 
· 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form within 14 days in Medidata 
Rave. 
2. Upload a copy of the pathology reports to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
· 
A secondary malignancy is a cancer CAUSED BY any prior 
anti-cancer treatment (including the treatment on this 
protocol).  Secondary malignancies require both routine and 
expedited reporting as follows: 
1. Complete a Second Primary Form within 14 days in Medidata 
Rave. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development 
of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must 
be provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) 
even if ECOG-ACRIN was not the patient's most recent 
trial. 
NOTE: 
Once data regarding survival and remission status are 
no longer required by the protocol, no follow-up data 
should be submitted via CTEP-AERS or by the Second 
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5.3 
Comprehensive Adverse Events and Potential Risks List 
The Comprehensive Adverse Events 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 (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 2678 patients. 
Below is the CAEPR for Ipilimumab (MDX-010). 
NOTE: If an AE meets the reporting requirements of the protocol, and it is listed 
on the SPEER, it should ONLY be reported via CTEP-AERS if the 
grade being reported exceeds the grade listed in the parentheses next 
to the event in the SPEER 
 Version 2.7, June 28, 20151 
 
 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%)  
 
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) 
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 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%)  
 
 
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 
 
  
 
 
Immune system disorders - 
Other (GVHD in the setting of 
allotransplant) 
  
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 
 
  
 
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 
 
  

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 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%)  
 
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 
 
  
1 This 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. 
2 Ipilimumab 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. 
3 Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with 
subsequent IL-2 therapy. 
4 In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
5 Gastrointestinal 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 
6 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 

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Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Ipilimumab 
(MDX-010) caused the adverse event: 
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 - Alopecia, 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. 
 

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5.4 
Dose Modifications 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.4.1 
Patients Receiving Ipilimumab 
5.4.1.1 
Dose and Schedule Modifications for Ipilimumab 
There will be no dose reductions for ipilimumab. The dose 
of ipilimumab will either be given or delayed/discontinued. 
Patients may develop study drug-related toxicities that may 
require delaying doses or dose discontinuation. Some of 
these adverse events may be consistent with potentially 
drug-related immune-mediated phenomena; termed IRAEs 
(Appendix X). Details of how to dose study medication in 
the presence of adverse drug reactions that may or may 
not be IRAEs are addressed below. 
Patients will delay or discontinue treatment with ipilimumab 
if they experience at least one adverse event, specified 
below, considered by the investigator to be possibly, 
probably or definitely related to ipilimumab treatment. 
The following criteria will be used to determine dosing 
delay, restarting doses, and whether ipilimumab 
should be permanently discontinued. For an adverse 
event, the investigator should review the following 
criteria in a stepwise manner: First, assess the dose 
delay criteria and decide whether a scheduled dose 
should be delayed. If a dose is delayed and does not 
meet the dosing criteria within the protocol allowed 3-
day window, it should be skipped and should not be 
made up for. The next opportunity to give an 
ipilimumab dose would be at the next scheduled dose 
per protocol/study calendar. Second, determine 
whether the permanent discontinuation criteria apply 
to the adverse event in question as well. 
NOTE:  
Due to the possible effect of treatment with 
ipilimumab on the immunologic response to 
infectious disease vaccines, patients must not 
have had any infectious disease vaccination 
(e.g., standard influenza, H1N1 influenza, 
pneumococcal, meningococcal, tetanus 
toxoid) 4 weeks before or after any dose of 
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5.4.1.1.1 
Criteria to delay one dose of ipilimumab 
Delay ipilimumab dosing for the following 
treatment related adverse events: 
· 
Any ≥ Grade 2 non-skin related adverse 
event (including IRAEs) except for 
laboratory abnormalities. 
· 
Any ≥ Grade 3 laboratory abnormality. 
· 
Any ≥ Grade 3 skin-related adverse 
event (including IRAEs) regardless of 
causality. 
5.4.1.1.2 
Criteria to resume ipilimumab treatment 
For adverse event(s) that do not meet the 
ipilimumab permanent discontinuation 
criteria as noted below, restart ipilimumab 
dosing if/when the dose delaying adverse 
event(s) resolve(s) to ≤ Grade 1 severity 
(except for diarrhea, it should return to 
baseline) or returns to baseline (e.g., for the 
induction phase, within 3 weeks [+/- 3 days] 
of initial dose administration): 
· 
If the adverse event has resolved (to < 
Grade 1 severity or returns to baseline; 
for diarrhea, it should return to 
baseline), restart ipilimumab dosing at 
the scheduled time point per protocol. 
· 
If the adverse event has not resolved in 
the protocol specified dosing window 
(e.g., for the induction phase 3 weeks 
[+/- 3 days]), the scheduled dose will be 
omitted. 
Please note that for each scheduled dose 
there is a [+/- 3 days] window within which a 
scheduled dose may still be given if the 
dose delaying AE(s) has resolved to ≤ 
grade 1 (for diarrhea, it should return to 
baseline before re-dosing). 
For patients with grade 2 diarrhea who meet 
the criteria for resuming dosing with 
ipilimumab after resolution to baseline 
should have a colonoscopy (with or without 
biopsy) to confirm the resolution of the 
inflammation before ipilimumab may be 
resumed. 
5.4.1.1.3 
Criteria for permanent discontinuation of 
ipilimumab for Related Adverse Events 

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Ipilimumab administration must be 
permanently discontinued if any of the 
following Related Adverse Events occur: 
· 
Any ≥ Grade 2 eye pain or reduction of 
visual acuity that does not respond to 
topical therapy and does not improve to 
≤ Grade 1 severity within 2 weeks of 
starting therapy for this adverse event, 
OR, requires systemic treatment.  
· 
Any ≥ Grade 3 bronchospasm or other 
hypersensitivity reaction. 
· 
Any other ≥ Grade 3 non-skin related 
adverse event with the exception of 
events listed under “Exceptions to 
Permanent Discontinuation” (Section 
5.4.1.1.4). 
· 
Any ≥ Grade 4 laboratory abnormalities, 
except AST, ALT, or Total Bilirubin: 
o AST or ALT > 8 x ULN. 
o Total Bilirubin > 5 x ULN. 
NOTE: An exception to permanent 
discontinuation of ipilimumab is 
made for laboratory abnormalities 
that are rapidly reversible, not life 
threatening, do not reflect 
underlying organ system 
dysfunction, and are not related to 
ipilimumab, such as transient 
elevations of uric acid, 
hypocalcaemia, 
hypophosphatemia. 
· 
Any other ≥ Grade 4 adverse event. 
· 
Any adverse event, laboratory 
abnormality or intercurrent illness which, 
in the judgment of the investigator, 
presents a substantial clinical risk to the 
patient with continued dosing. 
· 
Any motor neurologic toxicity ≥ Grade 3 
regardless of causality. 
· 
Any ≥ Grade 3 treatment related 
sensory neurologic toxicity. 
· 
Patients who require high dose steroids, 
other immune suppressants or anti-TNF 
drug therapy for the management of 
immune related adverse events as 
described in the Toxicity Management 
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ipilimumab permanently discontinued. 
Treatment with oral budesonide or 
moderate dose steroids for grade 2 
colitis or grade 2 or lower skin rash or 
higher dose IV steroids for grade 3 skin 
rash are criteria for ipilimumab dose 
delay but not permanent 
discontinuation. 
5.4.1.1.4 
Exceptions to permanent discontinuation of 
ipilimumab 
Ipilimumab administration may be resumed 
in the following cases: 
· 
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 and management. 
· 
Patients with the following conditions 
where in the investigator’s opinion 
continuing study drug administration is 
justified: 
─ Ocular toxicity that has responded to 
topical therapy. 
─  Endocrinopathies where clinical 
symptoms are controlled with 
appropriate hormone replacement 
therapy. 
NOTE:  
Ipilimumab may not be 
restarted while the patient is 
being treated with systemic 
corticosteroids except for 
patients on stable doses of 
hormone replacement therapy 
such as hydrocortisone. 
5.4.1.1.5 
Differentiating the primary attribution of a 
certain adverse event and implications on 
holding a dose and permanent 
discontinuation. 
NOTE:   An attempt should be made to 
differentiate the primary 
attribution of a certain adverse 

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event to ipilimumab versus IFN-α 
before a decision on permanent 
discontinuation is made. In 
general, most of IFN- α related 
AEs, especially laboratory 
abnormalities, rapidly improve 
with holding dosing and 
supportive measures. On the 
other hand, ipilimumab related 
immune mediated adverse events 
that are persistent or serious 
require intervention with 
corticosteroids or other immune 
suppressants. 
Adverse events that are related to 
the combination regimen and 
meet the thresholds for dose 
holding or delay per protocol 
criteria should lead to 
holding/delaying both agents until 
resolution to the protocol required 
criteria for resumption. Decisions 
on whether to permanently 
discontinue one or both agents 
should be made carefully and 
independently based on the 
attributions to one agent or the 
other. If one agent was 
discontinued based on a specific 
related adverse event, the other 
agent may continue to be dosed if 
it does not meet the protocol 
permanent discontinuation criteria 
for the specific adverse event or if 
the adverse event is determined 
to be unlikely related. Both agents 
may be discontinued at the 
discretion of the treating physician 
investigator if felt to be in the best 
interest of the patient to avoid 
recurrence or development of 
serious adverse events. 
5.4.1.2 
Supportive care considerations for ipilimumab 
administration 
5.4.1.2.1 
Treatment of infusion reactions associated 
with ipilimumab 
Since ipilimumab contains only human 
protein sequences, it is less likely that any 

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allergic reaction will be seen in patients. 
However, it is possible that infusion of 
ipilimumab will induce a cytokine release 
syndrome that could be evidenced by fever, 
chills, rigors, rash, pruritus, hypotension, 
hypertension, bronchospasm, or other 
symptoms. No prophylactic pre medication 
will be given unless indicated by previous 
experience in an individual patient. 
Reactions should be treated based upon the 
following recommendations. 
· 
For mild symptoms (e.g., localized 
cutaneous reactions such as mild 
pruritus, flushing, rash): 
o Decrease the rate of infusion until 
recovery from symptoms, remain at 
bedside and monitor patient. 
o Complete the ipilimumab infusion at 
the initial planned rate. 
o Diphenhydramine 25-50 mg I.V. may 
be administered at the discretion of 
the treating physician and patients 
may receive additional doses with 
close monitoring. 
o 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): 
o Interrupt ipilimumab. 
o Administer diphenhydramine 50 mg 
I.V. 
o Monitor patient closely until 
resolution of symptoms. 
o Corticosteroids may abrogate any 
beneficial immunologic effect, but 
may be administered at the 
discretion of the treating physician. 
o Resume ipilimumab infusion after 
recovery of symptoms. 
o At the discretion of the treating 
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be resumed at one half the initial 
infusion rate, then increased 
incrementally to the initial infusion 
rate. 
o If symptoms develop after 
resumption of the infusion, the 
infusion should be discontinued and 
no additional ipilimumab should be 
administered that day. 
o The next dose of ipilimumab will be 
administered at its next scheduled 
time and may be given with pre-
medication (diphenhydramine and 
acetaminophen) and careful 
monitoring, following the same 
treatment guidelines outlined above. 
o 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): 
o Immediately discontinue infusion of 
ipilimumab, and disconnect infusion 
tubing from the subject. 
o Consider bronchodilators, 
epinephrine 1 mg IV or 
subcutaneously, and/or 
diphenhydramine 50 mg IV, with 
solumedrol 100 mg IV, as needed. 
o Patients should be monitored until 
the investigator is comfortable that 
the symptoms will not recur. 
o 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). 
5.4.1.2.2 
Treatment of Ipilimumab-Related Isolated 
Drug Fever 
In the event of isolated drug fever, the 
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determine if the fever is related to the 
ipilimumab or to an infectious etiology. If a 
patient experiences isolated drug fever, for 
the next dose, pre-treatment with 
acetaminophen or non-steroidal anti-
inflammatory agent (investigator discretion) 
should be instituted and a repeated 
antipyretic dose at 6 and 12 hours after 
ipilimumab infusion, should be 
administered. The infusion rate will remain 
unchanged for future doses. If a patient 
experiences recurrent isolated drug fever 
following premedication and post dosing 
with an appropriate antipyretic, the infusion 
rate for subsequent dosing should be 
decreased to 50% of the previous rate. If 
fever recurs following infusion rate change, 
the investigator should assess the patient’s 
level of discomfort with the event and use 
clinical judgment to determine if the patient 
should receive further ipilimumab. 
5.4.1.3 
Immune-Related Adverse Events (irAEs): Definition, 
Monitoring, and Treatment 
Blocking CTLA 4 function may permit the emergence of 
auto-reactive T cells and resultant clinical autoimmunity. 
Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis, 
and hypopituitarism were drug-related, presumptive 
autoimmune events, now termed irAEs, noted in previous 
ipilimumab studies. 
For the purposes of this study, an irAE is defined as an AE 
of unknown etiology associated with ipilimumab exposure 
and consistent with an immune phenomenon. Efforts 
should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes prior to labeling 
an AE an irAE. Serological, immunological, and histological 
(biopsy) data should be used to support the diagnosis of 
an immune-mediated toxicity. Suspected irAEs must be 
documented on an AE or SAE form. 
Patients should be informed of and carefully monitored for 
evidence of clinically significant systemic irAE (e.g., 
systemic lupus erythematosus-like diseases) or organ 
specific irAE (e.g., rash, colitis, uveitis, hepatitis or thyroid 
disease). If an irAE is noted, appropriate work-up 
(including biopsy if possible) should be performed, and 
steroid therapy may be considered if clinically necessary. 
See Appendix XI for suggested work-up and treatment of 
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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.  
Corticosteroid replacement therapy is not allowed except 
for patients who develop endocrinopathies during this 
study that require corticosteroid replacement therapy (such 
as hydrocortisone) at stable doses. 
5.4.1.4 
Suggested evaluation and treatment for Immune Related 
Adverse Events (irAEs) associated with ipilimumab 
NOTE: This information has been summarized from 
the Ipilimumab Investigator Brochure (IB). 
Please refer to the current version of the IB 
for more details on the Suggested Work-up 
and Treatment for irAEs and Management 
Algorithms. Although these are suggested 
guidelines that take into consideration 
potential variations that may be required 
based on a specific clinical situation, these 
guidelines are strongly recommended. 
Management algorithms for the early detection and 
treatment of ipilimumab associated toxicities are provided 
in Appendices Appendix XII-Appendix XVI. 
5.4.1.4.1 
Immune-mediated Enterocolitis 
Diarrhea (defined as either first watery stool, 
or increase in frequency 50% above 
baseline with urgency or nocturnal bowel 
movement, or bloody stool) should be 
further evaluated and infectious or alternate 
etiologies ruled out. Subjects should be 
advised to inform the investigator if any 
diarrhea occurs, even if it is mild. An 
algorithm for managing subjects with 
diarrhea or suspected colitis is provided in 
Appendix XII and the IB. It is suggested that 
prednisone (for oral administration) or 
solumedrol (for IV administration) be the 
corticosteroids of choice in the treatment of 
colitis. 
Corticosteroid therapy (e.g., 1 to 2 
mg/kg/day of prednisone po or solumedrol 
I.V. or equivalent) is strongly recommended 
for ipilimumab related ≥ Grade 3 
diarrhea/colitis.  Upon improvement to 
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and continue to taper over at least one 
month. In clinical trials, rapid corticosteroid 
tapering resulted in recurrence or worsening 
symptoms of enterocolitis in some patients. 
Subjects with ipilimumab related Grade 2 
diarrhea/colitis may be initially treated 
conservatively, but should be immediately 
switched to corticosteroids if symptoms 
persist for more than one week or worsen. 
For severe or persistent symptoms, 
prednisone (e.g., 0.5 mg/kg/day) or 
equivalent may be required to control 
symptoms. Lower doses of prednisone may 
be considered for less severe cases of 
colitis. 
If the diarrhea is prolonged or severe or is 
associated with signs of systemic 
inflammation or acute phase reactants (e.g., 
increased CRP or platelet count; or 
bandemia), it is recommended that 
sigmoidoscopy (or colonoscopy, if 
appropriate) with colonic biopsy of 3 to 5 
specimens for standard paraffin block be 
performed. All subjects with confirmed 
colitis should also have an ophthalmologic 
examination, and a slit-lamp exam should 
be considered at the discretion of the 
treating physician investigator, to rule out 
uveitis. Also consider testing for stool 
calprotectin and stool WBCs as outlined in 
Appendix XII Negative stool testing for 
calprotectin or WBCs does not rule out 
autoimmune colitis. 
Infrequently, subjects will appear refractory 
to corticosteroids or will flare following taper 
of corticosteroids. In these subjects, unless 
contraindicated (i.e., sepsis and other 
serious infections, or perforation), a single 
dose of infliximab at 5 mg/kg may provide 
benefit. Infliximab 5 mg/kg may be repeated 
2 weeks later if clinically indicated. 
5.4.1.4.2 
Immune-mediated Hepatitis 
Liver function tests should always be 
performed and reviewed prior to 
administration of all ipilimumab doses. In 
addition, subjects presenting with right 
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have LFTs performed immediately and 
reviewed before administering the next dose 
of study drug. A Hepatotoxicity 
Management Algorithm is provided in 
Appendix XIII and the current IB. 
LFTs ≥ Grade 2 (for subjects with normal 
baseline LFT) or LFT ≥ 2 times baseline 
values (for subjects with baseline LFT of 
Grade 1 or 2) should prompt treating 
physicians to: (1) increase frequency of 
monitoring LFTs to at least every 3 days 
until LFT have stabilized or improved; (2) 
investigate to rule out non-irAE etiologies; 
and (3) initiate an autoimmunity evaluation. 
Disease progression, other malignancies, 
concurrent medications, viral hepatitis, and 
toxic etiologies should be considered and 
addressed, as appropriate. Imaging of the 
liver, gall bladder, and bile ducts should be 
considered to rule out neoplastic or other 
non-irAE-related causes for the increased 
LFTs. An ANA, perinuclear anti-neutrophil 
cytoplasmic antibody (pANCA), and anti-
smooth muscle antibody test should be 
performed if an autoimmune etiology is 
considered. Consultation with a hepatologist 
is appropriate for a suspected liver IRAE 
and a biopsy should be considered.  
For hepatic transaminases > 5 times the 
upper limit of normal (ULN) or total bilirubin 
is > 3 times the upper limit of normal: 
(1)ipilimumab dosing should be held 
according to the dose modification 
guidelines, (2) LFTs should be repeated 
every 24 hours until stabilization or 
improvement; and (3) therapeutic 
intervention with high dose corticosteroids 
should be strongly considered (e.g., 
prednisone PO or methylprednisolone I.V. 
1-2 mg/kg once or twice daily or equivalent). 
If symptoms or LFT elevations are 
controlled, the corticosteroid dose should be 
gradually tapered over a period of at least 1 
month. Flare in LFTs during this taper may 
be treated with an increase in the dose of 
steroid and a slower taper. Across the 
clinical development program for 
ipilimumab, mycophenolate treatment has 
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persistent severe hepatitis despite high-
dose corticosteroids. The most current 
experience with immune-related hepatitis 
has allowed further development of this 
management algorithm (see flow chart in 
Appendix XIII and current IB) to include 
recommendations for treatment. 
For hepatic transaminases > 8x the ULN or 
total bilirubin > 5x the ULN, It is 
recommended: 
a. Admit subject to hospital for evaluation 
and close monitoring.  
b. Stop any further ipilimumab dosing.  
c. Start high dose corticosteroids (e.g., 
2mg/kg methylprednisolone sodium 
succinate per day, given IV as a single 
or divided dose).  
d. Check liver laboratory test values (LFTs, 
T-bilirubin) daily until stable or showing 
signs of improvement for at least 3 
consecutive days.  
e. If no decrease in LFTs after 3 days or 
rebound hepatitis occurs despite 
treatment with corticosteroids, then add 
mycophenolate mofetil 1gm BID per 
institutional guidelines for 
immunosuppression of liver transplants 
(supportive treatment as required, 
including prophylaxis for opportunistic 
infections per institutional guidelines).  
f. 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). 
g. If target trough level is achieved with 
tacrolimus but no improvement is 
observed after 5 to 7 days, consider 
other immunosuppressant’s per 
institutional guidelines. 
h. Continue to check LFTs daily for at least 
2 weeks to monitor sustained response 
to treatment. 
5.4.1.4.3 
Immune-mediated Pancreas 
Symptoms of abdominal pain associated 
with elevations of amylase and lipase, 
suggestive of pancreatitis, may be 
associated with anti-CTLA-4 monoclonal 
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diagnosis of acute abdominal pain should 
include pancreatitis. Appropriate workup 
should include serum amylase and lipase 
tests. 
5.4.1.4.4 
Immune-mediated Dermatitis 
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.  A 
dermatologist should evaluate persistent or 
severe rash or pruritus. A biopsy should be 
performed if appropriate and if possible, 
photos of the rash should also be obtained. 
Any non-protocol drugs that could contribute 
to a drug reaction should be stopped if 
possible pending evaluation. 
Patients with low-grade ipilimumab-
mediated skin toxicity (Grade 1 or 2) may 
remain on therapy and could be treated with 
symptomatic therapy (e.g., antihistamines). 
Low-grade symptoms persisting for 1 to 2 
weeks and relapsing should be treated with 
topical or moderate dose oral corticosteroid 
therapy (e.g., prednisone 0.5 mg/kg once 
daily or equivalent).  
High-grade (persistent Grade 3 despite 
moderate dose oral corticosteroid such as 
prednisone 1 mg/kg once daily or 
equivalent, or any Grade 4) symptoms 
require high-dose IV corticosteroid therapy 
(e.g., prednisone PO or methylprednisolone 
I.V. at 1-2 mg/kg once or twice per day or 
equivalent) to control initial symptoms. A 
skin biopsy should be performed if 
appropriate. Once rash or pruritis is 
controlled, the initiation of corticosteroid 
taper should be based on clinical judgment; 
however, the corticosteroid dose should be 
gradually tapered over a period of at least 1 
month. 
Patients with any high-grade skin related 
toxicity (Grade 3 regardless of causality) 
have to skip ipilimumab and may only 
continue treatment with ipilimumab if the 
initial symptoms have improved to ≤ Grade 
1, while patients with grade 4 skin toxicities 
(e.g., Stevens-Johnson syndrome, toxic 

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epidermal necrolysis, or rash complicated 
by full thickness dermal ulceration, or 
necrotic, bullous, or hemorrhagic 
manifestations) have to permanently 
discontinue ipilimumab. 
5.4.1.4.5 
Immune-mediated Endocrinopathies 
Monitor thyroid function tests, other protocol 
required tests and clinical chemistries at the 
start of treatment, before each dose, and as 
clinically indicated based on symptoms. 
Subjects with unexplained symptoms such 
as fatigue, myalgias, impotence, mental 
status changes, or constipation should be 
investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies. An 
endocrinologist should be consulted if an 
endocrinopathy is suspected. If there are 
any signs of adrenal crisis such as severe 
dehydration, hypotension, or shock, 
intravenous corticosteroids with 
mineralocorticoid activity (e.g., 
methylprednisolone) should be initiated 
immediately. If the patient’s symptoms are 
suggestive of an endocrinopathy but the 
patient is not in adrenal crisis, endocrine 
laboratory results should be evaluated 
before corticosteroid therapy is initiated.  
Endocrine work up should include at least 
Thyroid stimulating hormone and free T4 
levels to determine if thyroid abnormalities 
are present. TSH, prolactin, and a morning 
cortisol level will help to differentiate primary 
adrenal insufficiency from primary pituitary 
insufficiency.  
Radiographic imaging (e.g., MRI) with 
pituitary cuts should be performed if 
hypophysitis is suspected. If the pituitary 
scan and/or endocrine laboratory tests are 
abnormal and suggestive of pituitary 
endocrinopathy, a short course of high dose 
corticosteroids (e.g., dexamethasone 4 mg 
every 6 hours or equivalent) should be 
strongly considered in an attempt to treat 
the presumed pituitary inflammation, but it is 
currently unknown if this will reverse the 
pituitary dysfunction.  
Abrupt discontinuation of corticosteroids 
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prolonged adrenal suppression. Once 
symptoms or laboratory abnormalities are 
controlled, and overall patient improvement 
is evident, the initiation of steroid taper 
should be based on clinical judgment; 
however the corticosteroid dose should be 
gradually tapered over a period of at least 1 
month. Appropriate hormone replacement 
therapy should be instituted if an 
endocrinopathy is documented, and it is 
possible that subjects may require life-long 
hormone replacement. 
Please see Appendix XIV and the current IB 
for the Endocrinopathy Management 
Algorithm. 
5.4.1.4.6 
Ocular Manifestations 
Ocular inflammation (episcleritis or uveitis), 
usually in association with colitis, was 
reported in a few subjects. These conditions 
responded to topical corticosteroid therapy. 
An ophthalmologist should evaluate visual 
complaints with examination of the 
conjunctiva, anterior and posterior 
chambers and retina; visual field testing and 
an electroretinogram should also be 
performed. Patients with ipilimumab related 
uveitis or episcleritis have been treated with 
topical corticosteroid eye drops. See 
Section 5.4.1.1.3 for ocular irAEs that may 
require ipilimumab permanent 
discontinuation. 
5.4.1.4.7 
Immune-mediated Neuropathies 
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 syndrome 
(GBS).  Institute medical intervention as 
appropriate for management of severe 
neuropathy. Consider initiation of systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone or equivalent for severe 
neuropathies. Withhold ipilimumab dosing in 
patients with moderate neuropathy (not 
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Appendix XV and the current IB for the 
Neuropathy Management Algorithm. 
5.4.1.4.8 
Other Immune-mediated Adverse Reactions 
The following clinically significant immune-
mediated adverse reactions were seen in 
less than 1% of ipilimumab-treated patients 
in reported studies to date: nephritis, 
pneumonitis, meningitis, pericarditis, uveitis, 
iritis, 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. 
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. 
5.4.2 
Patients Receiving Interferon (IFN) Alfa - 2b 
Overall, Induction Phase on this protocol includes the first 12 weeks 
where IFN is given by the I.V. route in the first 4 weeks then S.C. for 
the next 8 weeks. Maintenance Phase includes S.C. therapy the 
following 48 weeks. For the purposes of dose modifications for IFN, 
the 4 weeks of I.V. therapy shall be evaluated separately from the 
remaining weeks of S.C. IFN therapy. A patient requiring dose 
modification(s) for IFN in the first month of I.V. therapy will therefore 
commence month 2 without prejudice, at full IFN S.C. dosage. Doses 
missed during treatment due to toxicity, patient compliance, holiday, 
etc. should not be made up. 
Overview 
If a patient requires a dose modification (details are listed below), 
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IFN resumption. The first modification then requires a 33% reduction 
of dosage and the second modification requires a 66% reduction of 
dosage. A patient who requires a third dose modification will have IFN 
permanently discontinued. Dose re-escalation will not be attempted 
following resolution of toxicity that required dose interruption or 
attenuation. The following table summarizes IFN dose modifications. 
 
Full 
Treatment 
Dose Mod 1 
Dose Mod 2 
Dose Mod 3 
High Dose IFN Alfa - 2b I.V. 
(Weeks 1-4): 
20 MU/m² 
13.3 MU/m² 
6.6 MU/m² 
Off 
High Dose IFN Alfa - 2b 
Subcutaneous (Weeks 5+):  
10 MU/m² 
6.6 MU/m² 
3.3 MU/m² 
Off 
The following are the most common toxicities observed with 
interferon. Guidelines for HDI Dose Modification and Discontinuation 
are also provided. These toxicities and their management guidelines 
are based on experience from previous studies (E1684, E1690, 
E1694) and the following 2 publications that may also serve as 
additional resources on the toxicities associated with HDI and their 
management: 
Kirkwood JM, Bender C, Agarwala S, Tarhini A, Shipe-Spotloe J, 
Smelko B, Donnelly S, Stover L. Mechanisms and management of 
toxicities associated with high-dose interferon alfa-2b therapy. J Clin 
Oncol. 2002 Sep 1;20(17):3703-18. Review. 
Hauschild A, Gogas H, Tarhini A, Middleton MR, Testori A, Dréno B, 
Kirkwood JM. Practical guidelines for the management of interferon-
alpha-2b side effects in patients receiving adjuvant treatment for 
melanoma: expert opinion. Cancer. 2008 Mar 1;112(5):982-94. 
NOTE:  Dose modifications may be done for toxicities related to HDI 
therapy even if they don’t fit these guidelines if it is 
determined by the treating physician that it is in the best 
interest of the patient for safety reasons taking into 
consideration the overall clinical status of the subject. A note 
has to be made of such a modification. 
· 
Constitutional Toxicity: Fever, chill, myalgia/arthralgia, fatigue, 
headache: these constitutional toxicities are observed in the first 
weeks of treatment. Fatigue may worsen during the course of 
therapy and require a dose modification. In general, dose 
modifications are done for grade 3 or 4 toxicities.   
· 
Myelotoxicity: Leukopenia, anemia and thrombocytopenia are 
observed with acute and chronic interferon therapy. Dose 
modifications are indicated for grade 4 granulocytopenia and 
grade 3 thrombocytopenia. 
· 
Hepatotoxicity: Fatal hepatotoxicity has been observed in patients 
receiving sustained intensive high dosages of interferon, and 
close attention to the occurrence of hepatocellular enzyme 
abnormalities is warranted. Grade 3 or greater elevations of 

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bilirubin, AST or ALT require dosage modification. Isolated 
elevation in other LFT’s should also be examined carefully, 
preferably in consultation with a hepatology specialist and dose 
modification should be considered if underlying liver damage is 
suspected.   
· 
Nephrotoxicity: Acute kidney injury of Grade 1 (CTCAE v.4) that is 
not rapidly responsive to hydration (PO or IV) is an indication for 
dose modification and elevations of Grade 2 (not rapidly 
responsive to hydration) require withdrawal of therapy. Patients 
should be advised to maintain adequate oral fluid hydration of 
about 1.5 – 2 liters per day during IFN Alfa - 2b.  
· 
Neurotoxicity, including Neuropsychiatric, Neurosensory, and 
Neuromotor: Mood alterations and cognitive dysfunction have 
been reported as toxicities of the interferons, especially in the 
elderly and those with underlying disorders. Grade 3 or greater 
Neurotoxicity is a dose modification criterion, and if 
neuropsychiatric toxicity is encountered this ought to be evaluated 
by a capable specialist (psychiatrist, and/or clinical psychologist). 
· 
Cardiopulmonary: Cardiac arrhythmia has been reported as a 
complication of interferon therapy, and the  appearance of signs or 
symptoms of cardiac arrhythmia, or other cardiopulmonary toxicity 
of Grade 2 dictates dose modification, and resumption of 
treatment only after normalization and, in general, formal 
cardiologic evaluation and clearance. Grade 3 toxicity at any time 
requires withdrawal of therapy. 
· 
Gastrointestinal: Nausea, vomiting, and/or diarrhea are infrequent 
but well-defined toxicities of interferon, which may abate with 
supportive care but require dose modification if observed at Grade 
3, at any time, or if persistent for more than 2 weeks at Grade 2. 
Weight loss of Grade 2 is likewise a criterion for dose modification 
if observed over a period of one month. 

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Suggested HDI Dose Modification and Discontinuation Guidelines:  
Toxicity 
1. Threshold for Reduction 
2. % Dose Reduction from Starting Dose 
3. Threshold for Resumption 
First Dose Reduction 
Second Dose Reduction 
Treatment 
Discontinuation 
Autoimmune 
Reactions 
 
 
 
Hypothyroidism 
None 
None 
Discontinue if thyroid 
function is unstable with 
treatment. 
Psoriasis 
1.  ≥ grade 2 skin rash 
(localized desquamation or 
other lesions covering 
<50% of body surface 
area) 
2.  33% 
3.  Grade 1 (erythema 
without associated 
symptoms) 
1.  ≥ grade 2 skin rash 
(localized desquamation 
or other lesions covering 
<50% of body surface 
area) 
2.  66% 
3.  Grade 1 (erythema 
without associated 
symptoms) 
1.  ≥ grade 2 skin rash 
(localized desquamation 
or other lesions covering 
<50% of body surface 
area) 
2.  Discontinue 
 
Hematologic 
Toxicity 
 
 
 
Granulocytope
nia 
1.  < 500 cells/mm3  (Grade 
4) 
2.  33% 
3.  ≥1000 cells/mm3  
1. < 500 cells/mm3 
(Grade 4) 
2. 66% 
3. ≥1000 cells/mm3  
1. < 500 cells/mm3 
(Grade 4) 
2. Discontinue 
Thrombocytope
nia 
1. < 50,000 cells/mm3 
(Grade 3) 
2. 33% 
3. >75,000 cells/mm3 
(Grade 1) 
1. < 50,000 cells/mm3 
(Grade 3) 
2. 66% 
3. >75,000 cells/mm3 
(Grade 1) 
1. <50,000 cells/mm3 
(Grade 3) 
2. Discontinue 
Other 
 
 
 
Anorexia 
1. Grade 3 or 4 
2. 33% 
3. Grade 2 
1. Grade 3 or 4 
2. 66% 
3. Grade 2 
1. Grade 3 or 4 
2. Discontinue 
 
Cardiotoxicity 
1. Grade 2 
2. 33% 
3. Normalization and, 
consider formal cardiologic 
evaluation and clearance 
1. Grade 2 
2. 66% 
3. Normalization and, 
consider formal 
cardiologic evaluation 
and clearance 
1. Grade 2  
2. Discontinue. 
3. Grade 3 toxicity at any 
time requires withdrawal 
of therapy 

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Creatine 
Kinase (CPK) 
1. > 5 times normal (in the 
absence of a clinical 
suspicion of 
rhabdomyolysis) or any 
elevation and a clinical 
suspicion of 
rhabdomyolysis 
2. 33% 
3. ≤ 2 times normal 
1. > 5 times normal (in 
the absence of a clinical 
suspicion of 
rhabdomyolysis) or any 
elevation and a clinical 
suspicion of 
rhabdomyolysis 
2. 66% 
3. ≤ 2 times normal 
1. > 5 times normal  
2. Discontinue.  
3. Discontinue at any 
time if diagnosed with 
rhabdomyolysis. 
Depression 
1. Grade 3 or 4 
2. 33% 
3. Grade 1 
1. Grade 3 or 4 
2. 66% 
3. Grade 1 
1. Grade 3 or 4 
2. Discontinue 
 
Diarrhea 
1. Grade 3 or 4 or if 
persistent for more than 2 
weeks at Grade 2 
2. 33% 
3. Grade 1 
1. Grade 3 or 4 or if 
persistent for more than 
2 weeks at Grade 2 
2. 66% 
3. Grade 1 
1. Grade 3 or 4 or if 
persistent for more than 
2 weeks at Grade 2 
2. Discontinue 
 
Fatigue 
1. Grade 3 or 4 
2. 33% 
3. Grade 1 
1. Grade 3 or 4 
2. 66% 
3. Grade 1 
1. Grade 3 or 4 
2. Discontinue 
Flu-like 
Symptoms-
Constitutional 
Symptoms 
1. Grade 3 or 4 
2. 33% 
3. Grade 1 
1. Grade 3 or 4 
2. 66% 
3. Grade 1 
1. Grade 3 or 4 
2. Discontinue 
Hepatotoxicity 
(SGPT [ALT] 
SGPT [AST]) 
1. > 5 times normal (Grade 
3 or 4) 
2. 33% 
3. Grade 1 
1. > 5 times normal 
(Grade 3 or 4) 
2. 66% 
3. Grade 1 
1. > 5 times normal  
(Grade 3 or 4) 
2. Discontinue 
Nausea 
1. Grade 3 or 4 or if 
persistent for more than 2 
weeks at Grade 2 
2. 33% 
3. Grade 1 
1. Grade 3 or 4 or if 
persistent for more than 
2 weeks at Grade 2 
2. 66% 
3. Grade 1 
1.  Grade 3 or 4 or if 
persistent for more than 
2 weeks at Grade 2 
2. Discontinue 
Ocular toxicity 
None 
None 
Discontinue for any 
ocular toxicity 
Renal 
 
1. Grade 1 
2. 33% 
3. normal 
1. Grade 1 
2. 66% 
3. normal 
1. Grade 1 
2. Discontinue 
3. Elevations of Grade 2 
or higher at anytime 
require withdrawal of 
therapy 
Vomiting 
1. Grade 3 or 4 or if 
persistent for more than 2 
weeks at Grade 2 
2. 33% 
3. Grade 1 
1. Grade 3 or 4 or if 
persistent for more than 
2 weeks at Grade 2 
2. 66% 
3. Grade 1 
1. Grade 3 or 4 or if 
persistent for more than 
2 weeks at Grade 2 
2. Discontinue 
 

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Weight loss 
1.  Grade 2  if observed 
over a period of one month 
and is unintentional  
2. 33% 
3. Continue at the reduced 
dose if no other limiting 
adverse events 
1. Grade 2  if observed 
over a period of one 
month and is 
unintentional  
2. 66% 
3. Continue at the 
reduced dose if no other 
limiting adverse events 
1. Grade 2 is if observed 
over a period of one 
month and is 
unintentional  
2. Discontinue. 
5.5 
Supportive Care and Prohibited Therapies 
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5.2 
See Section 5.4.1.2 that provides supportive care considerations for 
ipilimumab administration. 
5.5.3 
Patients requiring chemotherapy or radiation therapy during the study 
will be taken off study treatment. Any exceptions must be discussed 
with the study chair. 
5.5.4 
Additional Prohibited and Restricted Therapies During the Study. 
5.5.4.1 
Prohibited Therapies 
Patients in this study may not use vaccines for the 
treatment of cancer or prevention of disease (including 
those for common medical conditions) for up to one month 
pre and post dosing with ipilimumab. Concomitant 
systemic or local anti-cancer medications or treatments are 
prohibited in this study while receiving ipilimumab or HDI 
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 agonists, PD-1 inhibitors 
· 
Immunosuppressive agents, unless indicated to 
manage study therapy induced irAEs 
· 
Chronic systemic corticosteroids, unless indicated to 
manage study therapy induced irAEs 
· 
Any non-oncology vaccine therapies used for the 
prevention of infectious diseases (for up to 30 days 
prior to or after any dose of study drug). 
5.5.4.2 
Precautions 
Caution is advised when considering treatment with high-
dose IL-2 in patients who have previously been 
administered ipilimumab, particularly in patients who 

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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. 
5.6 
Duration of Therapy 
The duration of therapy on all study arms is approximately 60 weeks. 
Patients will receive protocol therapy unless: 
5.6.1 
Melanoma disease progression by protocol criteria: in which case 
patients will be removed from study treatment. They will, however, 
continue to be followed for survival. In addition, data on salvage 
patterns post recurrence will be collected. 
5.6.2 
Patients will be discontinued from treatment in the event of 
unacceptable toxicity (see protocol therapy discontinuation criteria in 
Section 5), pregnancy, change in medical condition or noncompliance 
with the study protocol that in the opinion of the investigator, 
necessitates removal of patient from treatment. 
5.6.3 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event, submit forms according to the 
schedule in the E3611 Forms Completion Guidelines. 
5.6.4 
Patient withdraws consent. 
5.6.5 
Patient experiences unacceptable toxicity. 
5.6.6 
Prohibited non-protocol therapies are administered. 
5.7 
Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 10 years from the date of registration. 

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6. 
Measurement of Effect 
6.1 
Antitumor Effect – RECIST 
For the purposes of this study, patients should be re-evaluated for response 
every 12 weeks.  In addition to a baseline scan, confirmatory scans should also 
be obtained not less than 4 weeks following initial documentation of objective 
response. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in RECIST. 
The following general principles must be followed: 
1. 
To assess objective response, it is necessary to estimate the overall 
tumor burden at baseline to which subsequent measurements will be 
compared. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than four weeks 
before registration. 
2. 
Measurable disease is defined by the presence of at least one 
measurable lesion. 
3. 
All measurements should be recorded in metric notation by use of a ruler 
or calipers.  
4. 
The same method of assessment and the same technique must be used 
to characterize each identified lesion at baseline and during follow-up. 
6.1.1 
Definitions 
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 lesion assessment.  The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 

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6.1.2 
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, as  
≥ 10 mm with CT scan, or ≥ 10 mm with calipers by clinical exam. All 
tumor measurements must be recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area might or might not be considered measurable. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable.  Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected. 

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A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters.  If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum.  The baseline 
sum of the diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers.  All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
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 in diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the 

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availability of MRI is variable globally.  As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up 
must be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
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 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 

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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 generally a sign of PD based on a new lesion. 
However, immunotherapeutic agents such as ipilimumab as 
known to generate a systemic immune response leading to 
enhanced immune cellular infiltration or tumor or lymph nodes. 
Therefore, a positive FDG-PET lesion at follow-up needs to be 
carefully assessed to ensure accurate response assessment and 
a biopsy should be pursued if in doubt.  
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 generally a sign of PD, but care 
must be taken in assessing the tumor response, as noted in the 
prior paragraph.  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. 
b. 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. However, it 
must be acknowledged that both approaches may lead to false 

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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. 
6.1.4 
Response Criteria 
6.1.4.1 
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. 
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 progression, See Section 
6.1.4.3). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 6 weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (<10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s. 

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Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it a) increases in size to ≥ 
15 mm in the short axis, or b) there is new pathological 
confirmation that it is disease (regardless of size). 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the 

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achievement of both measurement and confirmation 
criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Best 
Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not 
evaluated 
No 
PR 
SD 
Non-PD***/not 
evaluated 
No 
SD 
Documented at 
least once ≥ 6 wks. 
from study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or 
CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must 
be representative of overall disease status change, not a single lesion increase. 
Please refer to the Evaluation of Non-Target Lesions – Progressive Disease 
section for further explanation. 
NOTE: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic deterioration.”  
Every effort should be made to document the objective progression even 
after discontinuation of treatment. 
6.1.4.5 
Confirmation of Response 
To be assigned a status of complete or partial response, 
changes in tumor measurements must be confirmed by 
repeat assessments performed no less than four weeks 
after the criteria for response are first met. 
6.1.4.6 
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). 

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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.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 6 weeks. 
6.2 
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. 
6.2.1 
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 (ie., 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. 
6.2.2 
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 

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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). 
6.2.3 
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. 
6.2.4 
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 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. 

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Table 11: 
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 
6.2.5 
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. 
6.2.6 
Response Endpoints 
Ipilimumab is expected to trigger immune-mediated responses, which 
require activation of the immune system prior to the observation of 
clinical responses. Such immune activation may take weeks to 
months to be evident. Some patients may have objective volume 
increase of tumor lesions or other disease parameters (based on 
study indication, ie, hematologic malignancies) within 12 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 volume increase detected or lack of 
laboratory parameter response documentation prior to week 12 but 
without rapid clinical deterioration should continue to be treated with 
ipilimumab and clinically observed with a stringent imaging schedule 
to allow detection of a subsequent tumor response. This will improve 
the overall assessment of the clinical activity or ipilimumab and more 
likely capture its true potential to induce clinical responses. Tumor 
assessments will be made using RECIST criteria. 

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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
1. 
Prestudy scans and x-rays used to assess all measurable or non-
measurable sites of disease must be done within 4 weeks prior to 
randomization. 
2. 
Prestudy (screening) CBC (with differential and platelet count) chemistries 
and other laboratory studies required in Section 3 (Selection of Patients) 
should be done ≤ 4 weeks before randomization.  
3. 
All required pretreatment laboratory studies should be done as outlined in 
the study calendars in Sections 7.2 and 7.3.  
4. 
For WOCBP, pregnancy test (b-HCG test; serum or urine, minimum 
sensitivity 25 IU/L or equivalent units of b-HCG) must be done during 
screening within four weeks prior to randomization. Following randomization, 
serum or urine pregnancy test must be done within 72 hours prior to each 
dose of ipilimumab. 
 

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7.2 
Arms A and C: Patients Treated with HDI and Ipilimumab at 10 mg/kg (Arm A) or 3 mg/kg (Arm C) 
Test/ Assessment 
Within 4 
weeks  
(28 days)  
of rando-
mization 
Induction Phasea 
Week 
12 
±1 wk 
Maintenance Phasea 
Until 12 weeks after last 
ipilimumab dose (or 6 
Weeks after last IFN-α2b 
dose if ipilimumab was 
discontinued >12 weeks 
earlier) or until relapse 
End of Study 
Assessmentn 
Follow 
Upm 
D1 
+ 3d 
(wk1) 
D8 
(wk2) 
D15 
(wk3) 
D22 
+ 3d 
(wk4) 
D29 
(wk5) 
D43 
± 3d 
(wk7) 
D64 
± 3d 
(wk10) 
 
Week 24, 
36, 48, 60  
± 1 Week 
Every 6 Wks 
±1 Week 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
History/Physical/ 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corticosteroid, 
immunosuppressant, 
hormone meds Log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology labsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry labsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysise 
See  Footnote e 
Pregnancy test (b-
HCG)f 
X f 
X f 
 
 
X f 
 
X f 
X f 
 
X f 
 
 
 
HIV, HBV, HCVg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Immunologic labsh,a 
See  Footnote h 
Hormonal studiesi,a 
 
Xi 
 
 
Xi 
 
Xi 
Xi 
Xi 
Xi 
 
Xi 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic 
examinationj 
Xj 
 
 
 
 
 
 
 
 
Xj 
 
 
Xj 
Ipilimumab infusion 
 
X 
 
 
X 
 
X 
X 
 
X 
 
 
 
Adverse events 
assessmentk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Imaging studiesl 
Xl 
 
 
 
 
 
 
 
Xl 
Xl 
 
Xl 
Interferon Diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X   
 
 
Biological sample 
submissions 
See Section 7.4 
a. All Study procedures, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 3 days prior to 
dosing. Chemistry results must be reviewed and confirm that subject’s liver function tests and other safety labs still meet inclusion criteria 
prior to administration of ipilimumab dose. Baseline pregnancy exam must be performed within 3 days of beginning ipilimumab dosing and 
determined to be negative. During the maintenance phase, in addition to the evaluations done on the dosing days every 12 weeks, patients 
will be seen and evaluated as noted in the study calendar every 6 weeks (-/+ 1 week), starting at week 18. They should be seen and 
evaluated more often if clinically indicated for the management of toxicities, at the discretion of the treating physician investigator. Hormonal 
studies and immunologic labs are required for monitoring at the specified time points and as clinically indicated. The results of these tests 
(hormonal studies and immunologic labs) are not required for dosing unless there are clinical indications and/or associated adverse events as 
described under the Section on Dose and Schedule Modifications for Ipilimumab and the Section on HDI Dose Modification and 
Discontinuation Guidelines. 
b. For first infusion only, vital signs to be collected prior to dosing, every 15 minutes (-/+ 5 minutes) during dosing and 30 - 60 minutes (-/+ 10 
minutes) after dosing until vital signs normalize or return to baseline. For subsequent infusions, vital signs should be collected prior to dosing, 
every 30 minutes (-/+ 10 minutes) during dosing, and 1 hour (-/+ 10 minutes) post dosing.  
c. Hematology labs to include hemoglobin, hematocrit, red blood cell count, white blood cell count, platelets (direct platelet count), as well as 
total and differential CBC counts. These labs must be done and reviewed before ipilimumab infusion. These labs are required to be done 
throughout follow-up regardless if the patient goes off treatment early for anything other than recurrence. Once recurrence occurs, these labs 
are no longer required to be completed. 
d. Chemistry laboratory analysis includes albumin, amylase, lipase, urea or BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, 
direct and total bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3 (CO2; venous blood), calcium, phosphorous. In follow up 
(after completion of ipilimumab treatment), amylase and lipase will be done only if clinically indicated. These labs must be done and reviewed 
before ipilimumab infusion. These labs are required to be done throughout follow-up regardless if the patient goes off treatment early for 
anything other than recurrence. Once recurrence occurs, these labs are no longer required to be completed. 
e. Urinalysis will be done as clinically indicated. Urinalysis tests to include gross examination including specific gravity, protein, glucose and 
blood. A microscopic evaluation will also be performed, as clinically indicated, to include WBC/HPF, RBC/HPF and any additional findings.  
f. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at screening. Serum or 
urine pregnancy test must be done within 72 hours prior to each dose of ipilimumab. 
g. At screening, testing should be performed for HIV antibody, hepatitis C antibody, and HBs antigen utilizing local standard informed consent 
procedures prior to this laboratory collection. These tests could be repeated later during the course of the study if clinically indicated. 
h. The following labs are to be done at baseline (within 4 weeks of starting the study drug) and at 12, 24, 42, 60, and 96 weeks, and at 
melanoma relapse (+/- 2 weeks for all time points except the 96 week time point, a +/- 4 weeks window is allowed). If melanoma relapse 
occurs before any of these time points, no additional testing needs to be done after the relapse time point: C-reactive protein,  Antinuclear 
antibody (ANA) Screen, Thyroid Stimulating Immunoglobulin (TSI), Antithyroglobulin antibody (ATGAB),  Antithyroperoxidase Antibody 
(ATPOAB), Anticardiolipin Antibody (TOTAL). These labs must be completed even if the patient goes off treatment early for any reason other 

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than progression. If melanoma progression occurs before any of these time points, no additional testing needs to be done after the relapse 
time point. 
i. Hormonal studies: To be done at the indicated visits and when clinically indicated. These include TSH, free T4, morning ACTH, morning 
cortisol. For Men: testosterone. For WOCBP: prolactin, LH, FSH, and estradiol that will be done only if a WOCBP is experiencing amenorrhea 
while on protocol treatment. For days 22 and 64 (-/+ 3 days) only TSH and free T4 are required while others are to be done only if clinically 
indicated.  
j. Ophthalmologic examination will be done at baseline only if clinically indicated. On this study, the last dose of ipilimumab will be at 
approximately week 60.  Ophthalmological examination is strongly recommended to be done at 6 and 18 months (± 4 weeks) after start of 
treatment, especially in patients who experienced diarrhea or colitis, preferably performed by an ophthalmologist. If melanoma recurrence 
occurs before these time points, the ophthalmological examination should still be done if clinically indicated.  It should also be performed at 
other time points if clinically indicated.  
k. Until 90 days after the last study drug administration. All adverse events must be collected whether they occur on treatment or non-treatment 
weeks and must be submitted utilizing the corresponding E1609 Adverse Event Forms, covering all time periods specified on the forms. 
l. Baseline imaging studies: should be done within 4 weeks prior to randomization. These must include a brain MRI or CT (if MRI is 
contraindicated or cannot be done) and CT of chest, abdomen and pelvis. A PET-CT scan may be done instead of CT. If for some reason a 
CT cannot be done, an MRI may be done instead. Imaging of other sites (e.g. neck, lower extremities) should be obtained when clinically 
indicated. Other imaging studies (e.g., bone scan) may be performed if clinically indicated. During treatment and on follow-up: CT (or MRI if 
CT cannot be done) chest/abdomen/pelvis will be done every 3 months (-/+ 1 week) for the first year from study entry, every  3 months (-/+ 2 
weeks) for the 2nd year, then every 6 months (+/- 4 weeks) for the 3rd, 4th and 5th years from study entry, and annually (+/- 4 weeks) if 
patient is >5 years from study entry for up to 10 years. A PET-CT is not required, but is acceptable if done. However, if PET-CT was done at 
baseline, it should also be done on follow up assessments. Brain MRI/CT or other imaging studies may be done as clinically indicated but are 
not required in the absence of clinical indications. 
m. Follow up period will start 12 weeks after the last ipilimumab dose (or 6 weeks after last IFN-a2b dose if ipilimumab was discontinued >12 
weeks earlier) for patients who have no disease progression. These patients should be seen at 6 weeks (-/+ 1 week) after the last dose then 
12 weeks (-/+ 1 week) after the last dose and later evaluated per the standard ECOG-ACRIN follow-up schedule: Every 3 months (+/- 2 
weeks) if patient is < 2 years from study entry, every 6 months (+/- 4 weeks) if patient is 2-5 years from study entry, and every 12 months (+/- 
4 weeks) if patient is > 5 years from study entry for up to 10 years. However, patients with ongoing toxicities should be seen more often as 
clinically indicated. Patients who develop melanoma progression will be followed for survival and for information on salvage patterns. The 
schedule of clinical follow up for these patients will be at the discretion of the treating physicians and according to established Standard of 
Care. Adverse Events Assessment on the study will continue for all patients until 90 days after the last study drug administration. 
n. End of Study Assessment will be done within 6 weeks (+/- 1 week) of the last dose of ipilimumab or interferon, whichever was given last. This 
is after completion/discontinuation of both regimen agents (ipilimumab and interferon). 

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7.3 
Arms B and D: Patients Treated with Ipilimumab alone at 10 mg/kg (Arm B) or 3 mg/kg (Arm D) 
Test/ Assessment 
Within 4 
weeks  
(28 days)  
of randomi- 
zation 
Induction Phasea 
Week 
12 
± 1 
week 
Maintenance Phasea 
(Until 12 weeks after the 
last ipilimumab dose or 
until relapse) 
End of Study 
Assessmentn 
Follow 
Upm 
Day 1±  
3 days 
(Week 1) 
Day 22 ± 
3 days 
(Week 4) 
Day 43 ± 
3 days 
(Week 7) 
Day 64 ± 
3 days 
(Week 
10) 
Week 24, 
36, 48, 60  
± 1 Week 
Every 6 
Weeks ±1 
Week 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
History/Physical/ ECOG 
PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corticosteroid, 
immunosuppressant, 
hormone meds Log 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology labsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry labsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysise 
See  Footnote e 
Pregnancy test (b-HCG)f 
X 
X 
X 
X 
X 
 
X 
 
 
 
HIV, HBV, HCVg 
X 
 
 
 
 
 
 
 
 
 
Immunologic labsh 
See  Footnote h 
Hormonal studiesi 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
 
Xi 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
Ophthalmologic 
examinationj 
Xj 
 
 
 
 
 
Xj 
 
 
Xj 
Ipilimumab infusion 
 
X 
X 
X 
X 
 
X 
 
 
 
Adverse events 
assessmentk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging studiesl 
Xl 
 
 
 
 
Xl 
Xl 
 
Xl 
Biological sample 
submissions 
See Section 7.4 
Rev. 5/14 

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a. All Study procedures, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 3 days prior to 
dosing. Chemistry results must be reviewed and confirm that subject’s liver function tests and other safety labs still meet inclusion criteria 
prior to administration of ipilimumab dose. Baseline pregnancy exam must be performed within 3 days of beginning ipilimumab dosing and 
determined to be negative. During the maintenance phase, in addition to the evaluations done on the dosing days every 12 weeks, patients 
will be seen and evaluated as noted in the study calendar every 6 weeks (-/+ 1 week), starting at week 18. They should be seen and 
evaluated more often if clinically indicated for the management of toxicities, at the discretion of the treating physician investigator. Hormonal 
studies and immunologic labs are required for monitoring at the specified time points and as clinically indicated. The results of these tests 
(hormonal studies and immunologic labs) are not required for dosing unless there are clinical indications and/or associated adverse events 
as described under the Section on Dose and Schedule Modifications for Ipilimumab and the Section on HDI Dose Modification and 
Discontinuation Guidelines. 
b. For first infusion only, vital signs to be collected prior to dosing, every 15 minutes (-/+ 5 minutes) during dosing and 30 - 60 minutes (-/+ 10 
minutes) after dosing until vital signs normalize or return to baseline. For subsequent infusions, vital signs should be collected prior to 
dosing, every 30 minutes (-/+ 10 minutes) during dosing, and 1 hour post dosing. 
c. Hematology labs to include hemoglobin, hematocrit, red blood cell count, white blood cell count, platelets (direct platelet count), as well as 
total and differential CBC counts. These labs must be done and reviewed before ipilimumab infusion. These labs are required to be done 
throughout follow-up regardless if the patient goes off treatment early for anything other than recurrence. Once recurrence occurs, these labs 
are no longer required to be completed. 
d. Chemistry laboratory analysis includes albumin, amylase, lipase, urea or BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, 
direct and total bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3 (CO2; venous blood), calcium, phosphorous. In follow up 
(after completion of ipilimumab treatment), amylase and lipase will be done only if clinically indicated. These labs must be done and 
reviewed before ipilimumab infusion. These labs are required to be done throughout follow-up regardless if the patient goes off treatment 
early for anything other than recurrence. Once recurrence occurs, these labs are no longer required to be completed. 
e. Urinalysis will be done as clinically indicated. Urinalysis tests to include gross examination including specific gravity, protein, glucose and 
blood. A microscopic evaluation will also be performed, as clinically indicated, to include WBC/HPF, RBC/HPF and any additional findings.  
f. 
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at screening. Serum 
or urine pregnancy test must be done within 72 hours prior to each dose of ipilimumab. 
g. At screening, testing should be performed for HIV antibody, hepatitis C antibody, and HBs antigen utilizing local standard informed consent 
procedures prior to this laboratory collection. These tests could be repeated later during the course of the study if clinically indicated. 
h. The following labs are to be done at baseline (within 4 weeks of starting the study drug) and at 12, 24, 42, 60, and 96 weeks, and at 
melanoma relapse (+/- 2 weeks for all time points except the 96 week time point, a +/- 4 weeks window is allowed). If melanoma relapse 
occurs before any of these time points, no additional testing needs to be done after the relapse time point: C-reactive protein,  Antinuclear 
antibody (ANA) Screen, Thyroid Stimulating Immunoglobulin (TSI), Antithyroglobulin antibody (ATGAB),  Antithyroperoxidase Antibody 
(ATPOAB), Anticardiolipin Antibody (TOTAL). These labs must be completed even if the patient goes off treatment early for any reason other 
than progression. If melanoma progression occurs before any of these time points, no additional testing needs to be done after the relapse 
time point. 
i. 
Hormonal studies: To be done at the indicated visits and when clinically indicated. These include TSH, free T4, morning ACTH, morning 
cortisol. For Men: testosterone. For WOCBP: prolactin, LH, FSH, and estradiol that will be done only if a WOCBP is experiencing 
amenorrhea while on protocol treatment. For days 22 and 64 (-/+ 3 days) only TSH and free T4 are required while others are to be done only 
if clinically indicated. 

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j. 
Ophthalmologic examination will be done at baseline only if clinically indicated. On this study, the last dose of ipilimumab will be at 
approximately week 60.  Ophthalmological examination is strongly recommended to be done at 6 and 18 months (± 4 weeks) after start of 
treatment, especially in patients who experience diarrhea or colitis, preferably performed by an ophthalmologist. If melanoma recurrence 
occurs before these time points, the ophthalmological examination should still be done if clinically indicated.  It should also be performed at 
other time points if clinically indicated.  
k. Until 90 days after the last study drug administration. All adverse events must be collected whether they occur on treatment or non-treatment 
weeks and must be submitted utilizing the corresponding E1609 Adverse Event Forms, covering all time periods specified on the forms. 
l. 
Baseline imaging studies: should be done within 4 weeks prior to randomization. These must include a brain MRI or CT (if MRI is 
contraindicated or cannot be done) and CT of chest, abdomen and pelvis. A PET-CT scan may be done instead of CT. If for some reason a 
CT cannot be done, an MRI may be done instead. Imaging of other sites (e.g. neck, lower extremities) should be obtained when clinically 
indicated. Other imaging studies (e.g., bone scan) may be performed if clinically indicated. During treatment and on follow-up: CT (or MRI if 
CT cannot be done) chest/abdomen/pelvis will be done every 3 months (-/+ 1 week) for the first year from study entry, every  3 months (-/+ 2 
weeks) for the 2nd year, then every 6 months (+/- 4 weeks) for the 3rd, 4th and 5th years from study entry, and yearly (+/- 4 weeks) if patient 
is >5 years from study entry for up to 10 years. A PET-CT is not required, but is acceptable if done. However, if PET-CT was done at 
baseline, it should also be done on follow up assessments. Brain MRI/CT or other imaging studies may be done as clinically indicated but 
are not required in the absence of clinical indications. 
m. Follow up period will start 12 weeks after the last ipilimumab dose for patients who have no disease progression. These patients should be 
seen at 6 weeks (-/+ 1 week) after the last dose, then 12 weeks (-/+ 1 week) after the last dose, and later evaluated per the standard ECOG-
ACRIN follow-up schedule: Every 3 months (+/- 2 weeks) if patient is < 2 years from study entry, every 6 months (+/- 4 weeks) if patient is 2-
5 years from study entry, and every 12 months (+/- 4 weeks) if patient is > 5 years from study entry for up to 10 years. However, patients 
with ongoing toxicities should be seen more often as clinically indicated. Patients who develop recurrent melanoma will be followed for 
survival and for information on salvage patterns. The schedule of clinical follow up for these patients will be at the discretion of the treating 
physicians and according to established Standard of Care. Adverse Events Assessment on the study will continue for all patients until 90 
days after the last study drug administration.  
n. End of Study Assessment will be done within 6 weeks (+/- 1 week) of the last dose of ipilimumab. 

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7.4 
Biological Sample Submissions 
1. Submission of pathology samples at baseline for diagnostic review is mandatory in order for the patient to be 
considered evaluable. See Section 10 (Pathology Review) and Appendix I (Pathology Submission Guidelines). 
2. Pathology samples for future laboratory studies should be submitted as outlined in Section 10 per patient 
consent. 
3. Blood samples for future laboratory studies should be submitted as outlined in Section 11 per patient consent. 
NOTE: 
It is required that biological sample submissions be logged into the ECOG-ACRIN Sample Tracking 
System (STS) for purposes of monitoring compliance. 
NOTE:  
An informed consent must be signed prior to the submission of any samples, including mandatory 
diagnostic reviews and future laboratory studies. Blood samples for future use should be submitted only 
from patients who have given written consent for the use of their samples for these purposes. 
Material 
Baseline1 
Day 19 [+ 4 day window] (End 
Week3 / Start Week4)10 
After 12 Weeks of 
Initiating Treatment2 
At 48 Weeks2, 
3 
Progression/ 
Relapse 
Pathology Samples6 
X9 
 
 
 
X8 
Patient consents “Yes” to “I agree to provide additional blood for research.” 
Peripheral Blood Mononuclear Cells (ten 
10cc green top heparin tubes)4,5,7 
X 
X 
X 
X 
X2,3 
Serum (three 10cc red top tubes)4,5,7 
X 
X 
X 
X 
X2,3 
PAXgene RNA Tube (1)4,5,7 
X 
X 
X 
 
 
ACD Tube (one 10cc yellow top tube)4,5,7 
X 
 
 
 
 
1. Prior to treatment 
2. +/- 1 week. 
3. If relapse occurs before the 48 week time point, no additional blood samples are required after the relapse blood sample is sent. 
4. Kits are being provided for the collection and shipment of the blood samples. Please refer to Section 11.3 for instructions. 
5. Please completely fill all blood tubes as full as possible. 
6. Submit to ECOG-ACRIN Central Biorepository and Pathology Facility. 
7. Submit to ECOG-ACRIN Immunologic Monitoring and Cellular Products Laboratory. 
8. Submit from patients who have consented to future laboratory studies. 
9. Mandatory submission for central review. 
10. Day 19 (+ 4day window) sample should be obtained before giving the second dose of ipilimumab. 
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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
Drug Ordering: Bristol-Myers-Squibb is supplying ipilimumab, through the Division of 
Cancer Treatment and Diagnosis, NCI, for this protocol. Maintenance of NCI drug 
accountability records is required. Ipilimumab (NSC 732442) (IND #10200) may be 
requested by the Principal Investigator (or their authorized designees) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that 
drug 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 – see general information). 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 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 240-276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
NCI Supplied Agent(s) – General Information 
NOTE: Under no circumstances can commercially supplied ipilimumab be used or 
substituted for the NCI-supplied ipilimumab. 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575.  
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at 240-
276-6575. 
8.1 
Ipilimumab 
In this study, the investigational product is ipilimumab. 
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8.1.1 
Drug Name 
Ipilimumab (NSC 732442) 
8.1.2 
Other Names  
Anti-CTLA-4 monoclonal antibody, MDX-010 (MDX-CTLA4, 
Transfectoma-derived) 
8.1.3 
Classification  
Human monoclonal antibody, IgG1 subclass 
M.W.: 147, 991 Daltons 
Ipilimumab has two manufacturing processes- ongoing trials have 
been using substances manufactured using Process B. This trial, 
E3611, uses 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. 
8.1.4 
Mode of Action  
Ipilimumab is specific for the CTLA4 antigen expressed on a subset of 
activated T cells. CTLA4 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 CTLA4 with the B7 ligand, resulting in a blockade of the 
inhibitory effect of T-cell activation. The CTLA4/B7 creates the 
interaction. 
8.1.5 
Storage and Stability  
Ipilimumab is available in 5 mg/mL single-use vials (40 mL). The 
sterile solution in the vial is clear and colorless. Ipilimumab is 
administered via intravenous infusion only. Ipilimumab must be stored 
in a secure area according to local regulations. The investigator must 
ensure that it is stored at a temperature  2C and  8C. 
Ipilimumab is given undiluted or further diluted in 0.9% NaCl Injection, 
USP or 5% Dextrose Injection, USP to a concentration between 1 
mg/mL and 4 mg/mL. Undiluted or diluted ipilimumab solution is stable 
in a polyvinyl chloride (PVC), non- PVC/non DEHP (di-(2-ethylhexul) 
phthalate) IV bag or glass container up to 24 hours refrigerated at 
(2C to 8C) or at room temperature/ room light. 
Shelf-life surveillance of the intact vials is ongoing. 
CAUTION: Ipilimumab does not contain antibacterial preservatives. 
Use prepared IV solution immediately. Discard partially 
used vials.  
Each vial is a Type I flint glass vial with gray butyl stoppers and 
sealed with aluminum seals. 

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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 
a Includes 0.7 overfill 
b Includes 2.6 mL overfill. 
c Nitrogen is used to transfer the bulk solution through the pre-filled and sterilizing filters into the aseptic 
area. 
8.1.6 
Dose Specifics 
Induction Phase: 
Ipilimumab 10 mg/kg (Arm A and Arm B) or 3 mg/kg (Arm C and Arm 
D), administered by IV infusion every three weeks for a total of four 
doses, until local recurrence or distant progression, unacceptable 
toxicity or withdrawal of consent. 
Maintenance Phase 
Ipilimumab 10 mg/kg (Arm A and Arm B) or 3 mg/kg (Arm C and Arm 
D), administered by IV infusion every 12 weeks (3 months), beginning 
at Week 24, then at weeks 36, 48, 60, until disease recurrence, 
unacceptable toxicity or withdrawal of consent for a maximum of 4 
maintenance doses. 
Dose delays are allowed as per the dosing criteria.  Infusions should 
be given over 90 minutes (not bolus or IV push). 
8.1.6.1 
Dose Calculations: Calculate Total Dose as follows: 
Patient body weight in kg x [10 mg or 3 mg/kg] = total dose 
in mg 
Calculate Total Infusion Volume as follows: 
Total dose in mg ÷ 5 mg/mL = infusion volume in mL 
Calculate Rate of Infusion as follows: 
Infusion volume in mL ÷ 90 minutes = rate of infusion in 
mL/min. 
For example, a patient on Arm A weighing 114 kg (250 lb) 
would be administered 1140 mg of ipilimumab (114 kg x 10 
mg/kg = 1140 mg) with an infusion volume of 228 mL 

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(1140 mg ÷ 5 mg/mL = 228 mL) at a rate of approximately 
2.5 mL/min (228 mL ÷ 90 minutes) in 90 minutes. 
8.1.7 
Preparation 
The supplies needed for Ipilimumab preparation and administration 
include calibrated syringes and infusion containers.  Ipilimumab is to 
be administered as an intravenous infusion using an in-line filter (pore 
size of 0.2 micrometer to 1.2 micrometer) and a volumetric pump, at 
the 10 mg/kg dose or the 3mg/kg dose, to complete the infusion in 90 
minutes, with a 10-mL normal saline flush at the completion of the 
infusion. 
· 
As ipilimumab is stored at refrigerated temperatures (2-8ºC), allow 
the appropriate number of vials of ipilimumab to stand at room 
temperature for approximately five minutes. 
· 
Aseptically withdraw the required volume of ipilimumab solution 
into a syringe. Insert the needle at an angle into the ipilimumab 
vial by placing the needle – bevel side down – against the glass, 
with the tip touching the neck of the vial. The initial solution 
concentration is 5 mg/mL. [Note: A sufficient excess of ipilimumab 
is incorporated into each vial to account for withdrawal losses]. 
· 
Ensure that the ipilimumab solution is clear colorless, essentially 
free from particulate matter on visual inspection. If multiple vials 
are needed for a subject, it is important to use a separate sterile 
syringe and needle for each vial to prevent problems such as 
dulling of needle tip, stopper coring, repeated friction of plunger 
against syringe barrel wall, etc. 
· 
Inject ipilimumab solution withdrawn into an appropriate size 
evacuated infusion bag to produce a final infusion volume that has 
been calculated from the weight of the patient. For example, if 
preparing a 10mg/kg treatment for a 65 kg patient you will use 4 
vials of the 200 mg vial size (or 650 mg). 
· 
If the total dose calculates to less than 90 mL of solution then the 
total dose needed should be diluted to at least 90 mL at a 
concentration between 1 mg/ml and 4 mg/ml. 
· 
Mix by GENTLY inverting several times. DO NOT shake. 
· 
Visually inspect the final solution. If the initial diluted solution or 
final dilution for infusion is not clear or contents appear to contain 
precipitate, the solution should be discarded. 
· 
Do not draw into each vial more than once. Any partial vials 
should be safely discarded and should not be stored for reuse. 
8.1.8 
Route of Administration 
Ipilimumab is administered as an IV infusion only. Infusions should be 
given over 90 minutes (not bolus or IV push).  Ipilimumab should be 
administered under the supervision of a physician experienced in the 
use of intravenous (IV) agents. 

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8.1.9 
Incompatibilities  
No compatability information is available. 
8.1.10 
Availability  
Bristol-Myers-Squibb is supplying ipilimumab, through the Division of 
Cancer Treatment and Diagnosis, NCI, for this protocol. 
8.1.11 
Side Effects  
See Section 5.3 (CAEPR). 
8.1.12 
Nursing/Patient 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. 
Ipilimumab may be excreted in milk or cross the placenta; therefore, 
nursing women and women with known or suspected pregnancy 
should not take ipilumumab. 
Closely monitor patients who are on narcotics during the treatment 
with ipilumumab. Narcotics may mask GI signs and symptoms such 
as diarrhea or abdominal pain, which are relevant complications of a 
bowel perforation. Minor diarrhea can be a potential sign of colitis and 
require immediate attention. 
8.1.13 
Handling and Disposal 
As with all injectable drugs, care should be taken when handling and 
preparing ipilimumab. Whenever possible, ipilimumab should be 
prepared in a laminar flow hood or safety cabinet using standard 
precautions for the safe handling of intravenous agents applying 
aseptic technique. Latex gloves are required. If ipilimumab 
concentrate or solution comes in contact with skin or mucosa, 
immediately and thoroughly wash with soap and water. After final drug 
reconciliation, unused ipilimumab solution should be disposed at the 
site following procedures for the disposal of anticancer drugs. 
8.1.14 
Ipilimumab Destruction 
Partial vials can be destroyed on site per institution policy. Intact vials 
of the expired drug, recalled, or when protocol is closed to treatment 
cannot be destroyed on site without the PMB/NCI approval. If 
ipilimumab is to be destroyed on site, it is the investigator’s 
responsibility to ensure that arrangements have been made for 
disposal and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and 
institutional procedures. Appropriate records of the disposal must be 
maintained. 
8.2 
Alfa Interferon 
8.2.1 
Other Names 
Interferon Alfa - 2b, Intron A, IFN-alpha 2b, NSC #377523 

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8.2.2 
Classification 
Biological response modifier. 
8.2.3 
Mode of Action 
Interferon Alfa - 2b has antiviral, antiproliferative (cytostatic) and 
immunomodulatory properties. Its direct antiproliferative properties 
(e.g., inhibition of cell growth) may explain its activity in certain 
malignancies. 
8.2.4 
Storage and Stability 
Interferon Alfa - 2b is provided as a lyophilized powder which must be 
reconstituted prior to administration. Unreconstituted drug vials bear 
expiration dates and are stored under refrigeration. 
Reconstituted solutions of interferon Alfa - 2b are stable for 1 month at 
refrigeration temperatures and for 2 weeks at room temperature when 
reconstituted as directed by the manufacturer. Reconstituted solutions 
of interferon Alfa - 2b, left in the original vials, are stable for 1 month in 
the freezer and through 4 freeze-thaw cycles. 
In plastic or glass syringes the drug is stable for 1 month frozen and 
through 2 freeze-thaw cycles. When interferon Alfa - 2b is 
reconstituted to a concentration ≥100,000 u/ml in normal saline, it is 
stable for only 24 hours at room or refrigeration temperatures. 
NOTE: 
Intron A Solution for Injection is not recommended for 
intravenous administration and should not be used for the 
induction phase of malignant melanoma. 
8.2.5 
Dose Specifics 
Induction Phase 
For this study the induction phase is defined as the first 12 weeks of 
treatment, as follows: 
Interferon Alfa - 2b, 20 MU/m²/d (rounded to the nearest 1.0 million 
unit) administered IV x 5 consecutive days out of 7 (e.g., M-F) every 
week x 4 weeks. Then, 10 MU/m²/d (rounded to the nearest 1.0 
million unit) subcutaneous every other day (e.g., M,W,F) three times 
each week x 8 wks. 
Maintenance Phase 
Interferon Alfa - 2b, 10 MU/m²/d (rounded to the nearest 1.0 million 
unit) subcutaneous every other day (e.g., M,W,F) three times each 
week x 48 wks. 
8.2.6 
Preparation 
The lyophilized product is reconstituted as directed by the 
manufacturer. 
For intravenous injection, it is recommended that interferon Alfa - 2b 
be administered as a 100,000 U/mL solution to minimize adsorption of 
the drug to glass and plastic containers. 

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8.2.7 
Administration 
It is recommended that Interferon Alfa-2b be prescribed in 10 million 
unit vials (with instructions to reconstitute with 1 mL of diluent to reach 
a final concentration of 10:1). 
However, other standard vial strengths are acceptable. Subcutaneous 
administration utilizes standard technique. The vial strength 
prescribed and final dose volume for each injection should be 
recorded in the comments section of the patient diary if self-
administered. Intravenous dose should be diluted in sodium chloride 
0.9% / 100 mL and given over 20 minutes. 
8.2.8 
Incompatibilities 
Interferon Alfa - 2b is incompatible with 5% dextrose in water and with 
a component of the Travenol Infusor. 
8.2.9 
Compatibilities 
Information regarding the compatibility, stability, etc. of drugs is 
constantly changing Consult your pharmacist to obtain the most up to 
date information. Interferon Alfa - 2b is compatible in normal saline, 
Ringer's injection, Lactated Ringers' and 5% sodium bicarbonate 
injection. 
8.2.10 
Availability 
Interferon Alfa - 2b is a commercial product. 
8.2.11 
Side Effects 
Flu-like symptoms: Fever, chills, diaphoresis and rigors occur 
universally regardless of dose, route or schedule. Usual onset is in 1-
2 hours with peak in 4-8 hours and duration less than 18 hours. 
Symptoms tend to lessen with continued dosing. 
Constitutional Symptoms: Fatigue, malaise, anorexia, weight loss, 
Raynaud's phenomenon, muscle pain, arthralgias, headaches; may 
be doselimiting, usually occurring during the first or second week of 
treatment. 
Hematologic: Leukopenia, thrombocytopenia and anemia 
(uncommon). 
Hepatic: Increased bilirubin, increased alkaline phosphatase, 
increased transaminases occasionally, hepatitis (uncommon). 
Cardiovascular: Hypotension, hypertension, dizziness, syncope, 
arrhythmia (atrial or ventricular), tachycardia, congestive heart failure 
and myocardial infarction have been reported. 
Neurologic: Somnolence, confusion with high doses; numbness, 
paresthesia, neuropathy; depression, personality disorder, 
psychomotor retardation, acute paranoid reactions, hallucinations, 
inability to concentrate, agitation, anxiety; visual disturbances, eye 
pain, hemianopsia, retinal infarction with vision loss (1 patient); sleep 
disturbances, insomnia; tremor, seizures, acute aphasia, coma, 
cerebral edema. 

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Gastrointestinal: Mild nausea, vomiting, diarrhea, dysphagia, 
anorexia, taste change, flatulence, constipation, abdominal pain and 
gastric distress have been reported. 
Dermatologic: Alopecia, rash, pain at injection site, dry skin, flushing, 
urticaria, epidermal necrosis. 
Renal: Proteinuria, microscopic hematuria, pyuria, azotemia, acute 
renal failure, nephrotic syndrome (1 patient), glycosuria, albuminuria, 
polyuria. 
Pulmonary: Orthopnea, dyspnea, bronchospasm, cough, pulmonary 
edema/acute respiratory distress syndrome, pharyngitis. 
Metabolic: Hyperglycemia, hypertriglyceridemia, hypothyroidism. 
Coagulation: Increased PT, PTT. 
8.2.12 
Nursing Implications 
Inform patient of expected side effects and reassure him/her that 
symptoms are not necessarily related to tumor progression. 
Instruct patient in keeping a daily record of temperature, symptoms 
and activity level (Refer to E3611 Patient Diary - Interferon, Appendix 
III). 
Review and document type, character and duration of side effects. 
Fever, rigors and other flu-like symptoms: Acetaminophen 
administered prior to treatments and every four hours following the 
initial injections may decrease severity of symptoms. Nonsteroidal or 
steroidal anti-inflammatory agents should be avoided (as much as 
possible for this indication with IFN) since their effect on the immune 
system is not known. 
Fatigue and CNS toxicity: Patient performance status and mental 
status should be assessed regularly and appropriate dose 
adjustments made per protocol. Instruct patient to arrange most 
important activities in the morning and allow for frequent rest periods. 
Anorexia: Monitor weight regularly. Encourage patient to maintain 
adequate fluid, caloric and protein intake. Antiemetics as needed. 
Granulocytopenia, thrombocytopenia, liver enzyme elevations: 
Monitor blood counts closely and modify dosage per protocol. Advise 
patient of special precautions regarding infection and/or bleeding 
when appropriate.  
8.2.13 
References 
Kirkwood JM, et al. Kirkwood JM, Strawderman MH, Ernstoff MS, et 
al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous 
melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. 
J Clin Oncol. 1996; 14(1):7–17. 
Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose 
interferon alfa-2b in high-risk melanoma: ﬁrst analysis of intergroup 
trial E1690/S9111/C9190. J Clin Oncol. 2000; 18(12):2444–2458. 

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Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon 
alfa-2b signiﬁcantly prolongs relapse-free and overall survival 
compared with the GM2-KLH/QS-21 vaccine in patients with resected 
stage IIB–III melanoma: results of intergroup trial 
E1694/S9512/C509801. J Clin Oncol. 2001; 19(9):2370–2380. 
Kirkwood JM, Bender C, Agarwala S, Tarhini A, Shipe-Spotloe J, 
Smelko B, Donnelly S, Stover L. Mechanisms and management of 
toxicities associated with high-dose interferon alfa-2b therapy. J Clin 
Oncol. 2002 Sep 1;20(17):3703-18. Review. 
Hauschild A, Gogas H, Tarhini A, Middleton MR, Testori A, Dréno B, 
Kirkwood JM. Practical guidelines for the management of interferon-
alpha-2b side effects in patients receiving adjuvant treatment for 
melanoma: expert opinion. Cancer. 2008 Mar 1;112(5):982-94. 
Kirkwood JM, Tarhini AA, Panelli MC, Moschos SJ, Zarour HM, 
Butterfield LH, Gogas HJ. Next generation of immunotherapy for 
melanoma. J Clin Oncol. 2008 Jul 10;26(20):3445-55. 

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9. 
Statistical Considerations 
This is a phase II randomized study with a 2 by 2 factorial design with (i) no HDI vs. HDI 
(across Ipilimumab treatment status) and (ii) ipilimumab 3mg/kg vs. Ipilimumab 10mg/kg 
(across HDI treatment status). We hypothesize that HDI + ipilimumab treatment will lead 
to improved PFS in comparison to ipilimumab alone (primary hypothesis). An important 
secondary objective of this study is to assess toxicity data in the tested combinations of 
treatment.  Other secondary objectives include to: (i) assess response rate and PFS for 
ipilimumab 10mg/kg treatment in comparison to ipilimumab 3mg/kg; (ii) assess OS in the 
tested combinations (no HDI vs. HDI) of treatment. 
9.1 
Endpoints and Sample Size 
9.1.1 
Primary Endpoint 
Progression-free survival (HDI will improve PFS compared to no HDI). 
To account for ineligible cases, 88 patients (for 80 eligible) will be 
accrued.  Based on E1608 accrual, accrual is expected to be 
completed within 6 months and patients will be followed for additional 
5 months.  
The primary comparison will be PFS. Primarily, it is assumed that HDI 
will improve the median PFS from 3 to 6 months from no HDI. In 
addition, it is assumed 10mg/kg Ipi will improve the median PFS from 
3 to 6 months from 3mg/kg Ipi.  Based on the log-rank test, these 
comparisons will have at least 82% power at a two-sided type I error 
rate of 0.10.    
The distribution of PFS will be compared using the log-rank test. 
9.1.2 
Secondary Endpoints 
· 
Safety 
· 
Overall survival (within the constraints of the sample size) for HDI 
versus no HDI 
· 
Response rate by RECIST and by irRC. For this endpoint, irRC 
will be utilized as secondary and investigational criteria. The irRC 
data will be associated with the RECIST-based tumor response, 
PFS and OS. 
· 
Assess RR, PFS and OS for ipilimumab 10mg/kg in comparison to 
ipilimumab 3mg/kg 

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Regimen limiting serious adverse events (RLE) would be defined 
as grade 3 or higher immune mediated adverse events that require 
steroids or immunosuppressive therapy and include the following: 
diarrhea/colitis, immune mediated hepatitis, endocrinopathies, skin 
toxicity (grade 4 or higher for skin), neuropathies, immune cytopenias 
or other grade 3 or higher immune mediated adverse events that 
require steroids or immunosuppressive therapy. We will evaluate the 
RLE rate for each treatment arm. In addition, OS data will be 
described for each treatment arm using the Kaplan-Meir method. 
No formal interim analysis is planned as this study is expected to 
accrue rapidly (≤ 6 months) and has a short additional follow-up time 
(< 6 months). However, toxicity data will be monitored and reviewed 
carefully on a monthly basis. 
Toxicity Monitoring: 
The population for the safety analysis will be comprised of all patients 
who received at least one dose of study medication. Patients will be 
monitored for adverse events using the National Cancer Institute’s 
(NCI) Active Version of the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4. All treatment-emergent and baseline 
adverse events and hematological/biochemical toxicities based on 
laboratory measurements, as well as drug related AE’s, will be 
summarized by treatment group and NCI CTCAE worst grade. 
In regards to toxicity management during the study, TOXICITY 
MANAGEMENT GUIDELINES for both HDI and Ipilimumab have 
been adopted and described in detail in the study protocol.  
Specific guidelines for managing ipilimumab-related toxicities on an 
end-organ basis have been provided as part of this study. An 
ipilimumab toxicity management training module will be made 
available to study investigators.  
A monthly conference call between ECOG-ACRIN investigators will 
be conducted to review the adverse events reported. Toxicity data will 
be monitored and reviewed carefully on a monthly basis. Incidence 
data of specific toxicity type as well overall worst degree toxicity data 
will be summarized and compared between the two arms. The result 
of this analysis will be discussed with the ECOG-ACRIN Data 
Monitoring Committee. 
9.2 
Stratification 
Stage: III/M1a, M1b, M1c 

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9.3 
Gender and Ethnicity  
Based on previous data from E1608/E1602/E2603/E3695 the anticipated accrual 
in subgroups defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
0 
Not Hispanic or Latino 
32 
56 
88 
Ethnic Category: Total of all subjects 
32 
56 
88 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
31 
56 
87 
Racial Category: Total of all subjects 
32 
56 
88 
Overall Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Monitoring Committee 
(DMC). The DMC meets twice each year. For each meeting, all monitored 
studies are reviewed for safety and progress toward completion. When 
appropriate, the DMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DMC. Any DMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DMC Policy can be 
obtained from the ECOG-ACRIN Operations Office - Boston. 

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10. 
Pathology Review 
Pathology samples must be submitted for review and classification (baseline only) and 
for future laboratory studies. Submission of pathology samples for diagnostic review is 
mandatory in order for the patient to be considered evaluable.  If insufficient material is 
available after diagnostic pathology, the pathologist must contact the Study Chair and 
send a letter and pathology report stating this to the ECOG-ACRIN Central Biorepository 
and Pathology Facility. 
Diagnostic materials will be forwarded to Dr. Uma Rao for central review. 
The submitting pathologist and clinical research associate should refer to Appendix I 
(Pathology Submission Guidelines) for guidelines and summary of submission 
requirements. 
10.1 
Pathology Materials Required For This Protocol 
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (STS). An STS 
shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.3. 
1. Forms to be submitted with all tissue submissions: 
· 
ECOG-ACRIN Generic Specimen Submission Form (#2981). Please 
identify the type of material submitted and (i.e., paraffin block, slide sub 
number A, B, etc.) clinical status of the submitted material (i.e., 
pretreatment as opposed to remission and relapse). 
· 
A copy of the surgical pathology report 
· 
Immunologic studies, if available 
· 
Sample Tracking System Shipping Manifest Form (see Section 10.3) 
In addition to the surgical pathology report, if immunologic studies have been 
performed at the home institution, it is necessary that these be forwarded as 
well. 
2. Mandatory Pathology Submission for Diagnostic Review 
· 
Primary Melanoma (for patients with known primary cutaneous 
melanoma) 
One (1) H & E of the primary melanoma and fifteen (15) unstained slides 
preferably from the thickest portion of the tumor for immunostains (please do 
not deparaffinise slides) OR, if the primary pathologist is willing, please 
request the corresponding block, which will be promptly returned upon 
request.  If the patient has more than one primary lesion, please include 
above slides and/or block for each primary. 
NOTE: 
Sections of surgical margins of skin, unless positive for tumor, are 
not required.  A surgical pathology report is sufficient. 
· 
Regional Lymphadenectomy Specimen 
One (1) H & E section of the tumor bearing lymph nodes ONLY, with a copy 
of pathology report.  An alternative is to send two (2) unstained slides or two 
(2) H & E slides on each positive lymph node.  Pathology report should 
indicate: 
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a. Total number of lymph nodes 
b. Number of lymph nodes positive 
c. Size of the largest lymph node 
d. Whether there was gross soft tissue tumor involvement 
e. Whether there was evidence of extra-capsular spread 
f. Whether a lymph node was a sentinel lymph node 
(Please include report on immunostains if any). 
· 
In-transit or satellite metastases, or distant cutaneous metastases, or 
distant lymph node metastases, or lung or other visceral metastases 
One (1) H & E section of the metastatic lesion and fifteen to twenty (15-
20) unstained slides from the thickest part of the tumor or, if the primary 
pathologist is willing, please request the corresponding block, which will 
be promptly returned upon request. 
3. Progression/Relapse Biopsy (if performed, for future laboratory studies per 
patient consent) 
· 
One (1) H & E section of the metastatic lesion and fifteen to twenty (15-
20) unstained slides from the thickest part of the tumor, or, if the primary 
pathologist is willing, please request the corresponding block, which will 
be promptly returned upon request. 
NOTE:  
A copy of the completed submission form will be sent to the 
ECOG-ACRIN Operations Office - Boston by the Central 
Biorepository and Pathology Facility. 
10.2 
Shipping Procedures 
The required diagnostic materials must be submitted within one month of patient 
randomization. 
The optional pathology samples from progression/relapse should be submitted 
within one month of disease progression. 
Access to the shipping account for specimen shipments to the ECOG-ACRIN 
CBPF at MD Anderson Cancer Center can only be obtained by logging onto 
fedex.com with an account issued by the ECOG-ACRIN CBPF. For security 
reasons, the account number will no longer be provided in protocols, over the 
phone, or via email. If your site needs to have an account created, please contact 
the ECOG-ACRIN CBPF by email at eacbpf@mdanderson.org. 
Shipping Address 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
An STS shipping manifest form must be generated and shipped with all sample 
submissions. 
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10.3 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst 
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the 
software.  A user manual and interactive demo are available by 
clicking this link: http://www.ecog.org/general/stsinfo.html. Please 
take a moment to familiarize yourself with the software prior to using 
the system. 
An STS generated shipping manifest form should be generated and shipped with 
all sample submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
An Generic Specimen Submission Form (#2891) will be required only if STS is 
unavailable at the time of sample submission. Indicate the appropriate Lab ID # 
on the submission form: 
· 
ECOG-ACRIN Central Biorepository and Pathology Facility 
· 
0009= ECOG-ACRIN Immunologic Monitoring and Cellular Products 
Laboratory 
The day of shipment, notify the IMCPL ECOG-ACRIN study coordinator by FAX 
(412-623-6625) using the Specimen Shipment/Requisition Form (Appendix VII).  
If you are unable to get through to the laboratory by FAX, telephone the ECOG-
ACRIN study coordinator at: (412) 624-0078 and provide the FedEx tracking 
number.  
Retroactively enter all collection and shipping information when STS is available.
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11. 
Submission of Samples 
Blood samples are being collected for future use in laboratory corollary studies, including 
the performance of novel biomarker evaluations that are of prognostic and therapeutic 
predictive value. Due to the potential future therapeutic predictive implications (targeting 
treatment to those who are likely to benefit) and economic implications (avoiding the 
toxicities and cost for those who are not likely to benefit) of such studies, patients are 
encouraged to participate. However, participation in providing these blood samples is 
optional. 
ECOG-ACRIN requires that all biological samples submitted be entered and tracked via 
the online ECOG-ACRIN Sample Tracking System (STS). An STS shipping manifest 
form must be generated and shipped with the sample submissions.  See Section 10.3. 
11.1 
Sample Submission Schedule 
Blood should be collected as specified below for each tube type at: 
· 
baseline (prior to treatment) 
· 
day 19 (+ 4 day window) 
· 
after twelve (12) weeks of initiating treatment (+/- 1 week) 
· 
48 weeks 
· 
disease relapse (if relapse occurs earlier than 48 weeks).   
No further blood samples are to be submitted after the relapse blood is sent. 
NOTE: 
Blood should NOT be collected on Fridays. 
Instructions to order kits are outlined in Section 11.3 
Questions are to be directed to the Immunological Monitoring and Cellular 
Products laboratory (IMCPL) ECOG-ACRIN study coordinator at (412) 624-0078. 
11.2 
Sample Preparation Guidelines 
Please completely fill all blood tubes as full as possible and collect the 
correct number and tube type as outlined below. Each tube must be clearly 
labeled to include: 
· 
ECOG-ACRIN protocol number E3611 
· 
ECOG-ACRIN five-digit patient sequence number 
· 
Patient initials 
· 
Originating institution/investigator name  
· 
Date and time drawn 
· 
Collection time point 
1. At EACH time point please submit the following: 
· 
Three (3) FULL 10 cc RED top tubes (BD cat #367820 or SST 367988 gel 
separator/gold top/ tiger tubes if the center can centrifuge them) 
· 
Ten (10) FULL 10 cc GREEN top heparin tubes (BD cat # 366480). 
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2. Baseline, Day 19 [+4 day window] and after and twelve (12) weeks of 
initiating treatment ONLY, please submit the following: 
· 
One (1) FULL PAXgene RNA tube (Fisher #23 021 01). 
3. At Baseline ONLY please submit the following: 
· 
One (1) FULL 10 cc YELLOW top ACD tube (BD cat # 364606) 
11.3 
Shipping Kits 
Specimen shipping kits must be requested from the IMCPL.  Please fax the 
request using the Shipping Kit Request Facsimile Form (Appendix VI) to (412) 
623-6625 or call the IMCPL at (412) 624-0078. Please allow ten days for 
shipment and provide the following information: 
· 
Study Number 
· 
Participating Site Number 
· 
Contact Person and Telephone Number 
The kits will be shipped via FedEx Express Saver. Please plan ahead, priority 
overnight shipment is not possible. 
All blood samples should be shipped the day of collection using the shipping kit. 
Follow shipping instructions provided in the kit carefully. 
The shipping kit consists of the following: 
· 
Insulated shipping container and packing material 
· 
FedEx Priority Overnight return label  
· 
Shipping Instructions 
· 
Shipping Kit Request Form 
11.4 
Shipping Procedures 
Log the samples into the ECOG-ACRIN STS the day of shipment.  If the STS is 
unavailable, a Generic Specimen Submission Form (#2981) must be submitted 
with the samples. Once STS is available, retroactively log the shipment into STS, 
using the actual collection and shipping dates.   
If the STS is unavailable, notify the IMCPL ECOG-ACRIN study coordinator by 
fax (412-623-6625) using the Specimen Shipment/Requisition Form Appendix 
VII). If you are unable to get through to the laboratory by fax, telephone the 
ECOG-ACRIN study coordinator at (412) 624-0078 and provide the tracking 
number. 
Blood collected into the appropriate tubes should be sealed, wrapped and placed 
in the specimen shipper kit and shipped on the same day they are drawn by 
Federal Express Priority overnight courier using the return label provided in the 
kit. The green top tubes should be shipped at ambient temperature (no wet or dry 
ice). The red, yellow, and PAXgene RNA tubes should be refrigerated 
immediately and shipped at 2-8°C. Shipments must be timed to arrive during 
normal working hours and should be shipped in one box.   

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The laboratory will be open Monday through Friday to receive samples.  Do NOT 
ship on Fridays or Saturdays, or the day before a legal holiday.  Ship by 
overnight courier Monday - Thursday only to: 
Immunologic Monitoring and Cellular Products Laboratory 
University of Pittsburgh Cancer Institute 
UPCI-IMCPL 
ECOG-ACRIN Study Coordinator 
Hillman Cancer Center 
5117 Centre Avenue, L 1.26 
Pittsburgh, PA 15213 
Tel: (412) 624-0078 
FAX: (412) 623-6625 
An STS shipping manifest form must be generated and shipped with all sample 
submissions. 
Federal Guidelines for the Shipment of Blood Products: Sites should follow IATA 
regulations for Packaging UN3372 shipments. Please refer to FedEx guidelines. 
11.5 
Use of Specimens in Research 
Specimens from patients who consented to allow their specimens to be used for 
future approved research studies, including residuals from the mandatory 
diagnostic reviews, will be retained in an ECOG-ACRIN-designated central 
repository. For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility and the ECOG-ACRIN Immunologic 
Monitoring and Cellular Products Laboratory. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects and may include, but are not limited to, extradition of 
plasma, serum, DNA and RNA. 
If future use is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. Pathology materials may be 
retained for documentation purposes or returned to the site. All other specimens 
will be destroyed per guidelines of the respective repository. 
11.6 
Sample Inventory Submission Guidelines 
Inventories of all specimens collected and aliquoted will be submitted 
electronically by secure web application to the ECOG-ACRIN Operations Office - 
Boston on a monthly basis or upon request by any laboratory holding and/or 
using specimens associated with this study. 
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12. 
Electronic Data Capture 
Please refer to the E3611 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
12.1 
Records Retention 
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
· 
two years after the FDA approves the marketing application, or 
· 
two years after the FDA disapproves the application for the indication being 
studied, or 
· 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted. 
Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying 
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13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. 
Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final 
version of the American Joint Committee on Cancer staging system for cutaneous 
melanoma. J Clin Oncol. 2001;19:3635-48. 
2. 
Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, et al. 
Randomized phase III study of temozolomide versus dacarbazine in the treatment 
of patients with advanced metastatic malignant melanoma. J Clin Oncol. 
2000;18:158-66. 
3. 
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose 
recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 
270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-16. 
4. 
Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. 
CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271-5. 
5. 
Hamid O. Dose effect of ipilimumab in patients with advanced melanoma: Results 
from a phase II, randomized, dose-ranging study.  J Clin Oncol 26: 2008 (May 20 
suppl; abstr 9025); 2008; 2008. 
6. 
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. 
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J 
Med. 2010;363:711-23. 
7. 
Robert C, Thomas L, Bondarenko I, O'Day S, M DJ, Garbe C, et al. Ipilimumab plus 
Dacarbazine for Previously Untreated Metastatic Melanoma. N Engl J Med. 2011. 
8. 
Ribas A, Hauschild A, Kefford R, Punt CJ, Haanen JB, Marmol M, et al. Phase III, 
open-label, randomized, comparative study of tremelimumab (CP-675,206) and 
chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with 
advanced melanoma. J Clin Oncol 26 (May 20 suppl; abstr LBA9011) 2008; 2008. 
9. 
Kirkwood JM, Richards T, Zarour HM, Sosman J, Ernstoff M, Whiteside TL, et al. 
Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients 
with high-risk resected melanoma: the E2690 laboratory corollary of intergroup 
adjuvant trial E1690. Cancer. 2002;95:1101-12. 
10. Wang W, Edington HD, Rao UN, Jukic DM, Land SR, Ferrone S, et al. Modulation 
of signal transducers and activators of transcription 1 and 3 signaling in melanoma 
by high-dose IFNalpha2b. Clin Cancer Res. 2007;13:1523-31. 
11. Paquette RL. Interferon-alpha and granulocyte-macrophage colony-stimulating 
factor differentiate peripheral blood monocytes into potent antigen-presenting cells. 
J Leukoc Biol. 1998;64:358-67. 
12. Parlato S, Santini SM, Lapenta C, Di Pucchio T, Logozzi M, Spada M, et al. 
Expression of CCR-7, MIP-3beta, and Th-1 chemokines in type I IFN-induced 
monocyte-derived dendritic cells: importance for the rapid acquisition of potent 
migratory and functional activities. Blood. 2001;98:3022-9. 

ECOG-ACRIN 
E3611 
Cancer Research Group 
Version Date: March 2, 2016 
121 
13. Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon alpha increases the 
frequency of interferon gamma-producing human CD4+ T cells. J Exp Med. 
1993;178:1655-63. 
14. Wenner CA, Guler ML, Macatonia SE, O'Garra A, Murphy KM. Roles of IFN-gamma 
and IFN-alpha in IL-12-induced T helper cell-1 development. J Immunol. 
1996;156:1442-7. 
15. Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, et al. Selective 
expression of an interleukin-12 receptor component by human T helper 1 cells. J 
Exp Med. 1997;185:825-31. 
16. Palmer KJ, Harries M, Gore ME, Collins MK. Interferon-alpha (IFN-alpha) stimulates 
anti-melanoma cytotoxic T lymphocyte (CTL) generation in mixed lymphocyte 
tumour cultures (MLTC). Clin Exp Immunol. 2000;119:412-8. 
17. Carballido JA, Molto LM, Manzano L, Olivier C, Salmeron OJ, Alvarez de Mon M. 
Interferon-alpha-2b enhances the natural killer activity of patients with transitional 
cell carcinoma of the bladder. Cancer. 1993;72:1743-8. 
18. Tough DF. Type I interferon as a link between innate and adaptive immunity 
through dendritic cell stimulation. Leuk Lymphoma. 2004;45:257-64. 
19. Yurkovetsky ZR, Kirkwood JM, Edington HD, Marrangoni AM, Velikokhatnaya L, 
Winans MT, et al. Multiplex analysis of serum cytokines in melanoma patients 
treated with interferon-alpha2b. Clin Cancer Res. 2007;13:2422-8. 
20. Moschos SJ, Edington HD, Land SR, Rao UN, Jukic D, Shipe-Spotloe J, et al. 
Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon 
alfa-2b induces objective tumor regression in association with modulation of tumor 
infiltrating host cellular immune responses. J Clin Oncol. 2006;24:3164-71. 
21. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. 
Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the 
Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17. 
22. Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, et al. 
High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of 
intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444-58. 
23. Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, et 
al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall 
survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage 
IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 
2001;19:2370-80. 
24. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. 
Annu Rev Immunol. 1996;14:233-58. 
25. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and 
B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992;71:1065-8. 
26. Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA, et al. 
Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte 
molecules CD28 and CTLA-4. Cell. 1992;71:1093-102. 
27. Townsend SE, Allison JP. Tumor rejection after direct costimulation of CD8+ T cells 
by B7-transfected melanoma cells. Science. 1993;259:368-70. 

ECOG-ACRIN 
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Version Date: March 2, 2016 
122 
28. Townsend SE, Su FW, Atherton JM, Allison JP. Specificity and longevity of 
antitumor immune responses induced by B7-transfected tumors. Cancer Res. 
1994;54:6477-83. 
29. Allison JP, Hurwitz AA, Leach DR. Manipulation of costimulatory signals to enhance 
antitumor T-cell responses. Curr Opin Immunol. 1995;7:682-6. 
30. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is 
a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561-9. 
31. Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. 
Immunity. 1997;7:445-50. 
32. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. 
CTLA-4 can function as a negative regulator of T cell activation. Immunity. 
1994;1:405-13. 
33. Kearney ER, Walunas TL, Karr RW, Morton PA, Loh DY, Bluestone JA, et al. 
Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ 
T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. J 
Immunol. 1995;155:1032-6. 
34. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response 
of T cells to stimulation. J Exp Med. 1995;182:459-65. 
35. Krummel MF, Sullivan TJ, Allison JP. Superantigen responses and co-stimulation: 
CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and in vivo. Int 
Immunol. 1996;8:519-23. 
36. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of 
CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue 
destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 
1995;3:541-7. 
37. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. 
Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 
1995;270:985-8. 
38. Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4-deficient 
mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity. 
1997;7:885-95. 
39. Tarhini AA, Cherian J, Moschos SJ, Tawbi HA, Shuai Y, Gooding WE, et al. Safety 
and efficacy of combination immunotherapy with interferon alfa-2b and 
tremelimumab in patients with stage IV melanoma. J Clin Oncol. 2012;30:322-8. 
40. Tarhini AA MS, Schlesselman JS, Sander C, Kirkwood JM. Preliminary safety and 
clinical activity results of the combination of high-dose interferon alfa-2b and 
tremelimumab for recurrent inoperable stage III or stage IV melanoma. J Clin Oncol 
26: 2008 (May 20 suppl; abstr 9009). 2008; Chicago; 2008. 
41. Tarhini AA, Cherian J, Moschos SJ, Tawbi HA, Shuai Y, Gooding WE, et al. Safety 
and Efficacy of Combination Immunotherapy With Interferon Alfa-2b and 
Tremelimumab in Patients With Stage IV Melanoma. J Clin Oncol. 2011. 

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123 
42. Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, et al. Meta-
analysis of phase II cooperative group trials in metastatic stage IV melanoma to 
determine progression-free and overall survival benchmarks for future phase II 
trials. J Clin Oncol. 2008;26:527-34. 
43. Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic 
T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients 
with advanced cancers. Expert Opin Biol Ther. 2008;8:1583-93. 
44. Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott DF, et al. A 
phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or 
relapsed melanoma. J Clin Oncol 26 (May 20 suppl; abstr 9023^) 2008; 2008. 
45. Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. 
Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or 
relapsed melanoma. Clin Cancer Res. 2010;16:1042-8. 
46. Gogas H, Kirkwood JM. Prognostic significance of autoimmunity during treatment of 
melanoma with interferon. N Engl J Med. 2006;354:709-18. 
47. Atkins MB, Mier JW, Parkinson DR, Gould JA, Berkman EM, Kaplan MM. 
Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer 
cells. N Engl J Med. 1988;318:1557-63. 
48. Weijl NI, Van der Harst D, Brand A, Kooy Y, Van Luxemburg S, Schroder J, et al. 
Hypothyroidism during immunotherapy with interleukin-2 is associated with 
antithyroid antibodies and response to treatment. J Clin Oncol. 1993;11:1376-83. 
49. Scalzo S, Gengaro A, Boccoli G, Masciulli R, Giannella G, Salvo G, et al. Primary 
hypothyroidism associated with interleukin-2 and interferon alpha-2 therapy of 
melanoma and renal carcinoma. Eur J Cancer. 1990;26:1152-6. 
50. Krouse RS, Royal RE, Heywood G, Weintraub BD, White DE, Steinberg SM, et al. 
Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma 
treated with interleukin-2 alone. J Immunother Emphasis Tumor Immunol. 
1995;18:272-8. 
51. Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA. Factors associated with 
response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin 
Oncol. 2001;19:3477-82. 
52. Becker JC, Winkler B, Klingert S, Brocker EB. Antiphospholipid syndrome 
associated with immunotherapy for patients with melanoma. Cancer. 1994;73:1621-
4. 
53. Rosenberg SA, White DE. Vitiligo in patients with melanoma: normal tissue antigens 
can be targets for cancer immunotherapy. J Immunother Emphasis Tumor Immunol. 
1996;19:81-4. 
54. Franzke A, Peest D, Probst-Kepper M, Buer J, Kirchner GI, Brabant G, et al. 
Autoimmunity resulting from cytokine treatment predicts long-term survival in 
patients with metastatic renal cell cancer. J Clin Oncol. 1999;17:529-33. 
55. Phan GQ. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-
associated antigen 4 blockade in patients with metastatic melanoma.  Proc Natl 
Acad Sci; 2003; 2003. p. 8372-7. 

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56. Sanderson K, Scotland R, Lee P, Liu D, Groshen S, Snively J, et al. Autoimmunity 
in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal 
antibody with multiple melanoma peptides and Montanide ISA 51 for patients with 
resected stages III and IV melanoma. J Clin Oncol. 2005;23:741-50. 
57. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, et al. 
Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-
macrophage colony-stimulating factor stimulates potent, specific, and long-lasting 
anti-tumor immunity. Proc Natl Acad Sci U S A. 1993;90:3539-43. 
58. Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA, Millham R, et 
al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the 
anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. 
J Clin Oncol. 2005;23:8968-77. 
59. Tarhini AA, Moschos SJ, Tawbi H, Shuai Y, Gooding WE, Sander C, et al. Phase II 
evaluation of tremelimumab (Treme) combined with high-dose interferon alpha-2b 
(HDI) for metastatic melanoma. J Clin Oncol 28:15s, (suppl; abstr 8524) 2010; 
2010. 
60. Stuckert J, Tarhini AA, Lee S, Schlesselman J, Wang Y, Sander C, et al. Interferon 
alfa-induced autoimmunity in patients with high-risk melanoma participating in 
ECOG trial E2696.  AACR; 2007; Los Angeles; 2007. 
61. Hanson DC CP, Primiano MJ, Donovan CB, Gardner JP, Natoli EJ, Morgan RW, 
Mather RJ, Singleton DH, Hermes PA, Neveu MJ, Andrews GC, Castro CD, Elliott 
EA, Bedian V Preclinical in vitro characterization of anti-CTLA4 therapeutic antibody 
CP-675,206.  PROC AM ASSOC CANCER RES 2004 45 Abs 3802. 
62. Ribas A DT, Comin-Anduix B, de la Rocha P, Glaspy JA, Economou JS, Gomez-
Navarro J, Cochran AJ Changes in intratumoral immune cell infiltrates, Foxp3 and 
indoleamine 2, 3-dioxygenase (IDO) expression with the CTLA4 blocking MAB CP-
675,206. J IMMUNOTHER 2006;29 636. 
63. Hamid O, Chasalow SD, Tsuchihashi Z, Alaparthy S, Galbraith S, Berman D. 
Association of baseline and on-study tumor biopsy markers with clinical activity in 
patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol 
27:15s, 2009 (suppl; abstr 9008) 2009; 2009. 
64. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab 
monotherapy in patients with pretreated advanced melanoma: a randomised, 
double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-
64. 
 

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Combination with High Dose Interferon-α in Advanced Melanoma 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. List of Required Materials for E3611 
4. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
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126 
Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility: 
· 
Institutional Surgical Pathology Report 
· 
Pathology materials (see attached List of Required Material) 
· 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
Instructions: 
1. Complete blank areas of the pathologist's instructional memo and forward it, along with the 
List of Required Material, to the appropriate pathologist. 
2. The pathologist should return the required pathology samples and surgical pathology 
reports, along with the completed ECOG-ACRIN Generic Specimen Submission Form 
(#2981). If any other reports are required, they should be obtained from the appropriate 
department at this time. 
3. Keep a copy of the ECOG-ACRIN Generic Specimen Submission Form (#2981)for your 
records.  (The original should be sent to the CBPF.) 
4. Double-check that ALL required forms, reports and pathology samples are included in the 
package to the Central Biorepository and Pathology Facility. (See appropriate List of 
Required Material.)  
Pathology specimens submitted WILL NOT be processed by the Central 
Biorepository and Pathology Facility until all necessary items are received. 
5. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
If you have any questions concerning the above instructions or if you anticipate any problems 
in meeting the pathology material submission deadline of one month, contact the Pathology 
Coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by telephone 1-
844-744-2420or by emailing eacbpf@mdanderson.org. 
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List of Required Material 
E3611: A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in 
Combination With High Dose Interferonα in Advanced Melanoma 
Baseline (submit within one month of patient randomization) 
1. 
ECOG-ACRIN Generic Specimen Submission Form (#2981).  
2. 
Institutional pathology report (must be included with EVERY pathology submission) 
3. 
Pathology Materials:  
· 
Primary Melanoma (for patients with known primary cutaneous melanoma): 
o One (1) H & E of the primary melanoma and fifteen (15) unstained slides 
preferably from the thickest portion of the tumor for immunostains (please 
do not deparaffinise slides) OR, if the primary pathologist is willing, please 
request the corresponding block, which will be promptly returned upon 
request. If the patient has more than one primary lesion, please include 
above slides and/or block for each primary. 
· 
Regional Lymphadenectomy Specimen: 
o One (1) H & E section of the tumor bearing lymph nodes ONLY, with a copy 
of pathology report. An alternative is to send two (2) unstained slides or two 
(2) H & E slides on each positive lymph node. Pathology report should 
indicate: 
a. 
Total number of lymph nodes 
b. 
Number of lymph nodes positive 
c. 
Size of the largest lymph node 
d. 
Whether there was gross soft tissue tumor involvement 
e. 
Whether there was evidence of extra-capsular spread 
f. 
Whether a lymph node was a sentinel lymph node 
(Please include report on immunostains, if any). 
In addition, please include fifteen to twenty (15-20) unstained slides from 
the thickest part of the tumor OR, if the primary pathologist is willing, 
please request the corresponding block, which will be promptly returned 
upon request. 
· 
In-transit or satellite metastases, or distant cutaneous metastases, or distant 
lymph node metastases or lung or other visceral metastases: 
o One (1) H & E section of the metastatic lesion and fifteen to twenty (15-20) 
unstained slides from the thickest part of the tumor OR, if the primary 
pathologist is willing, please request the corresponding block, which will be 
promptly returned upon request. 
NOTE: 
Sections of surgical margins of skin, unless positive for tumor, are not 
required.  A surgical pathology report is sufficient. 
NOTE:  
A copy of the completed submission form will be sent to the ECOG-
ACRIN Operations Office - Boston by the Central Biorepository and 
Pathology Facility. 
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NOTE: 
Submission of pathology samples for diagnostic review is mandatory in 
order for the patient to be considered evaluable. 
Progression/Relapse (submit within one month of disease progression) 
1. 
ECOG-ACRIN Generic Specimen Submission Form (#2981). 
2. 
Institutional pathology report (must be included with EVERY pathology submission) 
If biopsy was performed submit: 
· 
One (1) H & E section of the metastatic lesion and fifteen to twenty (15-20) 
unstained slides from the thickest part of the tumor or, if the primary pathologist 
is willing, please request the corresponding block, which will be promptly 
returned upon request. 
 

 
129 
MEMORANDUM 
TO:  
 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
 
SUBJECT: 
Submission of Pathology Materials for E3611: A Randomized Phase II 
Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in Combination 
With High Dose Interferon-α in Advanced Melanoma 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for pathology review and 
future laboratory studies. 
Please complete PART B of the Submission Form. Keep a copy of the submission form 
for your records and return the surgical pathology report(s), the slides and/or blocks and 
any other required material (see List of Required Material) to the Clinical Research 
Associate (CRA).  The CRA will forward all required pathology material to the ECOG-
ACRIN Central Biorepository and Pathology Facility. 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN 
Central Repository for future laboratory studies.  Blocks will be returned for future 
purposes of patient management upon request. 
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at 1-844-744-2420or EMAIL 
eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 

ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
130 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 

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A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in 
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Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions 
remain unanswered in cancer.  With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will 
maintain very close contact with you.  This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
Rev. 5/14 

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Combination with High Dose Interferon-α in Advanced Melanoma 
Appendix III 
 
Patient Interferon Diary 
 
Diary Card 
 
Interferon 
 
 
Dates: ____/____/____ to ____/____/____ 
 
Patient Number: 
_________________ 
 
Patient Initials: _________________ 
 

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ECOG-ACRIN patient sequence number: 
 
 
 
Dose 
No. 
 
 
 
Date 
 
 
TIME 
Record Time of Dose 
(Circle AM or PM) 
Use the space below to make 
notes about things you would like 
to tell the doctor (include any 
unusual symptoms you 
experience, other medicine you 
have taken and anything else you 
think may be of interest. 
Month 
Day 
Year 
 
 
1 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
2 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
3 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
4 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
5 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
6 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
7 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
8 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
9 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
10 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
11 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
12 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
13 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
14 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
15 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
16 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
17 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
18 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
19 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
20 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
21 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
22 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
23 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
24 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
25 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
26 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
27 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
28 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
29 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
30 
 
 
 
 
 
 
 
 
: 
 
AM  PM 
 
 

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A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in 
Combination with High Dose Interferon-α in Advanced Melanoma 
 
Appendix IV 
 
E3611 Cooperative Research and Development Agreement (CRADA) 
The ipilimumab supplied by CTEP, DCTD, NCI used in this protocol is provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between Bristol-Myers Squibb (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/industry) 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 investigational 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 investigational Agent(s), each the subject of different collaborative 
agreements, the access to and 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 NIH, 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 
investigational 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 investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively 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. 

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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 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: 
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. 
 

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E3611: A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in 
Combination with High Dose Interferon-α in Advanced Melanoma 
 
Appendix V 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled.  Cannot carry on any self-care. Totally confined to bed or 
chair. 
 

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E3611: A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in 
Combination with High Dose Interferon-α in Advanced Melanoma 
Appendix VI 
 
Shipping Kit Request Facsimile Form 
ECOG-ACRIN – PROTOCOL E3611 
Immunologic Monitoring and 
Cellular Products Laboratory 
UPCI Research Pavilion at the Hillman Cancer Center 
Room L 1.26 
5117 Centre Avenue 
Pittsburgh, PA  15213-1863 
Telephone: 412-624-0078 
FAX:  412-623-6625 
 
To: ECOG-ACRIN Study Coordinator 
 
 
 
 
Fax:  412-623-6625 
From: 
Name:_________________________________________ 
 
 
Institution:______________________________________ 
 
 
Telephone: _____________________________________ 
 
 
Fax:  __________________________________________ 
 
Number of Kits Requested:  
Baseline (10GT/3RT/1ACD/1PAX) _____________________________ 
Day 19, Week 12 (10GT/3RT/1PAX)____________________________ 
Week 48 or Relapse (10GT/3RT) ______________________________ 
 
Shipping Address:  _______________________________________ 
 
 
 
_______________________________________ 
 
 
 
_______________________________________ 
 
 
 
_______________________________________ 
PLEASE ALLOW 10 WORKING DAYS FOR RECEIPT OF SHIPPING KITS 
 
NOTE: To order collection and shipping kits for E3611, patients must be registered to or in 
the process of being worked up for the E3611 trial.  Due to funding restrictions 
institutions cannot order multiple collection and shipping kits in advance. 
 
This message is intended only for the use of the individual or entity to which it is addressed and may contain 
information that is privileged, confidential, and exempt from disclosure under applicable law.  If the reader of this 
message is not the intended recipient or the employee or agent responsible for delivering the message to the 
intended recipient, you are hereby notified that any dissemination, distribution, or copying of this communications 
is strictly prohibited.  If you have received this communication in error, please notify us immediately by telephone 
and return the original facsimile to us at the above address via the U.S. Postal Service.  Thank you. 

ECOG-ACRIN 
E3611 
Cancer Research Group 
Version Date: March 2, 2016 
138 
E3611: A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in 
Combination with High Dose Interferon-α in Advanced Melanoma 
Appendix VII 
 
Specimen Shipment Requisition Form 
ECOG-ACRIN – PROTOCOL E3611 
It is required that samples submitted from patients participating in E3611 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System. This form is used only in 
the event that the STS is inaccessible and then the shipments are to be logged in 
retroactively, indicating the actual dates of collection and shipment. 
 
Immunologic Monitoring and 
Cellular Products Laboratory 
UPCI Research Pavilion at the Hillman Cancer Center 
Room L 1.26 
5117 Centre Avenue 
Pittsburgh, PA  15213-1863 
Telephone: 412-624-0078 
FAX:  412-623-6625 
 
Ship specimens by overnight express to arrive the next morning unless otherwise directed by the 
protocol.  Do NOT ship on Friday or Saturday, or the day before a legal holiday. 
Call the IMCPL ECOG-ACRIN Study Coordinator at 412-624-0078 with questions on 
shipping. 
Please complete the following information and include this form in the shipment. 
 
ECOG-ACRIN Patient Sequence Number:  _________________    
ECOG-ACRIN Patient Initials: __________ 
 
Last    First 
 
Clinical Site:_____________________________   Site Contact: __________________________ 
 
Telephone Number:  ______________________    Fax Number: _________________________ 
 
Federal Express® Air Bill No.: ________________________  Date of Shipment: _____________ 
 
 
Specimen 
Collection Date 
 
___/___/___ 
MM/DD/YY 
Specimen 
Collection Time:  
 
____ ____:____ ____ 
(24 hour clock) 
 

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Version Date: March 2, 2016 
139 
Time Points (check one): 
 
 
Baseline 
Three (3) red top tubes, Ten (10) green top tubes, One (1) PAXgene RNA tube 
and One (1) ACD yellow top tube 
 
Day 19 
Three (3) red top tubes, Ten (10) green top tubes, One (1) PAXgene RNA tube 
 
12 weeks 
Three (3) red top tubes and Ten (10) green top tubes, One (1) PAXgene RNA 
tube 
 
48 weeks 
Three (3) red top tubes and Ten (10) green top tubes 
 
Relapse 
(3) red top tubes and Ten (10) green top tubes 
 
Shipping checklist: (kits will be shipped / delivered to you from UPCI IMCPL upon request) 
 
____ Label vials with patient initials/sequence number, and date and time of draw. 
 
____ Seal, wrap, and place specimen tubes in specimen shipper kit. 
 
____ STS Shipping Manifest Form. Make a copy for your records and place the original form 
inside the specimen shipper kit. 
 
To be completed by IML Staff: 
IML Study Number 
IML Accession Number: 
Specimen Type received (if different from above): 
Specimen Acceptability: 
Comment: 
 
 
 
 
 
 
 
 
 
This message is intended only for the use of the individual or entity to which it is addressed and may contain 
information that is privileged confidential and exempt from disclosure under applicable law.  If the reader of this 
message is not the intended recipient or the employee or agent responsible for delivering the message to the 
intended recipient you are hereby notified that any dissemination distribution or copying of this communications is 
strictly prohibited.  If you have received this communication in error please notify us immediately by telephone and 
return the original facsimile to us at the above address via the U.S. Postal Service.  Thank you. 
 

ECOG-ACRIN 
E3611 
Cancer Research Group 
Version Date: March 2, 2016 
140 
E3611: A Randomized Phase II Study of Ipilimumab at 3 mg/kg or 10 mg/kg Alone or in 
Combination with High Dose Interferon-α in Advanced Melanoma 
Appendix VIII 
 
Administration of Interferon (Directions for Administration of Subcutaneous Doses) 
Patients deemed competent to self administer the Interferon may do so. The hospital or clinic 
staff will instruct the patient or interested family member in this technique. Patients should be 
allowed to administer these injections at home when they can independently perform a return 
demonstration for their instructor. The instructor will note this fact in the patient's record. 
Adequate contact persons and telephone numbers should be provided so that the patient will 
always be able to reach someone familiar with this procedure should they need assistance. 
For emergency contact: 
 
(insert site contact information) 
 
 
Instructions for Self-Administering Medication 
1.  
Preparation 
a.  Wash hands well. Take required dose of acetaminophen (Tylenol®). 
b.  Assemble necessary supplies. The Interferon should be kept refrigerated 
until several minutes before each treatment. You also need a syringe with a 
needle, at least 3 alcohol prep pads, and a container (an unbreakable, leak-
proof, reclosable container - milk carton, coffee can) for used materials. 
2.  
Reconstituting the Interferon Powder 
a.  If this is the first dose that will be coming from a vial, the Interferon powder 
must be dissolved, using the diluent provided. Snap the plastic cap off both 
vials, and cleanse both rubber stoppers with an alcohol pad and allow to air 
dry. 
b.  There may be a different syringe/needle provided that you will use to 
reconstitute the Interferon. Open the package containing one of these 
syringes and attach (or tighten) the appropriate needle to it. Pull back the 
plunger of the syringe so that the top of it rests right on the line representing 
the volume of diluent that you are to add to the Interferon powder. 
c.  Insert the needle through the stopper of the diluent vial, and invert the 
vial/syringe in front of you at eye level, holding the syringe in your dominant 
hand and the vial in the other. 
d.  Inject the air from the syringe into the vial slowly. If you feel like you are 
forcing it, pull back the plunger to allow some solution into the syringe, then 
push the remaining air into the vial. Ultimately, your syringe should be filled 
with diluent solution up to the correct line and no air will be left in the 
syringe. If you have bubbles, tap the syringe with your finger until they rise to 
the top, push them up into the vial and recheck the plunger to insure that it is 
still at the correct volume mark. 

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e.  Withdraw the needle from the diluent vial and insert it into the vial containing 
the Interferon powder. This time keep the vial on the surface and push the 
plunger down to inject the diluent into the powder vial. If you meet 
resistance, allow some air to rise into the syringe before pushing down and 
expelling the remaining solution into the vial. Eventually, all the solution will 
be in the vial. Pull back the plunger to return it to the line that is the same as 
the volume of solution that you injected. This will prevent pressure build-up 
in the Interferon vial. Remove the needle and discard it appropriately. 
f.  
To help dissolve the Interferon powder, you may need to roll the vial 
between your palms or swirl the solution around. DO NOT shake the vial. Be 
sure that all the powder is dissolved before proceeding to #3. 
3.  
Withdrawing Your Dose From the Vial 
a.  Cleanse the rubber stopper of the vial containing the Interferon solution with 
an alcohol pad and allow to air dry. 
b.  Open syringe package and needle package (if separate) and attach or 
tighten needle by twisting until tight. Pull back the plunger to the mark that 
represents your dose (i.e., 3 mU/0.5 ml, top of plunger should rest at the 0.5 
ml mark). This fills the syringe with air in a volume equal to the volume of 
your dose. 
c.  Uncap the needle and push it through the stopper, at least half-way into the 
vial. Now pick up the vial (with syringe/needle in it) with your left hand and 
turn it upside down, holding it at eye-level, about 12 inches from your face. 
You should now have the vial in one hand and your other hand free to 
manipulate the syringe. (Note: Left-handed persons should have the vial in 
their right hand, so that they can manipulate the syringe with their left hand.) 
d.  Inject air from the syringe into the vial slowly, and then withdraw the plunger. 
The syringe will gradually fill with drug solution. Repeat this procedure until 
only solution is in the syringe, solidly, to the mark that indicates your dose. 
Withdraw needle and recap it. 
4.  
Administration 
a.  Thoroughly clean the area to be injected with an alcohol pad. Areas 
appropriate for this type of injection have been shown to you. A new site 
should be used for each injection whenever possible. 
b.  As demonstrated, pinch 1½ to 2 inches of loose skin from the site to be 
injected. 
c.  Uncap the needle, and insert the needle approximately ¼ inch into the skin 
and push the syringe plunger in all the way, thereby giving the dose of 
Interferon. 
d.  Remove needle and wipe injection site with a new alcohol pad, but do not 
massage the area to any great extent. 

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e.  Needles are not to be recapped. Used needles and used syringes should be 
disposed of in the proper disposal container provided by your pharmacy and 
returned to the clinic pharmacy for disposal. If the Interferon vial contains 
more than one dose, write the date on the label. It is usable for 30 days. 
INTRON A injection vials should be stored in the refrigerator between 2° and 
8° C (36° and 46°F), not in the freezer. 
f.  
If a drug administration diary has been provided, remember to complete it 
after each dose. Enter the date and time of day given, along with any 
notable side effects that you may have experienced since previous dose 
was given. Also record vial strength and dose volume at each entry. 

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Appendix IX 
 
TNM Staging for Melanoma 
Table 1. TNM Staging Categories for Cutaneous Melanoma 
 
Classification 
 
Thickness (mm) 
Ulceration Status/Mitoses 
T 
 
 
Tis 
NA 
NA 
T1 
 1.00 
a: Without ulceration and mitosis < 1/mm2 
 
 
b: With ulceration or mitoses ≥ 1/mm2 
T2 
1.01-2.00 
a. without ulceration 
 
 
b. with ulceration 
T3 
2.01-4.00 
a: without ulceration 
 
 
b: with ulceration 
T4 
> 4.00 
a. without ulceration 
 
 
b: with ulceration 
N 
 
No. of Metastatic Nodes 
 
Nodal Metastatic Burden 
N0 
0 
NA 
N1 
1 
a: Micrometatasis* 
 
 
b: Macrometastasis 
N2 
2-3 
a: Micrometatasis* 
 
 
b: Macrometastasis 
 
 
c: In transit metastases/ 
    satellites without  
    metastatic nodes 
N3 
4+ metastatic nodes, or 
matted nodes, or in 
transit metastases/ 
Satellites with 
metastatic nodes 
 
M 
Site 
Serum LDH 
M0 
No distant metastases 
NA 
M1a 
Distant skin, 
subcutaneous, or nodal 
metastases 
Normal 
M1b 
Lung metastases 
Normal 
M1c 
All other visceral 
metastases 
Normal 
 
Any distant metastasis 
Elevated 
Abbreviations:  NA, not applicable; LDH, lactate dehydrogenase, 
*Micrometastases are diagnosed after sentinel lymph node biopsy. 
Macrometastases are defined as clinically detectable nodal metastases confirmed 
pathologically. 

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Table 2. Anatomic Stage Groupings for Cutaneous Melanoma 
 
Clinical Staging* 
 
Pathological Staging 
 
T 
N 
M 
 
T 
N 
M 
0 
Tis 
N0 
M0 
0 
Tis 
N0 
M0 
IA 
T1a 
N0 
M0 
IA 
T1a 
N0 
M0 
IB 
T1b 
N0 
M0 
IB 
T1b 
N0 
M0 
 
T2a 
N0 
M0 
 
T2a 
N0 
M0 
IIA 
T2b 
N0 
M0 
IIA 
T2b 
N0 
M0 
 
T3a 
N0 
M0 
 
T3a 
N0 
M0 
IIB 
T3b 
N0 
M0 
IIB 
T3b 
N0 
M0 
 
T4a 
N0 
M0 
 
T4a 
N0 
M0 
IIC 
T4b 
N0 
M0 
IIC 
T4b 
N0 
M0 
III 
Any T 
N> N0 
M0 
IIIA 
T1-4a 
N1a 
M0 
 
 
 
 
 
T1-4a 
N2a 
M0 
 
 
 
 
IIIB 
T1-4b 
N1a 
M0 
 
 
 
 
 
T1-4b 
N2a 
M0 
 
 
 
 
 
T1-4a 
N1b 
M0 
 
 
 
 
 
T1-4a 
N2b 
M0 
 
 
 
 
 
T1-4a 
N2c 
M0 
 
 
 
 
IIIC 
T1-4b 
N1b 
M0 
 
 
 
 
 
T1-4b 
N2b 
M0 
 
 
 
 
 
T1-4b 
N2c 
M0 
 
 
 
 
 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
IV 
Any T 
Any N 
M1 
*Clinical staging includes microstaging of the primary melanoma and clinical/radiologic 
evaluation for metastases.  By convention, it should be used after complete excision of the 
primary melanoma with clinical assessment for regional and distant metastases. 
 
Pathologic staging includes microstaging of the primary melanoma and pathologic 
information about the regional lymph nodes after partial (ie, sentinel node biopsy) or 
complete lymphadenectomy.  Pathologic stage 0 or stage IA patients are the exception; they 
do not require pathologic evaluation of their lymph nodes. 
Reference: Balch CM,et al.  Final version of 2009 AJCC melanoma staging and 
classification. J Clin Oncol. 2009 Dec 20;27(36):6199-206. 

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Appendix X 
 
General Recommendations for immune-related Adverse Events (IrAEs) 
 

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Appendix XI 
 
Suggested Work-up and Treatment for Immune-Related Adverse Events (irAEs) 
An IRAE is defined as an adverse event of unknown etiology, associated with drug 
exposure and is consistent with an immune phenomenon. Efforts should be made to rule 
out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an 
adverse event a non-dermatologic, immune-mediated event. Serological, immunological, 
and histological (biopsy) data should be used to support the diagnosis of an immune-
mediated toxicity. Documentation of test results should be included in the patient’s 
medical record. 
Gastrointestinal (diarrhea) and skin (rash)-related toxicities have been the most common 
IRAEs noted in prior studies with ipilimumab. Suggested work-up procedures for 
suspected IRAEs of the gastrointestinal tract, liver, skin, eye, pituitary, and adrenal gland 
are listed below. When symptomatic therapy is inadequate or inappropriate, an IRAE 
should be treated with steroids followed by a slow taper. 
Gastrointestinal Tract: Diarrhea (defined as either first watery stool, or increase in 
frequency 50% above baseline with urgency or nocturnal bowel movement, or bloody 
stool) should be further evaluated and infectious or alternate etiologies ruled out. 
Patients should be advised to inform the investigator if any diarrhea occurs, even if it is 
mild. An algorithm for working up patients with diarrhea or suspected colitis is provided 
in Appendix XII. 
If the event is of significant duration or magnitude or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased CRP or platelet count; or 
bandemia), it is recommended that sigmoidoscopy (or colonoscopy, if appropriate) with 
colonic biopsy with 3 to 5 specimens for standard paraffin block be performed. If 
possible, 1 to 2 biopsy specimens should be snap frozen and stored. All patients with 
confirmed colitis should also have an opthomological examination, including a slit-lamp 
exam, to rule out uveitis. Tests should also be performed for WBCs and for stool 
calprotectin. 
Patients with colitis should discontinue any non-steroidal anti-inflammatory medications 
or any other medications known to exacerbate colitis symptoms. Investigators should 
use their clinical judgment as to whether corticosteroids are necessary to treat colitis 
associated with ipilimumab therapy and as to what dose should be used. As guidance 
prior experience suggests that colitis manifested as ≥ Grade 3 diarrhea requires 
corticosteroid treatment. For severe symptoms, prednisone 60 mg or equivalent may be 
required to control initial symptoms and the dose should be gradually tapered over at 
least one month in duration. Lower doses of prednisone may be considered for less 
severe cases of colitis. It is suggested that prednisone (for oral administration) or 
solumedrol (for intravenous administration) be corticosteroid of choice in the treatment of 
colitis. 
Liver: Elevation of LFTs  3 fold from baseline should instigate an investigation into the 
underlying etiology for suspected IRAEs. Neoplastic, concurrent medications, viral 
hepatitis, and toxic etiologies should be considered and addressed, as appropriate. 
Imaging of the liver, gall bladder, and bile duct should be performed to rule out 
neoplastic or other causes for the increased LFTs. An ANA, pANCA, and anti-smooth 

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muscle antibody test should be performed if an autoimmune etiology is considered. 
Consultation with a hepatologist is appropriate for a suspected liver IRAE and a biopsy 
should be considered. 
Patients presenting with right upper-quadrant abdominal pain and/or unexplained 
nausea or vomiting should have LFTs performed immediately and reviewed before 
administering the next dose of study drug. 
Pancreas: Symptoms of abdominal pain associated with elevations of amylase and 
lipase, suggestive of pancreatitis, may rarely be associated with anti-CTLA-4 monoclonal 
antibody administration. The differential diagnosis of acute abdominal pain should 
include pancreatitis. Appropriate workup should include serum amylase and lipase tests. 
Skin: A dermatologist should evaluate persistent or severe rash or pruritus. A biopsy 
should be performed if appropriate and if possible, photos of the rash should also be 
obtained. Any non protocol drugs that could contribute to a drug reaction should be 
stopped if possible pending evaluation. Patients with low-grade ipilimumab-mediated 
skin toxicity (Grade 1 or 2) may remain on therapy and could be treated with 
symptomatic therapy (e.g., antihistamines). Low-grade symptoms persisting for 1 to 2 
weeks and relapsing should be treated with topical or moderate dose oral corticosteroid 
therapy (e.g., prednisone 1 mg/kg once daily or equivalent). High-grade (Grade 3 or 4) 
symptoms require high-dose IV corticosteroid therapy (e.g., methylprednisolone 2 mg/kg 
once or twice per day or equivalent) to control initial symptoms. A skin biopsy should be 
performed if appropriate. Once rash or pruritis is controlled, the initiation of corticosteroid 
taper should be based on clinical judgment; however, the corticosteroid dose should be 
gradually tapered over a period of at least 1 month. 
Patients with any high-grade skin related toxicity (Grade 3 regardless of causality) have 
to skip ipilimumab and may only continue treatment with ipilimumab if the initial 
symptoms have improved to ≤ Grade 1, while patients with grade 4 skin toxicities have 
to permanently discontinue ipilimumab. 
Eye: An ophthalmologist should evaluate visual complaints with examination of the 
conjunctiva, anterior and posterior chambers and retina; visual field testing and an 
electroretinogram should also be performed. Patients with ipilimumab related uveitis or 
episcleritis have been treated with topical corticosteroid eye drops. 
Endocrine: Subjects with unexplained symptoms such as fatigue, myalgias, impotence, 
mental status changes, or constipation should be investigated for the presence of 
thyroid, pituitary or adrenal endocrinopathies. An endocrinologist should be consulted if 
an endocrinopathy is suspected. If there are any signs of adrenal crisis such as severe 
dehydration, hypotension, or shock, intravenous corticosteroids with mineralocorticoid 
activity (e.g., methylprednisolone) should be initiated immediately. If the patient’s 
symptoms are suggestive of an endocrinopathy but the patient is not in adrenal crisis, 
endocrine laboratory results should be evaluated before corticosteroid therapy is 
initiated. 

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Endocrine work up should include at least Thyroid stimulating hormone and free T4 
levels to determine if thyroid abnormalities are present. TSH, prolactin and a morning 
cortisol level will help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency. Radiographic imaging (e.g., MRI) with pituitary cuts should be performed. If 
the pituitary scan and/or endocrine laboratory tests are abnormal suggestive of pituitary 
endocrinopathy, a short course of high dose corticosteroids (e.g., dexamethasone 4 mg 
every 6 hours or equivalent) should be strongly considered in an attempt to treat the 
presumed pituitary inflammation, but it is currently unknown if this will reverse the 
pituitary dysfunction. Abrupt discontinuation of corticosteroids should be avoided due to 
possible prolonged adrenal suppression. Once symptoms or laboratory abnormalities 
are controlled, and overall patient improvement is evident, the initiation of steroid taper 
should be based on clinical judgment; however the corticosteroid dose should be 
gradually tapered over a period of at least 1 month. Appropriate hormone replacement 
therapy should be instituted if an endocrinopathy is documented, and it is possible that 
subjects may require life-long hormone replacement. 
Patients diagnosed with hypophysitis should be permanently discontinued from 
additional ipilimumab therapy. 
Suspected irAEs should be documented in the patient’s medical record. 

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Appendix XII 
 
Diarrhea Management Algorithm 
Severity  of diarrhea/
colitis
Management
Follow-up
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and continue ipilimumab.
Opiates/narcotics mask symptoms of perforation! Infliximab should not be used in case of perforation/sepsis!
Grade 1
Diarrhea: < 4 stools/day over 
baseline;
Colitis: asymptomatic
Grade 2
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated < 24 
hrs; not interfering with ADL 
Colitis: abdominal pain; blood in 
stool
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of PO 
corticosteroids.
· 
Close monitoring for worsening symptoms
· 
Educate patient to report any worsening immediately
· 
Continue ipilimumab
· 
Symptomatic treatment
Grade 3-4
Diarrhea (G3*): ≥ 7 stools per 
day over baseline; 
incontinence; IV fluids  ≥ 24 
hrs;interfering with ADL 
Colitis (G3*): fever, ileus, 
peritoneal signs
· 
Permanently discontinue 
ipilimumab
· 
High dose IV steroids (e.g., 
methylprednisolone 1-2 mg/
kg/day)
· 
Consider endoscopy
· 
Withhold/delay ipilimumab
· 
Symptomatic treatment
Symptoms improve/resolve (grade 0/1): Resume ipilimumab
Symptoms persist for > 5-7 days, worsen,  or recur:
· 
Moderate to high dose steroids PO (e.g., prednisone
· 
0.5 - 1 mg/kg/day)
· 
Continue to hold/delay ipilimumab until grade 1
· 
When symptoms are grade 1 or less slowly taper steroids 
over at least 1 month and resume ipilimumab.
Symptoms worsen: Treat as grade 3/4
Symptoms improve:
· 
Continue steroids (same dose) until grade 1
· 
Then taper over at least 1 month 
Symptoms persist 3-5 days, or recur after improvement:
· 
1 dose* of infliximab 5 mg/kg (if no 
contraindication)
*Some patients have required a second dose of infliximab
*G4 = life-threatening, perforation

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Appendix XIII 
Hepatotoxicity Management Algorithm 
Severity  of 
hepatitis
Management
Follow-up
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and continue ipilimumab.
Caution: Infliximab is contraindicated in hepatic insufficiency!
Grade 1
AST or ALT ≤ 2.5 x ULN
RU
Total bilirubin ≤ 1.5 x 
ULN
Grade 2
AST or ALT
> 2.5 to ≤ 5.0 x ULN   
or
Total bilirubin
> 1.5 to ≤ 3.0 x ULN
*Ipilimumab may be held/delayed rather than discontinued if AST/ALT ≤ 8 x ULN and Tbili ≤ 5 x ULN.  Resume ipilimumab when AST/ALT/ Tbili return to 
grade 2 and meet protocol specific retreatment criteria.
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.
*** MMF, mycophenolate mofetil
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of PO 
corticosteroids.
· 
Continue monitoring LFT prior to each dose
· 
Continue ipilimumab
Grade 3-4
AST or ALT
> 5.0 x ULN
or
Total bilirubin
> 3.0 ULN
· 
Discontinue ipilimumab*
· 
Increase frequency of monitoring 
(q1-3d)
· 
High dose IV steroids (e.g., 
methylprednisolone 1-2 mg/kg/
day**)
· 
Increase frequency of monitoring
         (q3d)
· 
 Withhold/delay ipilimumab while 
investigating alternative etiology
Return to baseline
· 
Resume q3w monitoring
· 
Resume ipilimumab
Elevations persist for > 5-7 days or worsen,  
and no alternative etiologies are identified
· 
Consider moderate to high dose steroids PO 
(e.g., 0.5- 1 mg/kg/day prednisone or 
equivalent)
AST/ALT/Tbili return  to grade 2
· 
Taper steroids over at least 1 month
Labs do not decrease over 3-5 days,  
worsen  or rebound:
· 
Add MMF*** 1 g BID
· 
If no response within 3-5 days, consider other 
immunosuppressants per local guidelines
 

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Appendix XIV 
Endocrinopathy Management Algorithm 
Severity  of 
endocrinopathy
Management
Follow-up
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and continue ipilimumab.
Asymptomatic TSH 
elevation
Symptomatic 
endocrinopathy
Patients on IV steroids may be switched  to oral corticosteroid  (e.g., prednisone)  at an equivalent  dose at start of tapering or earlier, once 
sustained clinical improvement  is observed. Lower bioavailability  of oral corticosteroids  should be taken into account when switching to the 
equivalent dose of PO corticosteroids.
Continue ipilimumab
If TSH < 0.5 x LLN, or TSH > 2.0 x ULN, or consistently out of range in 2 subsequent measurements: Include fT4 
at subsequent cycles as clinically indicated; consider endocrinology consult
Symptoms resolve (with or 
without hormone substitution):
· 
Resume ipilimumab
· 
Taper steroids over at 
least 1 month*
· 
Evaluate endocrine function
· 
Consider pituitary scan
Symptomatic with  abnormal lab/pituitary scan:
· 
Withhold/delay ipilimumab
· 
High dose IV steroids (e.g., 1-2 mg/kg/day 
methylprednisolone) Initiate appropriate hormone therapy
· 
No abnormal lab/pituitary scan but symptoms persist:
· 
Repeat labs in 1-3 weeks / MRI in 1 month
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, hypotension, 
shock out of proportion 
to current illness)
· 
Rule out sepsis
· 
Stress dose of IV steroids with mineralocorticoid activity
· 
IV fluids
· 
Consult endocrinologist
*Patients with adrenal 
insufficiency might need to 
continue steroids with 
mineralcorticoid  component 
as substitution
 

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Appendix XV 
Neuropathy Management Algorithm 
Severity  of 
neurological 
toxicity
Management
Follow-up
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and continue ipilimumab.
Discontinue ipilimumab for any grade 3-4 motor neuropathy, regardless  of relationship.
Grade 1
Grade 3-4 sensory
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of PO 
corticosteroids.
Continue monitoring the patient. If symptoms worsen, 
treat as below.
· 
Continue ipilimumab
Grade 3-4 motor
· 
Discontinue ipilimumab regardless  
of relationship
· 
Obtain neuro consult
· 
Treat symptoms per local guidelines
· 
High dose IV steroids (e.g., 1-2 mg/
kg/ day methylprednisolone)
· 
Discontinue ipilmumab if 
considered related
· 
Obtain neuro consult
· 
Treat symptoms per local guidelines
· 
High dose IV steroids (e.g., 1-2 mg/
kg/ day methylprednisolone)
Symptoms  resolve / return to grade 2:
· 
Taper steroids over at least 1 month
Symptoms  resolve / return to grade 2:
· 
Taper steroids over at least 1 month
Symptoms  do not resolve or progress; atypical 
presention:
· 
Consider IVIg or other immunosuppressive therapies 
per local guidelines
Grade 2
· 
Hold/delay ipilimumab
· 
Treat symptoms per local 
guidelines
Resume ipilimumab when resolved / grade 1
If symptoms worsen, treat as below.
 

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Appendix XVI 
Skin Toxicity Management Algorithm 
Severity  of 
skin toxicity
Management
Follow-up
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and continue ipilimumab.
Grade 1-2
Grade 3-4
· 
Symptomatic therapy, e.g. antihistamines, 
topical steroids
· 
Continue ipilimumab
Symptoms resolve / return to grade 1: 
· 
Taper steroids over at least 1 month
· 
Resume ipilimumab
· 
Discontinue if grade 4 toxicity 
considered related
· 
Hold/delay ipilimumab (regardless of 
relationship)
· 
Take photos of rash
· 
Consider skin biopsy
· 
Dermatology consult
· 
High dose IV steroids (e.g., 
methylprednisolone 1-2 mg/kg/day)
Symptoms resolve: Continue ipilimumab
Symptoms persist > 1-2 weeks or recur:
· 
Continue ipilimumab
· 
Moderate to high dose steroids PO 
(e.g., prednisone 0.5 - 1 mg/kg/day)
· 
Once controlled, taper steroids over at 
least 1 month
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose at start of tapering or earlier, once sustained  
clinical improvement  is observed.  Lower bioavailability  of oral corticosteroids  should be taken into account when switching to the equivalent dose 
of PO corticosteroids.
 

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Appendix XVII 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on Ipilimumab or Interferon-
Alfa, or within 28 days of the patient’s last dose of Ipilimumab or Interferon-Alfa must be reported 
in an expeditious manner.  The outcome of the pregnancy and neonatal status must also be 
reported. 
How should the pregnancy be reported? 
· 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be 
reported via CTEP’s Adverse Event Reporting System (CTEP-AERS) 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported?  
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
· 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
· 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
· 
The start date of the pregnancy should be reported as the calculated date of conception.   
· 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
What else do I need to know when a pregnancy occurs to a patient? 
· 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
· 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN Operations 
Office - Boston.  Please contact the ECOG-ACRIN Operations Office - Boston to ask for a 
conference call to be set up with the appropriate individuals.   
· 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
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Version Date: March 2, 2016 
155 
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if 
the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report should 
be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects. For 
assistance in recording the grade or category of these events, please contact the CTEP AEMD 
Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed on a case by 
case basis. 
Reporting a Fetal Death 
A fetal death is defined in CTCAE as “A disorder characterized by death in utero; failure of the 
product of conception to show evidence of respiration, heartbeat, or definite movement of a 
voluntary muscle after expulsion from the uterus, without possibility of resuscitation.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy, puerperium and perinatal conditions 
- Other (pregnancy loss)” under the System Organ Class (SOC) “Pregnancy, puerperium and 
perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A disorder characterized by cessation of life occurring 
during the first 28 days of life” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention. However, for this protocol, any neonatal death that occurs 
within 28 days of birth, without regard to causality, must be reported via CTEP-AERS AND any 
infant death after 28 days that is suspected of being related to the in utero exposure to Ipilimumab 
or Interferon-Alfa must also be reported via CTEP-AERS. 
It must be reported via CTEP-AERS as Grade 4 “General disorders and administration - Other 
(neonatal loss)”under the System Organ Class (SOC) “General disorder and administration”.  
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the CTEP 
'Pregnancy Information Form' must be completed and faxed along with any additional medical 
information to CTEP (301-230-0159). This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportForm.
pdf) 
Rev. 5/15