A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High-Dose Interferon a-2b for Resected High-Risk Melanoma
Phase: PHASE3
Conditions: Melanoma of Unknown Primary, Recurrent Melanoma, 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 
28 State Street, Suite 1100, Boston, MA 02109 
p: 857.504.2900 
f: 617. 589.0914 ecog-acrin.org 
 
 
October 22, 2018  
 
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 #18 to E1609, A Phase III Randomized Study of Adjuvant Ipilimumab 
Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected High Risk Melanoma 
The following revisions to E1609 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page  
Updated Version Date 
2. 
Section 9 
Added paragraph regarding final statistical analysis time  
The following revisions to E1609 Informed Patient Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date  
The following revisions to E1609 Informed Pediatric Consent Document have been made in this 
addendum: 
 
Section 
Change 
2. 
Cover Page 
Updated Version Date  
If you have any questions regarding this addendum, please contact jdoyle@ecog-acrin.org or 
857-504-2900. 
We request review and approval of this addendum to E1609 so ECOG-ACRIN may activate it 
promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Protocol Development Manager 

ii 
Enclosure 
CC: 
Ahmad Tarhini, MD, PhD 
F. Stephen Hodi, MD 
Sandra Lee, ScD 
John Kirkwood, MD 
Uma Rao, MD 
Lynne Wagner, PhD 
Gary Cohen, MD 
Matthew Shimizu 
Sarah Archambault 
Donna Marinucci 
Amy Rose, RN 
 
 
 
 
Carol Chami, R.N. 
Juanita Andrews 
Melinda Flood 
Bruce Giantonio, M.D. 
Peter O’Dwyer, M.D 
Kerry Higgins, MPG 
Gayle Ipock 
Jean MacDonald, MPH 
Colin Burnett 
Julie Doyle 
Sally Morawski, MPH 
Lauren Lambert 
Allison Snowhite 
 
 
 

E1609 
 
1 
A Phase III Randomized Study of Adjuvant Ipilimumab 
Anti-CTLA4 Therapy Versus High Dose Interferon a-2b 
for Resected High Risk Melanoma 
STUDY CHAIR: Ahmad A. Tarhini MD, PhD 
STUDY CO-CHAIR: F. Stephen Hodi, MD 
STUDY STATISTICIAN: Sandra Lee, ScD 
MELANOMA COMMITTEE CHAIR: John M. Kirkwood, MD 
PATHOLOGY CO-CHAIR: Uma Rao, MD 
PATIENT OUTCOMES AND  
SURVIVORSHIP CO-CHAIR: Lynne Wagner, PhD 
COMMUNITY CO-CHAIR: Gary Cohen, MD 
LABORATORY CO-CHAIR: Ahmad A. Tarhini, MD, PhD 
Version Date:  October 22, 2018 
NCI Update Date:  September 6, 2017 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
NRG / NRG Oncology Foundation, Inc 
 
May 25, 2011 
ALLIANCE / Alliance for Clinical Trials in 
Oncology 
Addendum #1 – Incorporated Prior to Activation 
SWOG / SWOG 
Addendum #2 – Incorporated Prior to Activation 
NCIC-CTG / NCIC Clinical Trials Group 
Update #1 – 6/11 
COG / Children’s Oncology Group 
Addendum #3 – 10/11 
NOTE: As of 9/23/2014, accrual is limited to 
pediatric/adolescent patients from COG 
sites only. Please see Section 4.6.5. 
Addendum #4 – 2/12 
Addendum #5 – 8/12  
Addendum #6 – 2/13 
Addendum #7 – 11/13 
Addendum #8 – 2/14 
Addendum #9 – 4/14 
 
 
Addendum #10 – 9/14 
 
 
Addendum #11 - 9/14 
 
 
Addendum #12 - 9/14 
 
 
Addendum #13 - 10/14 
 
 
Addendum #14 - 3/15 
 
 
Addendum #15 - 5/15 
 
 
Addendum #16 – 3/16 
 
 
Update #2 – 9/17 
 
 
Addendum #17 
 
 
Addendum #18 
Agents 
IND # 
NSC # 
Supply 
Ipilimumab 
 
732442 
NCI Supplied 
Rev. 2/12 
Rev. 4/14 
Rev. 6/11, 
9/14 
Rev. 9/14, 
3/15 

2 
 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
3 
Table of Contents 
Schema ......................................................................................................8 
1. Introduction ..........................................................................................9 
1.1 Introduction to Melanoma ..............................................................9 
1.2 Immunity in melanoma and implications for adjuvant immunotherapy in 
the high-risk setting of operable disease ...........................................9 
1.3 Adjuvant interferon (IFN)-α2b for surgically resected melanoma that is 
at high-risk for recurrence and death .............................................. 10 
1.4 CTLA-4 and T cell activation ........................................................... 12 
1.5 CTLA-4 blockade with Ipilimumab .................................................. 13 
1.6 Study Rationale ........................................................................... 32 
1.7 Definition of a Positive Study ......................................................... 37 
2. Objectives ........................................................................................... 38 
2.1 Primary Endpoints ....................................................................... 38 
2.2 Secondary Endpoints .................................................................... 38 
3. Selection of Patients ............................................................................. 39 
3.1 Eligibility Criteria ......................................................................... 39 
4. Registration Procedures ........................................................................ 48 
4.1 Protocol Number ......................................................................... 51 
4.2 Investigator Identification ............................................................. 51 
4.3 Patient Identification.................................................................... 51 
4.4 Eligibility Verification.................................................................... 52 
4.5 Stratification Factors .................................................................... 52 
4.6 Additional Requirements .............................................................. 52 
4.7 Instructions for Patients who Do Not Start Assigned Protocol Treatment53 
5. Treatment Plan .................................................................................... 54 
5.1 Surgical Considerations................................................................. 54 
5.2 Administration Schedule ............................................................... 54 
5.3 Adverse Event Reporting Requirements .......................................... 56 
5.4 Comprehensive Adverse Events and Potential Risks List..................... 64 
5.5 Dose Modifications ...................................................................... 69 
5.6 Supportive Care........................................................................... 92 
5.7 Duration of Therapy ..................................................................... 93 
5.8 Duration of Follow-up .................................................................. 93 
5.9 Quality of Life Evaluations ............................................................. 93 
6. Measurement of Effect ......................................................................... 96 
6.1 Local, Regional Recurrence............................................................ 96 
6.2 Distant Recurrence ...................................................................... 96 
6.3 Recurrence-Free Survival .............................................................. 96 
6.4 Survival ...................................................................................... 96 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
4 
6.5 Histological or cytological evidence of recurrence should be attempted 
in all cases except for brain metastases. Strong consideration should be 
given to resection of solitary brain lesions in the absence of other 
systemic disease. ......................................................................... 96 
6.6 Documentation of recurrence will require specification of all sites 
involved to establish the pattern of recurrence. ............................... 96 
6.7 The following criteria of treatment failure constitute the only acceptable 
evidence of disease recurrence. ..................................................... 96 
7. Study Parameters ................................................................................. 97 
7.1  Therapeutic Parameters for all arms .............................................. 97 
7.2 Arms A,C, D, and F: Patients Treated with Ipilimumab at 10 mg/kg (Arm 
A and D) or 3 mg/kg (Arm C and F) ................................................. 99 
7.3 Arm B and E: Patients treated with interferon-α2b: ........................ 102 
7.4 Biological Sample Submissions ..................................................... 105 
8. Drug Formulation and Procurement ...................................................... 107 
8.1 Ipilimumab ............................................................................... 107 
8.2 Alfa Interferon........................................................................... 111 
9. Statistical Considerations..................................................................... 115 
9.1 Previous Study Design ................................................................ 115 
9.2 Primary Objective ...................................................................... 116 
9.3 Sample Size and Accrual ............................................................. 116 
9.4 First Step: Comparison of Low-dose Ipi vs. HDI ............................... 117 
9.5 Second Step: Comparison of High-dose Ipi vs. HDI .......................... 117 
9.6 Interim Analysis ......................................................................... 118 
9.7 Secondary Objectives ................................................................. 119 
9.8 Statistical Analysis Plan ............................................................... 121 
9.9 Gender and Ethnicity.................................................................. 123 
9.10 Study Monitoring....................................................................... 124 
9.11 Adolescent Patients ................................................................... 125 
10. Pathology Review ............................................................................... 126 
10.1 Pathology samples must be submitted for review and classification 
(baseline only) and banking. ........................................................ 126 
10.2 Materials Required For This Protocol ............................................ 126 
10.3 Shipping Procedures................................................................... 127 
10.4 ECOG-ACRIN Sample Tracking System ........................................... 128 
10.5 Banking .................................................................................... 129 
11. Correlative Studies ............................................................................. 130 
11.1 Blood Sample Collection ............................................................. 130 
11.2 Shipping Procedures................................................................... 131 
11.3 Banking .................................................................................... 132 
11.4 Sample Inventory Submission Guidelines....................................... 132 
11.5 Lab Data Transfer Guidelines ....................................................... 132 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
5 
12. Records to Be Kept ............................................................................. 133 
12.1 Records Retention ..................................................................... 133 
13. Patient Consent and Peer Judgment...................................................... 133 
14. References ........................................................................................ 133 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Amendment #6].................................................. 137 
Appendix I-A  Informed Consent Template for Cancer Treatment Trials (English 
Language, Non-CCOP Institutions) [Deleted in Amendment #6]................. 138 
Appendix II Pathology Submission Guidelines............................................... 139 
Appendix III  Patient Thank You Letter ........................................................ 145 
Appendix IV  Patient Interferon Diary (for patients who self-administer Interferon)146 
Appendix V  E1609 Cooperative Research and Development Agreement (CRADA)148 
Appendix VI  ECOG Performance Status ...................................................... 150 
Appendix VII  Suggested Surgical Considerations and Techniques for 
Lymphadenectomy ............................................................................. 151 
Appendix VIII  Shipping Kit Request Facsimile Form....................................... 154 
Appendix IX  Specimen Shipment Requisition Form....................................... 155 
Appendix X  Administration of Interferons (Directions for Administration of 
Subcutaneous Doses).......................................................................... 157 
Appendix XI  TNM Staging for Melanoma .................................................... 159 
Appendix XII  General Recommendations for immune-related Adverse Events 
(IrAEs) .............................................................................................. 161 
Appendix XIII  Suggested Work-up and Treatment for Immune-Related Adverse 
Events (irAEs)..................................................................................... 162 
Appendix XIV GI Management Algorithms ................................................... 165 
Appendix XV Hepatotoxicity Management Algorithms................................... 169 
Appendix XVI Endocrinopathy Management Algorithm ................................. 170 
Appendix XVII Neuropathy Management Algorithms..................................... 172 
Appendix XVIII Skin Toxicity Algorithm ........................................................ 177 
Appendix XIX Biomarkers of the Proinflammatory Response and Elements of 
Immune Suppression .......................................................................... 178 
 
 
 
Rev. 2/12 
Rev. 
Add17

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
6 
STUDY CHAIR 
Ahmad A. Tarhini, MD, PhD 
Cleveland Clinic Taussig Cancer Institute 
Taussig Cancer Center 
9500 Euclid Ave, CA6-157 
Cleveland, OH 44195 
Tel: (216) 636-0200 
Fax: (216) 444-0528  
E-mail: tarhina1@ccf.org 
 
STUDY CHAIR LIAISON (SCL) 
Amy Rose, RN BSN OCN 
University of Pittsburgh Cancer Institute 
5150 Centre Avenue 
Third Floor 
Pittsburgh, PA 15232 
Phone: (412) 647-8587 
Fax: (412) 623-7862 
E-mail: kennaj@upmc.edu 
 
STUDY CO-CHAIR 
F. Steven Hodi, MD 
Dana-Farber Cancer Institute 
44 Binney Street 
Boston, MA 02115 
Tel: (617) 632-5053 
Fax: (617) 582-7992 
E-mail: stephen_hodi@dfci.harvard.edu 
 
 
 
Rev. 2/13 
Rev. 8/12, 2/13 
Rev. 2/13 
Rev. 8/12 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
7 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  directly to 
the Lead Cooperative Group 
unless otherwise specified in 
the protocol:  
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately at 
1-866-651-2878 to receive 
further instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on using 
the Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations Office - 
Boston,  
28 State St., Suite 1100 
Boston, MA 02109 
(ATTN: DATA). 
Phone # 857-504-2900 
Fax # 617-589-0914 
Data should be sent via postal 
mail (preferred), however fax is 
accepted. 
Do not submit study data or forms 
to CTSU Data Operations. Do not 
copy the CTSU on data 
submissions.   
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
– Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-
IAM username and password.  
For clinical questions (i.e. patient eligibility or treatment-related questions) Contact the Study PI of 
the lead protocol organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website 
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org. 
 
Rev. 9/14 
Rev. 
Add17

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
8 
Schema 
R
A
N
D
O
M
I
Z
E
Arm A: Ipilimumab Highdose 
(CLOSED TO ADULT ACCRUAL) 
Arm D: PEDIATRIC ACCRUAL ONLY
Induction Phase
Ipilimumab:10 mg/kg I.V. infusion every 
three weeks for four doses.
Arm C: Ipilimumab Lowdose
Arm F: PEDIATRIC ACCRUAL ONLY
Induction Phase 
Ipilimumab: 3 mg/kg I.V. infusion every 
three weeks for four doses.
Stratify
Patients with 
surgically resected 
AJCC stage:
• IIIB 
• IIIC
• M1a 
• M1b
Maintenance Phase
Ipilimumab:10 mg/kg I.V. infusion 
every 12 weeks (3 months), beginning 
at week 24, for a maximum of 4 doses 
(week 24, 36, 48, 60)
Maintenance Phase
Ipilimumab: 3 mg/kg I.V. infusion every 
12 weeks (3 months), beginning at 
week 24, for a maximum of 4 doses 
(week 24, 36, 48, 60).
Accrual ~ 1,500*
*Additional cohort of up to 45 patients aged 12-17 will be part of the study.
NOTE: As of August 15, 2014 adult accrual has completed on Arms A, B, and C. Adolescent patients (ages 12 -17) are randomized to all 3 
Study Arms D, E, and F which will follow the same treatment regimen as Arms A, B, and C, respectively.
Rev. 2/12
Rev. 2/12
Rev. 
2/12
Arm B: HDI
Arm E: PEDIATRIC ACCRUAL ONLY
Induction Phase 
Interferon Alfa - 2b: 20 MU/m²/d I.V. for 5 
consecutive days out of 7 (e.g., M-F) every 
week for 4 weeks. 
Maintenance Phase
Interferon Alfa-2b: 10 MU/m²/d 
Subcutaneous every other day (e.g., 
M,W,F) 3 times each week for 48 
weeks.
Rev. 9/14
Rev. 9/14
Rev. 9/14
Rev. 2/15
 
 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
9 
1. 
Introduction 
1.1 
Introduction to Melanoma 
Survival of patients with melanoma varies widely by stage, from a highly curable 
disease when detected in early stages to a disease with dismal prognosis when it 
reaches advanced, inoperable stages (1). The American Joint Committee on 
Cancer (AJCC) divides cutaneous melanoma into four stages. In the 2002, 6th 
edition, stages I and II are assigned to primary tumors confined to the skin and 
without regional lymph node involvement. These stages are defined on the basis 
of the thickness (depth) of the tumor, ulceration of the overlying epithelium, or 
invasion of the reticular dermis or subcutaneous fat (Clark level IV or V). In the 7th 
edition, the prognostic significance of the mitotic activity (histologically defined as 
mitoses/mm2) has been recognized as an important primary tumor prognostic 
factor. The mitotic rate (equal to or greater than 1/mm2) has now replaced the 
level of invasion as a primary criterion for defining the subcategory of T1b in 
addition to tumor ulceration. Stage III comprises a disease with clinical or 
pathological evidence of regional lymph node involvement, or the presence of in-
transit or satellite metastases. Stage IV disease is defined by the presence of 
distant metastasis. Patients with stage I melanoma have an excellent prognosis 
with surgical treatment alone and a cure rate of more than 85%. The 3-5 year 
post-surgical relapse rate in patients with stages IIA and IIB is 20-30% and 40-
55% respectively. Stage III melanoma patients with regional lymph node 
involvement have a 5-year relapse rate of 40-80%, while stage IV disease has a 
dismal prognosis with a median survival of only 6 to 9 months (2,3). 
1.2 
Immunity in melanoma and implications for adjuvant immunotherapy in the high-
risk setting of operable disease 
Immunity to melanoma appears to be important for disease control in the 
adjuvant and advanced disease settings. Spontaneous regression of disease has 
been reported in patients with melanoma, suggesting a role for host immunity, 
indirectly supported by the pathological evidence for the presence of lymphoid 
infiltrates at primary melanoma associated with tumor regression. Host cellular 
immune responses within melanoma have potential prognostic and predictive 
significance. T-cell infiltrates in primary melanoma have been suggested to be of 
prognostic significance (4), and T-cell infiltrates within regional nodal metastases 
predict benefit in patients treated with neoadjuvant IFNα2b therapy (5-7). 
The quality of the host immune response has been shown to differ between 
earlier and more advanced disease settings. While T helper type 1 (Th1)-type 
CD4+ antitumor T-cell function appears to be critical to the induction and 
maintenance of antitumor cytotoxic T-lymphocyte (CTL) responses in-vivo, and 
Th2- or Th3/Tr-type CD4+ T-cell responses may subvert Th1-type cell mediated 
immunity yielding a microenvironment that facilitates disease progression, 
patients with active melanoma or renal cell carcinoma have been shown to 
display strong tumor antigen-specific Th2-type polarization. On the other hand, 
normal donors and patients who were disease free following therapy 
demonstrate either weak mixed Th1-/Th2-type or strongly polarized Th1-type 
responses to the same epitopes (8,9). Therefore, host immune tolerance appears 
to be an impediment to the therapy of advanced disease. This may be avoidable 
in the high-risk setting of operable disease, where the host susceptibility to 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
10 
immunologic interventions may be greater and where IFN-α2b has demonstrated 
its significant impact upon melanoma relapse and survival. 
1.3 
Adjuvant interferon (IFN)-α2b for surgically resected melanoma that is at high-
risk for recurrence and death 
Three national cooperative group studies have evaluated the benefit of high-dose 
IFN-α2b (HDI) as adjuvant therapy for resectable high-risk cutaneous melanoma. 
These included patients with regional lymph node metastases and primary 
localized deep melanomas that have a 5-year post-surgical relapse rate of more 
than 40-50%. The first and third of these studies both demonstrated significant 
survival prolongation, compared to observation (E1684; The median relapse-free 
survival (RFS) was 1.72 years in the HDI arm versus 0.98 year in the Obs arm 
[stratified log-rank one-sided P value (P1) = 0.0023], and the median OS was 
3.82 versus 2.78 years (P1 = 0.0237), respectively) (10) and compared to a 
vaccine (GMK) that was selected as the optimal vaccine candidate at the time 
(E1694). The results of this trial were reported in 2001 based on a final analysis 
in June 2000, with a median follow-up interval of 16 months. Among eligible 
patients in this trial, HDI provided a statistically significant RFS benefit (HR = 
1.47; P1 = 0.0015) and overall survival (OS) benefit (HR = 1.52; P1 = 0.009) 
compared with GMK. A similar benefit was observed in the intent-to-treat analysis 
of RFS (HR = 1.49) and OS (HR = 1.38) (11). The second trial, E1690, conducted 
in part before and in part after the US FDA approval of HDI, was associated with 
systematic crossover of patients from the observation-assigned arm (Obs) to 
treatment at nodal relapse with HDI. This trial showed differences in terms of 
relapse-free but not overall survival. In the intent-to-treat analysis of RFS, 
treatment with HDI was associated with a statistically significant benefit 
compared with observation (HR = 1.28; P1 = 0.025). In contrast, low-dose IFN-
α2b (LDI) was not associated with a significant RFS benefit compared with Obs. 
Neither HDI nor LDI regimens had any apparent impact on OS compared with 
observation in this trial. However, a retrospective analysis of salvage therapy 
demonstrated the occurrence of a disproportionate crossover of patients from the 
observation arm to HDI therapy post  protocol in those patients who developed 
regional recurrence (stage IIB patients in this trial were not required to undergo 
lymphadenectomy), which may have confounded the survival analysis (12). The 
analysis of each of the foregoing studies has been updated in a pooled analysis 
of survival and relapse-free outcomes to April 2001 (13). The pooled analysis has 
firmly demonstrated that melanoma relapse has been prevented by IFN to 
intervals that now approach 20 years, and yet this analysis (that included the 
observation-controlled trials E1684 and E1690, but not E1694) has not yielded 
compelling evidence of an impact upon overall survival despite the positive 
survival results of two randomized US Cooperative Group and Intergroup studies 
(E1684 and E1694). This may not be surprising, given that the larger of the two 
observation-controlled trials included in the pooled analysis (E1690) did not show 
an OS benefit for HDI . As discussed previously, the confounding of the OS 
analysis of E1690 by the routine crossover to HDI of all but one of 37 patients 
assigned to observation who had nodal relapse, associated with an unusually 
prolonged post-relapse survival of those patients in the observation arm treated 
with HDI, may have been responsible for this outcome variability. Patients treated 
with HDI in E1694 have not been included in the pooled analysis because the 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
11 
comparator in that trial was the GMK vaccine and not observation as was the 
case in E1684 and E1690. 
Overall, there is wide agreement and evidence of a significant improvement of 
RFS with HDI that is supported by all 3 US Cooperative Group randomized trials 
(E1684, E1690, E1694) as well as data from multiple lower-dose IFN trials that 
have been summarized in 2 meta-analyses by Wheatley and Ives (14,15). 
Multiple IFN-α2b regimens, that may be categorized as high-dose, intermediate-
dose, or low-dose regimens, have been evaluated as adjuvant therapy for 
intermediate/high-risk (T3-4, lymph node positive) surgically resected melanoma. 
The only randomized controlled trials that have shown durable relapse-free and 
overall survival impact have utilized the high-dose IFN-α2b regimen (HDI) 
(10,12,16). The first meta-analysis of 12 randomized trials of adjuvant IFN-α2b 
confirmed a highly significant reduction in the odds of recurrence in patients 
treated with IFN compared to observation. The analysis also demonstrated 
evidence of increased benefit with increasing IFN dose and a trend for improved 
benefit with increasing total dose. This meta-analysis did not find a statistically 
significant overall survival benefit for IFN-α2b. However, the larger second 
individual patient data meta-analysis of 13 randomized trials showed a significant 
though small impact of interferon upon overall survival (17,18).  In this latter 
meta-analysis, there was statistically significant benefit for IFN for both event-free 
survival (EFS) (OR=0.87, CI=0.81-0.93, p=0.00006) and OS (0.9, 0.84-0.97, 
p=0.008). This survival advantage translates into an absolute benefit of about 3% 
(CI 1%-5%) at 5 years. This analysis did not, however, clarify whether there is an 
optimal (high, intermediate or low) dose of IFN (18). 
In regards to stage IV melanoma, IFN-α was the first recombinant cytokine to be 
investigated clinically for the therapy of advanced metastatic melanoma. Initial 
phase I-II studies yielded overall response rates of about 16% and about one 
third achieved complete and durable responses. Responses were observed as 
late as 6 months from initiation of therapy, and up to one third of the responses 
were durable. However, the median duration of response was only about 4 
months (19-22). The use of IFN-α for adjuvant therapy of patients with operable 
melanoma is based on the hypothesis that micrometastatic disease is the source 
of future relapse, and is less established in its induction of host tolerance of 
tumor. While patients with advanced inoperable metastatic melanoma display 
immunological tolerance, the adjuvant setting may be more susceptible to 
interventions designed to induce Th1 host-effector mechanisms to eradicate 
micrometastases. In addition, no other agent has ever been demonstrated to 
provide similar relapse free or survival benefit for the high-risk adjuvant patient 
population. Therefore, HDI continues to be the only option available for patients 
with high-risk surgically resected melanoma outside of a clinical trial. 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
12 
1.4 
CTLA-4 and T cell activation 
Figure 1: Mechanism of action of ipilimumab 
 
Advances in the understanding of the mechanisms that regulate T-cell activation 
have allowed the rational design of new strategies for immunotherapy of tumors, 
including melanoma. It has been known for some time that engagement of the T-
cell antigen receptor by itself is not sufficient for full T-cell activation; a second 
co-stimulatory signal is required for the induction of IL-2 production, proliferation 
and differentiation to effector function of naive T cells. 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) (23). (See Figure 
1). Expression of B7 has been shown to be limited to “professional” antigen 
presenting cells; that is, specialized cells of the hematopoietic lineage, including 
dendritic cells, activated macrophages, and activated B cells. It has been 
suggested that this sharply-defined restriction of B7 expression is a fail-safe 
mechanism for maintenance of peripheral T-cell tolerance, insuring that T-cell 
activation can only be stimulated by appropriate APCs (24). The fact that tumor 
cells do not express B7 contributes to their poor capacity to elicit immune 
responses (25,26). 
The demonstration that induction of expression of B7 on many tumor cells by 
transfection, transduction, or other means heightens tumor immunogenicity led to 
great interest in pursuing this as an approach to tumor immunotherapy. As 
demonstrated in vivo in murine tumor models, the utility of B7 expression as a 
vaccination approach is limited by the following factors: (1) B7-expressing tumor 
cell vaccines are only effective when the tumor cells have a high degree of 
inherent immunogenicity; (2) while B7-expressing vaccines have been shown in 
many cases to be effective in inducing protective immune responses, they have 
demonstrated only limited utility in inducing responses to established tumors; and 
(3) inactivation of tumor cells by radiation has been shown to destroy the 
immuno-enhancing activity of the B7 gene product (27,28). 
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 (29). Although there was initially some controversy as to the 

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role of CTLA-4 in regulating T-cell activation, it has become clear that CTLA-4 
down-regulates T-cell responses (30). 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 (31-34). Blocking CTLA-4-B7 interaction while preserving signaling via 
CD28 resulted in enhanced T-cell responses in vitro (32). 
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-
4 came from examination of mice with a null mutation (35-37). 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 (34). 
1.5 
CTLA-4 blockade with Ipilimumab 
1.5.1 
Pharmacology of Ipilimumab 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 
monoclonal antibody (mAb). In vitro studies were performed with 
ipilimumab to demonstrate that it is specific for CTLA-4, actively 
inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any 
cross-reactivity with human B7.1, B7.2 negative cell lines, and stains 
the appropriate cells without non-specific cross-reactivity in normal 
human tissues, as demonstrated by immunohistochemistry. 
Ipilimumab does cross-react with CTLA-4 in non-human primates 
including cynomolgus monkeys. 
Ipilimumab was originally produced and purified from a hybridoma 
clone. Subsequently, a transfectoma (CHO cell) has been generated 
that is capable of producing more ipilimumab on a per cell basis than 
the hybridoma. Material from the transfectoma will be utilized in this 
and future ipilimumab clinical studies. Biochemical, immunologic and 
in vivo preclinical primate assessments demonstrated similarity 
between hybridoma and transfectoma-derived ipilimumab. 
1.5.2 
Pre-clinical Toxicology of Ipilimumab 
Complete information on the pre-clinical toxicology studies can be 
found in the Ipilimumab Investigator Brochure (IB). Non-clinical toxicity 
assessments included in vitro evaluation for the potential of 
ipilimumab to mediate complement-dependent 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 
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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. 
1.5.3 
Human pharmacokinetics and pharmacodynamics of ipilimumab 
(Ipilimumab IDB) 
Pharmacokinetic (PK) profiles for ipilimumab have been analyzed. 
The primary objective of Protocol MDX-010-015 was to determine the 
safety and PK profile of single and multiple doses of ipilimumab 
derived from a transfectoma or hybridoma cell line. This study is still 
ongoing and data are preliminary. Mean plasma concentrations of 
ipilimumab administered at dosages of 2.8 mg/kg (transfectoma-
derived drug product), 3 mg/kg (hybridoma-derived drug product), 
5 mg/kg and 7.5 mg/kg (transfectoma) appear to be dose proportional 
over time. Preliminary PK analyses reveal that the volume variables 
were approximately that of plasma volume (range of mean apparent 
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 (Cl) was, low (range 0.11 to 0.29 mL/h/kg) and reflective of 
the half-life (range 297 to 414 h). Mean residence time (MRT) was 
long (range 435 to 538 h), consistent with the long terminal disposition 
phase of ipilimumab. In general, there was moderate variability in the 
PK parameters among patients, with coefficient of variation (CV) of 
11% to 48% in AUC (0-21d), 20% to 59% in Cl and 17% to 46% in 
steady state. Future clinical studies, including this study, will utilize the 
transfectoma-derived product. 
The pharmacokinetics of ipilimumab 10 mg/kg in 3 pivotal studies in 
advanced melanoma (CA184007, CA184008, CA184022) have been 
summarized. All 3 studies were conducted with transfectoma-derived 
ipilimumab (the proposed formulation). The mean (± SD) clearance 
(CL) values after IV administration of 10 mg/kg was 18.3 ± 5.4 mL/hr 
and the mean (± SD) volume of distribution at steady-state (Vss) 
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Exposure-response (E-R) relationships for efficacy and toxicity were 
characterized with data obtained from 3 Phase II studies in subjects 
with advanced melanoma (CA184007, CA184008, and CA184022). E-
R relationship was assessed for 2 measures of efficacy: best overall 
response (BOR) defined by mWHO criteria, and immune-related 
clinical activity (irCA). ir-Clinical Activity includes subjects with ir 
complete response irCR, or ir partial response (irPR), or late response 
(irCR or irPR or ir stable disease (irSD) after tumor progression), or 
subjects who achieved irSD of ≥ 25% reduction in tumor burden from 
baseline. The safety endpoint employed was the incidence of 
immune-related adverse events (irAEs). The probability of BOR and 
irCA increased with increasing minimum plasma concentration (Cmin) 
of ipilimumab at steady-state (Cminss) over the range of exposures 
achieved by ipilimumab doses ranging from 0.3 to 10 mg/kg. Likewise, 
the probability of experiencing Grade ≥ 2 and Grade ≥ 3 irAEs also 
increased with Cminss of ipilimumab. The majority of these events 
were medically manageable and resolved within days to weeks 
following cessation of ipilimumab or treatment with corticosteroids or 
other anti-inflammatory agents. 
Recent data (in press; cross study analysis from CA184007, 
CA184008, CA184022) has been provided by the BMS Ipilimumab 
Team. In cell based competition assays in vitro, a Cminss (minimum 
plasma concentration at steady-state) of 20mcg/ml of ipilimumab has 
been shown to maximally block CTLA-4 binding to B7-1 and B7-2. 
Analysis of PK data from patients treated with ipilimumab at 0.3 mg/kg 
(N=47), 3 mg/kg (N=60) and 10 mg/kg (N=311), showed that the 
target Cminss target threshold of 20 mcg/ml was exceeded in 0% 
subjects receiving 0.3 mg/kg, 30% subjects receiving 3 mg/kg and 
95% subjects receiving 10 mg/kg. In addition the 10 mg/kg dose level 
has been shown to be more biologically active than 3 or 0.3 mg/kg. 
The mean absolute lymphocyte count (ALC) increases proportionally 
with the ipilimumab dose with an ALC slope that is correlated with 
ipilimumab dose (p<0.0001) and with clinical benefit (CR, PR, SD ≥ 6 
months) (p=0.0013). 
1.5.4 
Clinical Safety with Ipilimumab 
Ipilimumab immunotherapy is currently under investigation in patients 
with advanced melanoma (unresectable Stage III or Stage IV) to 
potentially demonstrate improvement in clinical outcome. Ipilimumab 
has been administered to approximately 2901 patients with different 
cancers in 25 completed or ongoing clinical trials as of March 31, 
2009 with a dose range between 0.3 mg/kg and 20 mg/kg and various 
combinations. Most experience with ipilimumab exists at the 3 mg/kg 
and 10 mg/kg dose levels. Patients who received ipilimumab at 
3 mg/kg were treated in clinical studies conducted early in the 
development program and received either a single or multiple 
injections. Intra-patient dose escalation indicated that patients who 
were unresponsive at the 3 mg/kg dose level may have responded to 
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ipilimumab, the ongoing clinical program investigating ipilimumab in 
metastatic melanoma utilizes the 10 mg/kg dose level. 
The overall summary of safety for the 2901 patients treated with 
ipilimumab in the completed or ongoing clinical trials and the subset of 
658 patients treated at the 10 mg/kg dose level is presented in Table 
1. 
Table 1: 
Ipilimumab - Overall Summary of Safety 
 
Number of Subjects (%) 
 
Ipilimumab 0.3 - 20 mg/kg 
N = 2901 
Ipilimumab 10 mg/kg 
N = 658 
Any Drug-related AE 
2357 (81.2) 
561 (85.3) 
 
Grade 1  
699 (24.1) 
158 (24.0) 
 
Grade 2  
889 (30.6) 
198 (30.1) 
 
Grade 3  
617 (21.3) 
163 (24.8) 
 
Grade 4 
127 (4.4) 
38 (5.8) 
 
Grade 5 
20 (0.7) 
4 (0.6) 
Any Serious Adverse Events 
1258 (43.4) 
310 (47.1) 
 
Grade 3 - 4 
806 (27.8) 
179 (27.2) 
Any Drug-related Serious Adverse Events
595 (20.5) 
179 (27.2) 
 
Grade 3 - 4 
469 (16.2) 
140 (21.3) 
1.5.4.1 
Details of Drug-Related Adverse Events 
Treatment-emergent adverse events (AEs) considered by 
the investigator to be related to study drug were reported 
for 81.2% of all treated subjects and 85.3% of subjects 
treated with ipilimumab at 10 mg/kg. 
Among all treated subjects, the most frequently reported 
treatment-related AEs of any grade included fatigue 
(27.8%), diarrhea (27.5%), nausea (23.4%), rash (21.8%), 
pruritus (19.9%), pyrexia (11.9%), and vomiting (11.7%).  
Similarly, among subjects treated with ipilimumab at 10 
mg/kg, the most frequently reported treatment-related AEs 
of any grade included diarrhea (38.1%), fatigue (30.5%), 
rash (34.5%), pruritus (29.8%), nausea (17.6%), pyrexia 
(12.3%), vomiting (10.9%). and colitis (10.2%). 
1.5.4.2 
Drug-related Serious Adverse Events (SAEs) 
Among all 2901 treated subjects, SAEs considered 
possibly, probably, or definitely related to study drug were 
reported for 20.5% of subjects. Drug-related SAEs 
reported in at least 1% of the 2901 subjects included 
diarrhea (5.8%), colitis (4.7%), ALT increased (2.3%), AST 
increased (2.2%), pyrexia (1.6%), and vomiting (1.3%). 

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Among the 658 subjects who received ipilimumab at 10 
mg/kg, SAEs considered possibly, probably, or definitely 
related to study drug were reported for 27.2% of subjects. 
Drug-related SAEs reported in at least 1% of the 658 
subjects treated at 10 mg/kg included diarrhea (8.5%), 
colitis (7.0%), vomiting (2.1%), AST increased (2.1%), ALT 
increased (2.0%), autoimmune hepatitis (2.0%), pyrexia 
(1.8%), hypopituitarism (1.7%), dehydration (1.7%), 
nausea (1.2%), and abdominal pain (1.1%). 
1.5.4.3 
Immune-Related Adverse Events (irAEs) with Ipilimumab 
Many of the adverse events considered related to 
ipilimumab may be immune in nature and presumably a 
consequence of the intrinsic biological activity of 
ipilimumab. An irAE is defined as any adverse event 
associated with drug exposure and consistent with an 
immune-mediated event. Disease progression, infections 
and other etiologic causes are ruled out or deemed 
unlikely as contributing to the event. Supportive data, such 
as autoimmune serology tests or biopsies, are helpful but 
not necessary to deem an event an irAE. Events of unclear 
etiology which were plausibly “immune-mediated” have 
been conservatively categorized as irAEs even if serologic 
or histopathology data are absent. These irAEs likely 
reflect a loss of tolerance to some self antigens or an 
unchecked immune response to gut or skin flora. Some 
breakthrough of immunity may be inseparably linked to the 
clinical antitumor activity of ipilimumab. 
Immune-related AEs predominately involve the GI tract, 
endocrine glands, liver or skin. Among all 2901 treated 
subjects, 59.6% (1729/2901) of subjects reported any irAE 
and 15.2% (441/2901) of subjects reported serious irAEs. 
Among subjects who received ipilimumab at 10 mg/kg, 
21.9% (144/658) of subjects reported serious irAEs. Table 
2 summarizes the incidence of serious irAEs among all 
treated subjects and subjects who received ipilimumab 10 
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Table 2: 
Serious Immune-related Adverse Events Reported for at Least 
2% of Subjects in any Event Category 
 
 
Number of Subjects (%) 
 
 
Ipilimumab 0.3 - 20 mg/kg 
Ipilimumab 10 mg/kg 
 
 
N = 2901 
N = 658 
 
irAEsa 
 
 
 
 
Any 
441 (15.2) 
144 (21.9) 
 
 
Grade 3 
298 (10.3) 
87 (13.2) 
 
 
Grade 4 
59 (2.0) 
25 (3.8) 
 
GI irAEa 
 
 
 
 
Any 
236 (8.1) 
85 (12.9) 
 
 
Grade 3 
166 (5.7) 
58 (8.8) 
 
 
Grade 4 
17 (0.6) 
10 (1.5) 
 
Liver irAEa 
 
 
 
 
Any 
109 (3.8) 
33 (5.0) 
 
 
Grade 3 
72 (2.5) 
18 (2.7) 
 
 
Grade 4 
32 (1.1) 
13 (2.0) 
 
Endocrine irAEa 
 
 
 
 
Any 
61 (2.1) 
21 (3.2) 
 
 
Grade 3 
44 (1.5) 
12 (1.8) 
 
 
Grade 4 
3 (0.1) 
1 (0.2) 
a Based on treatment-related adverse events retrieved from the clinical database using pre-
defined MedDRA terms that were considered potential irAEs. 
With few exceptions, irAEs were clinically manageable and 
reversible with supportive care or corticosteroids. 
Corticosteroid treatment did not adversely affect antitumor 
responses in those subjects who had both an irAE 
requiring steroid therapy and an objective tumor response. 
Systemic corticosteroids do not appear adversely 
associated with ipilimumab-induced clinical response when 
used to manage irAEs in patients with advanced 
melanoma. Similar results were observed regardless of 
whether mWHO or the novel irRC criteria were used. 
Steroids can be used promptly to manage severe irAEs 
and minimize the risk for serious complications. (42) 
In the setting where subjects were enrolled to receive 
ipilimumab every 3 weeks dosing until progression, irAEs 
could be reported at any time, with colitis and rash 
reported most often during the early doses and 
hypophysitis reported with later doses. 
Gastrointestinal irAEs 
The most common Grade 3 or greater irAE involved the 
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hematochezia. Diarrhea resulting from treatment with 
ipilimumab ranged from mild to severe and was life-
threatening in some cases. Some cases of diarrhea began 
as mild and became very severe. Among subjects who 
received ipilimumab at 10 mg/kg, GI irAEs of any grade 
were reported for 40.0% (263/658) of subjects, and Grade 
3 - 4 GI irAEs were reported for 12.6% (83/658) of 
subjects. Serious GI irAEs, mostly involving diarrhea or 
colitis, were reported in 12.9% (85/658) of subjects treated 
with ipilimumab at 10 mg/kg. 
Inflammatory Hepatotoxicity 
Immune-related hepatic dysfunction, including hepatitis or 
abnormal liver function tests (LFT) attributed to ipilimumab 
therapy, has been reported. Subjects may develop 
elevations in LFTs in the absence of clinical symptoms. 
Inflammatory hepatotoxicity includes non-infectious 
hepatitis (eg, autoimmune hepatitis). Among subjects who 
received ipilimumab at 10 mg/kg, inflammatory 
hepatotoxicity of any grade was reported for 9.0% (59/658) 
of subjects, and Grade 3 - 4 inflammatory hepatotoxicity 
was reported for 6.4% (42/658). Serious inflammatory 
hepatotoxicity has been reported in 5.0% (33/658) of 
subjects who received ipilimumab at 10 mg/kg. 
Inflammatory hepatotoxicity is usually reversible when 
immediately treated with high-dose steroids, if applicable, 
with or without additional immunosuppressants as 
recommended in the hepatotoxicity management algorithm 
presented as an appendix in the IB. 
Hypophysitis/Hypopituitarism and Other Endocrine 
Conditions 
Hypophysitis/hypopituitarism, clinically manifested by 
fatigue, has been reported. Most subjects with 
hypopituitarism presented with nonspecific complaints 
such as fatigue, confusion, visual disturbance, or 
impotence. Some had headache as the predominant 
presentation. The majority of subjects with hypopituitarism 
demonstrated enlarged pituitary glands based on brain 
magnetic resonance imaging (MRI). Low 
adrenocorticotropic hormone (ACTH) and cortisol were the 
most common biochemical abnormality reported; low 
thyroid stimulating hormone (TSH), testosterone, or 
prolactin was also reported in some subjects. (43) 
Hypophysitis/hypopituitarism was controlled with 
appropriate hormone-replacement therapy and may be 
dose related. Among subjects who received ipilimumab at 
10 mg/kg, endocrinopathy of any grade was reported for 
7.6% (50/658) of subjects, and Grade 3-4 endocrinopathy 
was reported for 2.4% (16/658) of subjects. Serious drug-
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hypophysitis/hypopituitarism, was reported in 3.2% 
(21/658) of subjects who received ipilimumab at 10 mg/kg. 
The first onset of endocrine irAEs typically occurred 
between weeks 6 and 12 of treatment. Endocrine events 
were generally manageable with hormone-replacement 
therapy, and the majority of subjects were not weaned 
from steroids. 
Rash and Other Skin Conditions 
Rash was one of the most common irAEs, and most cases 
were Grade 1 or 2 in intensity; pruritus has also been 
reported. (44) When biopsied, pleomorphic infiltrates were 
noted in the skin. Among subject who received ipilimumab 
at 10 mg/kg, skin irAEs of any grade were reported for 
52.9% (348/658) of subjects, and Grade 3 - 4 skin irAEs 
were reported for 2.9% (19/658) of subjects. Serious skin 
irAEs were reported in < 1% (4/658) of subjects who 
received ipilimumab at 10 mg/kg. Skin irAEs were 
generally reversible.  
Other reported irAEs 
Ocular inflammation, manifested as Grade 2 or Grade 3 
episcleritis or uveitis, was associated with concomitant 
diarrhea in a few subjects and occasionally occurred in the 
absence of clinically apparent GI symptoms. (45) Serious 
ocular inflammation was reported in 1 of 658 (0.2%) 
subjects who received ipilimumab at 10 mg/kg (8 [0.3%] of 
2901 subjects program-wide reported serious occular 
inflammation). Preliminary analysis (based on the manual 
extraction of the SAE data from the internal safety 
database) indicated that the median time to event onset 
was approximately 61 days (range: 14 - 114 days). Based 
on the available data with known outcome, most of the 
subjects recovered or improved with or without 
corticosteroid therapy with a median duration of 
approximately 6 days (range: 5 - 23 days). 
Other presumed irAEs reported include, but were not 
limited to, arthritis/arthralgias, pneumonitis, pancreatitis, 
autoimmune (aseptic) meningitis, autoimmune nephritis, 
pure red cell aplasia, noninfective myocarditis, occular 
inflammation, Guillain-Barre syndrome (GBS), myasthenia 
gravis, and neuropathy (eg, motor neuropathy, neuritis), of 
which were individually reported for < 1% of subjects.  
Additionally, as of February 2006, there has been 
observation from a National Cancer Institute (NCI) study of 
bowel wall perforation in some patients who were 
administered a high-dose IL-2 following treatment with 
ipilimumab. Of the 22 patients administered high-dose IL-2, 
three patients experienced bowel wall perforations. This is 
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treatment alone. All three patients had metastatic 
melanoma and had previously received their last dose of 
ipilimumab > 77 days before the first dose of IL-2. Two of 
the patients had clinically significant ipilimumab-related 
diarrhea or colitis and the symptoms had completely 
resolved prior to IL-2 administration. One patient did not 
experience ipilimumab-related diarrhea. It is unknown 
whether this observation represents a true association or is 
mechanistically unrelated to prior ipilimumab exposure. 
1.5.4.4 
Drug-related Deaths 
A 32% all-cause mortality frequency has been reported for 
approximately 3800 subjects treated in the ipilimumab 
program who had data available in the BMS internal safety 
database as of June 30, 2009. Study-drug related deaths 
based on the investigator’s assessment were reported in 
35 subjects. Therefore, the reporting rate of drug-related 
deaths from the program-wide studies remained stable at 
approximately 1% (35/3800; Table 5.6.5 of the IDB), 
compared with the previous reporting period (28/3000, 
[1%]). Eleven of the 35 study-drug-related deaths were 
reported from subjects known to have received ipilimumab 
at 10 mg/kg multiple doses. While a causal role of 
ipilimumab in these 35 deaths could not be ruled out, 
confounding factors could be identified in most of these 
cases. Study-drug-related deaths reported in studies 
testing the 10 mg/kg dose are summarized below. For 
details on all drug-related deaths, refer to the current 
version of the Ipilimumab Investigator Brochure. 
Study CA184008 (10 mg/kg mono ipilimumab; melanoma) 
• 
1 multiorgan failure (with significant liver metastasis as 
possible cause of death)  
• 
1 hypovolemic shock (with possible sepsis and 
evidence of  hypopituitarism) 
• 
1 heart failure secondary to renal failure and disease 
progression (acute glomerulonephritis) 
• 
1 liver dysfunction (not treated according to the 
management algorithm) 
• 
1 acute myeloid leukemia (one month after one dose 
with ipilimumab) 
Study CA184024 (Blinded dacarbazine ± 10 mg/kg 
ipilimumab; melanoma) 
• 
1 fatal GI bleeding without evidence of colitis  
• 
1 systemic inflammatory response syndrome (with 
cause of death listed as pneumonia/unlikely related, 
septic shock and metastatic melanoma) 

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CA184004 (one each for 3 & 10 mg/kg ipilimumab; 
melanoma) 
• 
2 bowel perforation 
CA184041 (Blinded paclitaxel/carboplatin ± 10 mg/kg 
ipilimumab; lung cancer) 
• 
1 toxic epidermal necrolysis; concomitantly with 
pantoprazole and paclitaxel 
• 
1 erythema multiforme (cause of death hypoglycemia) 
• 
1 Guillain-Barre Syndrome (cause of death was 
aspiration pneumonia) 
CA184-042 (10 mg/kg, brain mets) 
• 
1 GI perforation 
CA184045 (10 mg/kg, compassionate use) 
• 
1 multiorgan failure  
• 
1 sepsis  
• 
1 ARDS (w/ extensive disease in lung and evidence of 
melanoma infiltration in alveolar spaces) 
• 
1 GI perforation 
1.5.4.5 
Safety of 10 mg/kg Multiple Doses 
Based on a review of the program-wide SAE data as 
previously reported, evidence had suggested that 
ipilimumab-associated irAEs were dose dependent in 
frequency, and higher irAE rates had been observed at 
10 mg/kg than at lower doses of ipilimumab. Subsequently, 
this dose-dependent effect was further demonstrated in 
CA184-022 in which three dose levels of ipilimumab were 
studied, including 0.3 vs 3 vs 10 mg/kg. Table 3 
summarizes the overall irAE frequencies by dose from 
CA184-022 based on safety data from the locked clinical 
database. 
Qualitatively, the safety profile of ipilimumab at 10 mg/kg 
remains consistent with the low-dose safety profile in that 
most of the drug-related SAEs are characteristic of 
immune-related toxicity, and most of the irAEs are reported 
in the GI, hepatic, and endocrine systems. However, the 
data presented in Table 3 suggest that the frequency of 
irAEs in association with 10 mg/kg of ipilimumab at multiple 
doses is higher compared with the irAE frequency reported 
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Table 3. 
Summary of Immune-Related Adverse Events (irAEs) by 
Treatment Groups - Treated Subjects (CA184-022) 
 
Number of Subjects (%) 
 
Ipilimumab 
 
0.3 mg/kg 
(N=72) 
3 mg/kg 
(N=71) 
10 mg/kg 
(N=71) 
Overall irAEs 
 Grade 3-4 
26.4 
0 
64.8 
7.0 
70.4 
25.4 
GI irAEs 
 Grade 3-4 
16.7 
0 
32.4 
2.8 
39.4 
15.5 
Hepatic irAEs 
 Grade 3-4 
0 
0 
0 
0 
2.8 
2.8 
Endocrine irAEs 
 Grade 3-4 
0 
0 
5.6 
2.8 
4.2 
1.4 
Skin irAEs 
 Grade 3-4 
12.5 
0 
45.1 
1.4 
46.5 
4.2 
1.5.4.6 
Clinical safety and tolerability data with ipilimumab at 10 
mg/kg from 4 phase II studies 
For the purpose of this study’s concept submission, the 
BMS ipilimumab team has provided the following safety 
report that summarizes data from 4 Phase II studies 
utilizing the 10 mg/kg dose. 
1.5.4.6.1 
Summary of safety and tolerability data 
(N=325) 
• 
Drug-related adverse events (AEs) in 
84.6% of patients 
• 
32.6% were Grade 3/4/5 
• 
Immune-related AEs (irAEs; 
inflammatory in nature) in 72.3% of 
patients 
• 
25.2% were Grade 3/4 and occurred 
in 4 main types 
• 
Gastrointestinal: e.g., colitis, 
diarrhea (12.3%) 
• 
Liver: e.g., transaminase 
elevation (6.8%) 
• 
Skin: e.g., rash pruritis (2.8 %) 
• 
Endocrine: e.g., hypophysitis, 
thyroiditis (2.5%) 
• 
Complications: bowel perforations, liver 
failure (~1%) 
• 
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• 
4 immune-related: multi-organ 
failure, abnormal hepatic function, 
acute glomerulonephritis, and 
hypovolemic shock 
• 
1 not immune-related: acute myeloid 
leukemia 
• 
irAE management algorithms are 
effective in resolving events and 
reducing risk of complications 
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). 
- 
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). 
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1.5.4.6.2 
Benefit: Risk Based on Dose. Study CA184-
022 (Table 4) 
Table 4: Benefit: Risk Based on Dose as reported in Study CA184-022 
 
CA184022 (N=217) 
10 mg/kg 
(N=72) 
3 mg/kg 
(N=72) 
0.3 mg/kg 
(N=73) 
BORR 
(95% CI) 
11.1% 
(4.9, 20.7) 
4.2% 
(0.9, 11.7) 
0 
Overall Survival, median months 
11.0 
(6.9, NR) 
8.7 
(6.9, 12.1) 
8.6 
(7.4, 13.0) 
Overall irAE rate 
70% 
65% 
26% 
High-grade irAE rate 
25% 
7% 
0 
Drug-related Deaths (<70 days) 
0 
0 
0 
1.5.4.6.3 
Time to onset of Grade 2-5 irAEs and time 
to resolution of Grade 2-4 irAEs (10 mg/kg); 
(Lebbé, C et al. Perspectives in Melanoma 
XII 2008; Abstract O-015) (Table 5): 
Table 5: Time to onset of Grade 2-5 irAEs and time to resolution of Grade 2-4 irAEs 
(10mg/kg) 
 
Time to onset of grade 2-5 irAEs 
Time to Resolution of 
Grade 2-4 irAEs 
GI 
Patients: 76 
Median: 6.6 weeks 
95% CI: 5.1–8.0 
Median: 2.29 weeks 
Liver 
Patients: 23 
Median: 6.7 weeks 
95% CI: 6.1–9.3 
Median: 4.00 weeks 
Endocrine  
Patients: 16 
Median: 9.2 
95% CI: 6.7–11.1 
Median: 20.1 weeks 
Skin 
Patients: 61 
Median: 3.6 
95% CI: 3.1–4.1 
Median: 6.14 weeks 
1.5.4.7 
Safety of 3 mg/kg as compared to 10 mg/kg multiple doses 
Based on a review of the program-wide SAE data as 
previously reported, evidence had suggested that 
ipilimumab-associated irAEs were dose dependent, and 
higher grade irAE rates had been observed at 10 mg/kg 
than at lower doses of ipilimumab, although overall 
frequency appeared similar. Subsequently, this dose-
dependent effect was further demonstrated in CA184-022 
as noted under Section 1.5.4.6.2 in which three dose 
levels of ipilimumab were studied, including 0.3 vs 3 vs 
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10 mg/kg.{38} Table 4 in Section 1.5.4.6.2 summarizes the 
overall irAE frequencies by dose from CA184-022 based 
on safety data from the locked clinical database. 
Qualitatively, the safety profile of ipilimumab at 10 mg/kg 
remains consistent with the low-dose safety profile in that 
most of the drug-related SAEs are characteristic of 
immune-related toxicity, and most of the irAEs are reported 
in the GI, hepatic, and endocrine systems. However, the 
data presented in table 4 suggest that the frequency of 
irAEs in association with 10 mg/kg of ipilimumab at multiple 
doses is higher compared with the irAE frequency reported 
for lower doses. 
The most common adverse reactions (≥5%) in patients 
who received ipilimumab at 3 mg/kg in the phase III pivotal 
trial MDX010-20 testing ipilimumab at 3 mg/kg were 
fatigue, diarrhea, pruritus, rash, and colitis. Table 6 
presents selected adverse reactions from the MDX010-20 
phase III trial, which occurred in at least 5% of patients in 
the ipilimumab-containing arms and with at least 5% 
increased incidence over the control gp100 arm for all-
grade events and at least 1% incidence over the control 
group for Grade 3–5 events. Table 7 presents the per-
patient incidence of severe, life-threatening, or fatal 
immune-mediated adverse reactions from MDX010-20. 
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 6: 
Selected Adverse Reactions in MDX010-20 
 
Percentage (%) of Patientsa 
 
Ipilimumab 3mg/kg 
n = 131 
Ipilimumab 3mg/kg  
+ gp100  
n = 380 
gp100 
n = 132 
System Organ 
Class/Preferred Term 
Any Grade Grade3-5 Any Grade 
Grade3-5 Any Grade Grade3-5 
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 
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Table 7 presents the per-patient incidence of severe, life-
threatening, or fatal immune-mediated adverse reactions 
from MDX010-20. 
Table 7: 
Severe to Fatal Immune-mediated Adverse Reactions in 
MDX010-20 
 
Percentage (%) of Patients  
 
Ipilimumab 3 mg/kg 
n = 131 
Ipilimumab 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 phase III pivotal trial evaluated the addition of 
10 mg/kg ipilimumab to dacarbazine in patients with 
previously untreated, metastatic melanoma. A total of 502 
patients were randomized to receive up to 8 cycles of 
dacarbazine 850 mg/m2 q3w, with either ipilimumab 10 mg 
or placebo for cycles 1-4 and as maintenance after 
completion of chemotherapy. Ipilimumab AEs were 
consistent with previous studies and predominately 
affected skin, I tract, liver,  and the endocrine system. 
Events were managed with established guidelines and 
were generally responsive to dose 
interruption/discontinuation, corticosteroids and/or other 
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with the mechanism of action of ipilimumab, regardless of 
attribution by the investigator) are shown in Table 8. 
Table 8: 
CA184024 Select Adverse Events 
 
Ipilimumab + DTIC 
n = 247 
Placebo + DTIC 
n = 251 
Total  
Grade 3 - 4 
Total 
Grade 3 - 4 
% Patients 
Dermatologic 
29.6 
2.0 
8.8 
0 
 
Pruritis 
24.7 
1.2 
6.8 
0 
 
Rash 
 
 
 
 
Gastrointestinal (GI) 
36.4 
4.0 
24.7 
0 
 
Diarrhea 
4.5 
2.0 
0.4 
0 
 
Colitis 
0 
0 
0 
0 
 
GI perforation 
 
 
 
 
Hepatic 
33.2 
21.9 
5.6 
0.8 
 
Increased ALT 
29.1 
18.2 
5.6 
1.2 
 
Increased AST 
 
 
 
 
Endocrine 
1.6 
0 
0.4 
0 
 
Hypothyroidism 
0.8 
0 
0 
0 
 
Autoimmune thyroiditis 
0.4 
0 
0.4 
0 
 
Hyperthyroidism 
0 
0 
0 
0 
 
Hypophysitisa 
 
 
 
 
a1 (0.4%) hypophysitis was reported on Day 364. 
1.5.4.8 
A Phase I Trial in Pediatric Patients with Advanced Solid 
Tumors (NCI 7458) 
A pediatric phase I, dose escalation study examined the 
safety, tolerability, pharmacokinetics, and immunogenicity 
of ipilimumab administered to patients less than 21 years 
old with recurrent or progressive solid tumors. Ipilimumab 
was administered at 1, 3, 5, and 10mg/kg IV in a standard 
3 + 3 design with 4 doses of induction therapy every 3 
weeks followed by maintenance every 3 months until 
disease progression or unacceptable toxicity. Twenty six 
patients (9 with melanoma, 7 osteosarcoma, 7 soft tissue 
sarcomas, 1 neuroblastoma, 1 renal cell carcinoma and 1 
transitional cell carcinoma) were enrolled with 24 
considered evaluable for toxicity. The following table 
summarizes the number of doses administered, the dose 
limiting toxicities (DLT) at each dose level, and the pattern 
and percentage of irAEs induced by ipilimumab. At the 
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highest dose level of 10mg/kg, two of three patients under 
the age of 12 developed a DLT (grade 3 colitis and 
concurrent norovirus in one patient and grade 3 
transaminitis in a second patient). One of seven patients 
between the ages of 12 and 21 developed a DLT in the 
form of a pleural effusion / pneumonitis in the setting of a 
progressive pleural based malignancy. 
1.5.5 
Clinical Efficacy of Ipilimumab 
Ipilimumab has been administered to over 1654 patients with different 
cancers in 22 completed or ongoing clinical trials as of March 31, 
2007 with a dose range between 0.1 mg/kg and 20 mg/kg. Treatment 
 
 
 

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with ipilimumab has demonstrated clinically important and durable 
tumor responses in several malignancies, including melanoma, the 
most extensively studied tumor type with ipilimumab. Ipilimumab is 
active in patients with advanced stage melanoma and has 
demonstrated important disease-control rates. The objective 
responses observed with ipilimumab are durable and have occurred 
across a spectrum of doses and schedules. In a study of 217 patients 
with unresectable stage III/IV melanoma treated with ipilimumab (0.3, 
3, 10 mg/kg every 3 weeks X 4; maintenance at week 24 assigned 
blinded dose; patients with PD could cross over to 10 mg/kg dose), 
the objective response rate was 15.3%. Disease control rates (DCR: 
CR+PR+SD) at 0.3, 3, 10 mg/kg dose levels were 13.7%, 26.4%, and 
29.2% respectively (38). A Phase II study of patients with 
unresectable stage III or stage IV melanoma tested ipilimumab at 10 
mg/kg every 3 weeks x 4 induction dosing in combination with placebo 
(Group A) or an oral steroid (budesonide) with minimal systemic 
exposure used to treat inflammatory bowel disease (Group B). For the 
115 patients treated, there was no clinically meaningful difference in 
the best overall response rate (BORR), disease control rate (DCR), or 
safety events. BORRs were 15.8% and 12.1%, and DCR were 35.1% 
and 31% in Groups A and B, respectively (39). 
Based on a preliminary analysis from a BMS study (MDX010-15) 
involving ipilimumab 10 mg/kg multiple doses, 34.8% of patients 
(N=23) were progression free at 6 months and about 17.4% were 
progression free at 1 year. In comparison, in another BMS study 
(MDX010-08) involving ipilimumab 3 mg/kg multiple doses, 10.8% 
patients (N=37) had progression-free survival at 6 months and 8.4% 
at 1 year. 
Two phase III pivotal trials with ipilimumab in advanced inoperable 
AJCC stage III and stage IV melanoma have been reported.  One trial 
(MDX010-20) tested the combination of ipilimumab with gp100 
vaccine versus gp100 vaccine alone and versus ipilimumab 
monotherapy in the second line setting. The other trial (CA184024) is 
a first line comparison study of combination therapy of ipilimumab and 
dacarbazine versus dacarbazine and placebo.  
The ipilimumab-Gp100 study (MDX010-20) randomized 676 
pretreated patients. (Hodi et. al. NEJM 2010) The vaccine arms meant 
this second-line trial was restricted to HLA-A2 patients, and 
ipilimumab induction therapy was given at 3 mg/kg every 3 weeks for 
four doses without maintenance, with responding patients eligible for 
re-induction with ipilimumab if they relapsed. The best objective 
response rate was 5.7% (ipilimumab + gp100), 10.9% (ipilimumab + 
placebo), 1.5% (gp100 + placebo). The disease control rate (DCR) 
was 20.1 % (ipilimumab + gp100), 28.5% (ipilimumab + placebo), 
11% (gp100 + placebo). Median OS increased from 6.4 months to 
10.0 months with the addition of ipilimumab to gp100 vaccine (HR 
0.68, p < 0.0001) and long-term survival rates improved. DCR 
improved from 11.0% to 20.1% (p = 0.02). The 1year and 2-year 
survival rates were 44% (ipilimumab + gp100), 46% (ipilimumab + 
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placebo), 25% (ipilimumab + placebo) and 22% (ipilimumab + gp100), 
24% (ipilimumab + placebo), 14% (gp100 + placebo) respectively. 
Approximately 20% in the group treated with ipilimumab alone were 
alive at 4 years (46). Based on these results the FDA has granted 
approval for ipilimumab in March 2011 for the treatment of 
unresectable or metastatic melanoma. The recommended dose and 
schedule for ipilimumab is 3 mg/kg as an intravenous infusion every 3 
weeks for a total of four doses.  
CA184024 evaluated the addition of 10 mg/kg ipilimumab to 
dacarbazine in patients with previously untreated, metastatic 
melanoma. (Robert et. al. NEJM. 2011) 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.  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). 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. 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). 
1.5.5.1 
Long-term survival benefit from ipilimumab 
In addition to the results of the phase III trials, long-term 
survival benefit from ipilimumab in patients with advanced 
melanoma has been updated by O’Day et al. in the 2009 
ASCO Annual Meeting (40). Data from 3 studies were 
updated: 
• 
Study CA184-008, a single arm study of ipilimumab 10 
mg/kg 
• 
Study CA184-022, a randomized dose-ranging study of 
ipilimumab 0.3, 3 or 10 mg/kg 
• 
Study CA184-007, a randomized placebo-controlled 
study of the effect of budesonide on gastrointestinal 
immune-related adverse events in patients receiving 10 
mg/kg 
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Ipilimumab was given every 3 weeks X4 (induction); 
eligible patients could continue to receive maintenance 
ipilimumab every 12 weeks from week 24 in all studies. 
Median follow up was from 10.1 to 16.3 months, with a 
range reaching up to 37.5 months:  
• 
12-month survival rates were >47% 
• 
18-month survival rates were >34% 
• 
24-month survival rates were ≥30% 
• 
For previously treated patients, 24-months survival 
rates ranged from 24% to 33% 
• 
In all 3 studies, a meaningful proportion of patients 
continued to survive beyond the updated follow-up 
period 
• 
Long-term survivors included patients with progressive 
disease according to the modified WHO criteria 
Median survival times (months) were as follows: 
• 
CA184-008 (N=155): 10.2, 95% CI (7.6-16.3) 
• 
CA184-022 (N=217 with 214 treated; 10 mg/kg n=72): 
11.4, 95% CI(6.9-16.1) 
• 
CA184-007 (N=115) 
o Ipilimumab + placebo (n=57): 19.3, 95% CI (12.0-
Not Reached) 
o Ipilimumab + budesonide (n=58): 17.7, 95% CI 
(6.8-Not Reached) 
Overall, these data demonstrate durable clinical antitumor 
activity of ipilimumab in advanced unresectable melanoma 
across a spectrum of doses and schedules. Other studies 
have tested combinations of ipilimumab with vaccines, 
interleukin-2, and chemotherapy, with relative safety and 
consistent clinical activity. 
1.6 
Study Rationale 
E1609 targets a patient population that is at a high and unacceptable risk of 
recurrence and death after standard surgical management. 
Patients with resectable high-risk deep cutaneous melanoma, patients with 
lymph node involvement by melanoma, patients with gross extra-nodal extension 
of disease, satellites, and/or in-transit lesions, as well as patients with completely 
resected stage IV disease, have the highest recurrence risk and the poorest 
disease-free and overall survival rates.  
The quality of the host immune response in the earlier adjuvant setting 
supports a higher likelihood of clinical benefit from immunologic 
interventions 
The quality of the host immune response has been shown to differ between 
patients with earlier micrometastatic and more advanced measurable disease 
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settings. While T helper type 1 (Th1)-type CD4+ antitumor T-cell function appears 
critical to the induction and maintenance of antitumor cytotoxic T-lymphocyte 
(CTL) responses in vivo, Th2- or Th3/Tr-type CD4+ T-cell responses may subvert 
Th1-type cell mediated immunity providing a microenvironment conducive to 
disease progression. Patients with active melanoma or renal cell carcinoma have 
been shown to display strong tumor antigen specific Th2-type polarization. By 
contrast, normal donors and patients who are disease free following therapy 
demonstrate either mixed Th1-/Th2-type or strongly polarized Th1-type 
responses to the same epitopes (8,9). Therefore, factors of host immune 
tolerance appear to impede advanced disease therapy, and these may be less 
pronounced in the high-risk operable setting, where the host may be more 
susceptible to immunological interventions. This observation is supported by the 
our clinical experience with HDI, which reduces relapse risk by up to 33% in the 
adjuvant setting, but induces response in 16% of patients with advanced 
inoperable disease. This provides support for the evaluation of clinically active 
immunological agents such as anti-CTLA4 blocking antibodies in the earlier 
adjuvant disease setting. Taken together with the demonstrable clinical activity of 
ipilimumab in advanced unresectable melanoma, this also provides support for 
our current proposal of adjuvant ipilimumab versus HDI for high-risk resected 
melanoma patients. 
HDI is the optimal control arm for the adjuvant study of ipilimumab in 
patients with high-risk resected melanoma 
Three reported national studies have evaluated the benefit of high dose 
interferon-α2b (HDI) as adjuvant therapy for patients with high-risk stage IIB and 
III melanoma. The first and third of these studies demonstrated significant 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, did not show evidence of an impact upon survival, but was 
associated with systematic crossover of patients from the observation-assigned 
arm to treatment at nodal relapse with HDI. In addition, there is wide agreement 
and evidence of a significant improvement of relapse-free survival with HDI that 
is supported by all 3 US Cooperative Group randomized trials (E1684, E1690, 
E1694) as well as data from multiple lower-dose IFN trials that have also been 
summarized in 2 meta-analyses of adjuvant IFN-a studies by Wheatley and Ives 
(14,15). The larger individual patient data meta-analysis of 13 randomized trials 
has also shown a significant impact of interferon-a up on overall survival. In 
addition, no other agent has ever been demonstrated to provide similar relapse 
free or survival benefits for this patient population.  
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). Unlike 
recently presented data on peg-IFN or old studies utilizing low dose IFN 
regimens, the benefit from HDI has been shown in both the lower and higher 
tumor burden stage III risk groups. In fact the largest accrual to the pivotal HDI 
trial occurred in the higher-risk groups with clinically apparent nodal metastasis at 
presentation or at recurrence. 
For stage IV melanoma, IFN-α was the first recombinant cytokine to be 
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Phase I-II studies yielded overall response rates of about 16% and about one 
third achieved complete and durable responses. Responses were observed as 
late as 6 months from initiation of therapy, and up to one third of the responses 
were durable (19-22). The use of IFN-α for adjuvant therapy of patients with 
operable melanoma is based on the hypothesis that micrometastatic disease is 
the source of future relapse, and is less established in its induction of host 
tolerance of tumor.  While patients with advanced inoperable metastatic 
melanoma display immunological tolerance, the adjuvant setting may be more 
susceptible to interventions designed to induceTh1 host-effector mechanisms to 
eradicate micrometastases. In addition, no other agent has ever been 
demonstrated to provide similar relapse free or survival benefit for the high-risk 
adjuvant patient population. Therefore, HDI continues to be the only option 
available for patients with high-risk surgically resected melanoma outside of a 
clinical trial. 
Durable clinical benefits have been demonstrated in the advanced 
inoperable melanoma setting with ipilimumab, and with relative safety 
Ipilimumab inhibits CTLA4, prolonging anti-tumor immune responses and leading 
to durable anti-tumor effects. Treatment with ipilimumab has demonstrated 
clinically important and durable tumor responses and disease control rates in 
patients with unresectable advanced melanoma. Durable objective responses 
have been reported across a spectrum of doses and schedules, with relative 
safety in this patient population. Toxicity associated with ipilimumab has not been 
excessive, and we plan a toxicity-specific, guidelines-driven management of 
treatment related toxicities based on the vast experience built over the past few 
years with this new class of agents. 
Rationale for testing the 3 mg/kg ipilimumab dose level compared to HDI in 
E1609 in addition to the testing of 10 mg/kg ipilimumab dose level 
compared to HDI 
The original design of intergroup E1609 was meant to evaluate the 
safety/efficacy of the 10 mg/kg dose of ipilimumab versus high-dose interferon. 
This trial was originally designed prior to the report of positive results of 3 mg/kg 
of ipilimumab in metastatic melanoma, MDX010-20, published in 2010, which 
resulted in the FDA approval of 3 mg/kg of ipilimumab in treatment of 
unresectable and metastatic melanoma. (46) 
Some data suggest a dose dependant effect of ipilimumab from 0.3 mg/kg to 10 
mg/kg (CA184-022, Section 1.5.4.6.2, Section 1.5.4.7), 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.  However, the magnitude of survival benefit for ipilimumab 10 mg/kg 
given with dacarbazine in untreated melanoma (CA 184-020, Section 1.5.5) 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; CA 184-020: HR 0.68 (p < 
0.0001), median OS 6.4 vs. 10.0 months). Given that the risk/benefit ratio for 
therapies differ in the adjuvant setting compared to the metastatic disease 
setting, 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 adjuvant setting of 
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melanoma.  This is supported by our long experience with IFNα, where despite 
multiple trials that have demonstrated a reduction in relapse/mortality risk, 
patients may still refuse treatment.  The following points are relevant to the 
consideration of adding a third arm of treatment to E1609 testing 3mg/kg of 
ipilimumab at this time: 
1. Immunologically, one hypothesis that supports the need to evaluate different 
doses of ipilimumab in the adjuvant setting is the hypothesis that melanoma 
patients in the adjuvant setting would mount a qualitatively superior (Th1 
polarized) and quantitatively greater immune response than patients with 
metastatic disease and a compromised host immune response, when given 
the same dose of ipilimumab or other immunotherapeutic agents.(8,9) This 
has been demonstrated with HDI in melanoma both clinically and 
immunologically.(10,11,12,48,7) Therefore, a lower dose of ipilimumab could 
theoretically have a more optimal safety/efficacy ratio in patients in the 
adjuvant setting as compared to those with metastatic melanoma. 
2. The CA184-022 trial in advanced inoperable melanoma patients suggested a 
dose-dependant 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). 
3. 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. 
4. Given that the frequency of adverse events for 10 mg/kg may be greater than 
3 mg/kg (in the metastatic setting) as tested in CA184-022, the 10 mg/kg 
dose level may not be the optimal dose for adjuvant treatment of melanoma 
and the 3 mg/kg should therefore be evaluated.  
5. The magnitude of survival benefit for ipilimumab 10 mg/kg given with 
dacarbazine in untreated melanoma (CA 184-020, Section 1.5.5) 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; CA 184-020: HR 0.68 (p < 
0.0001), median OS 6.4 vs. 10.0 months). 
6. At this stage in its conduct, intergroup E1609 trial provides the best 
opportunity to evaluate the 3 mg/kg ipilimumab dose while evaluating the 10 
mg/kg dose. 
In summary, 10 mg/kg ipilimumab was originally chosen to be tested as 
adjuvant melanoma therapy based on the dose ranging studies supporting 
the highest likelihood of benefit and also acceptable safety profile in the 
metastatic melanoma setting.  Given that the 3 mg/kg dose of ipilimumab is 
now commercially available as standard therapy for metastatic melanoma 
after demonstrating efficacy, adjuvant ipilimumab treatment of melanoma 
requires further evaluation to determine the optimal dose. E1609 would 
include study endpoints designed to capture relevant safety and efficacy data 
and adverse event monitoring for severity, duration, requirement for and 
duration of corticosteroid and other immunosuppressant use. 

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36 
Rationale for collecting quality of life (QOL) data and the potential 
impact of the trial on QOL 
An important matter in the adjuvant treatment of patients with high-risk 
melanoma is how patients weigh the tradeoffs between length of life and 
QOL. Adjuvant HDI has been demonstrated to provide relapse-free and 
overall survival benefits for this patient population, but it is also known to be 
associated with major grade 3/4 toxicities (41).  Similarly, patients treated 
with ipilimumab experience grade 3/4 drug-related, immune-related AEs 
(irAEs; inflammatory in nature). We therefore plan to collect QOL data 
utilizing the FACT-G and FACT-BRM health questionnaires and the FACIT-D 
(diarrhea assessment, one of the most common grade 3/4 irAEs related to 
ipilimumab) and investigate health-related, quality-of-life outcomes as 
compared between the HDI and ipilimumab arms. This component of the 
study will be open to patients enrolled by Community Clinical Oncology 
Programs (CCOPs). 
Rationale for collecting blood samples for prognostic and predictive 
biomarker studies 
As funding is secured, through the banking of serum and PBMC at baseline 
and multiple time points during and following therapy, this study will also 
allow us to perform novel prognostic and predictive biomarker evaluations 
nested within this intergroup trial. Specific and detailed grant proposals to 
fund these biomarker studies will be submitted separately to the respective 
funding agencies.   
Rationale for expanding the study age eligibility to allow the adolescent 
population (age 12 - 17 years) 
There is a clear medical need to test emerging novel therapeutic agents in 
the pediatric population and to allow access for these patients to major 
clinical trials. This would provide additional safety data that may help guide 
pediatric oncologists caring for pediatric patients with advanced 
malignancies. Study NCI 7458 has provided phase I study data that supports 
a relative safety and tolerability profile of ipilmumab at 10 mg/kg in patients 
with ages 12 - 21 years old. Given the high risk of recurrence and death of 
patients with stages IIIB, IIIC, M1a and M1b melanoma (E1609 study 
population), these data support providing these adolescent patients with 
access to E1609 trial therapeutic options both the standard (HDI) and the 
experimental (ipilimumab at 3 mg/kg or 10 mg/kg).  
Pediatric patients have been allowed on prior ECOG and intergroup adjuvant 
trials with HDI in collaboration with the Children’s Oncology Group (COG) and 
our clinical experience as well as reports in the literature have shown the 
feasibility and relative safety of treating pediatric patients with high dose IFNα 
(Shah et al. J Pediatric Hematology Oncology, 2006 Aug;28(8):496-500; 
Chao et al. PediatrBlood Cancer. 2005 May;44(5):441-8;  Navidet al. Cancer. 
2005 Feb 15;103(4):780-7). 
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1.7 
Definition of a Positive Study 
1.7.1 
The study will be considered a positive study if it meets any one of the 
following criteria: 
1.7.1.1 
The first co-primary endpoint of RFS is met 
1.7.1.2 
The second co-primary endpoint of OS is met 
1.7.2 
Rationale 
A number of new investigational agents have recently been shown to 
have a significant impact on the clinical outcome of patients with 
advanced metastatic melanoma. These include B-RAF kinase 
inhibitors that continue to be tested and show major promise and 
ipilimumab. For ipilimumab, a recently reported phase III clinical trial 
has demonstrated a significant overall survival prolongation of 
patients treated with ipilimumab compared to the control arm of 
peptide gp100 vaccine (46). This is in addition to the positive survival 
impact shown in CA184-024 phase III trial. Ipilimumab is currently 
approved by the FDA for the treatment of advanced/ 
inoperable metastatic melanoma. Therefore, there is a strong 
possibility that patients treated on the HDI arm may cross over to be 
treated with ipilimumab off protocol at disease recurrence which may 
confound a primary OS endpoint. On the other hand, a positive OS 
endpoint may be envisioned to also constitute a positive study even in 
the absence of a positive RFS endpoint, since OS prolongation is the 
ultimate desired outcome for all patients. In this case, the earlier 
application of ipilimumab as in E1609 may prove to be superior to 
delayed treatment in the metastatic unresectable setting given the 
quality of the host immune response that has been shown to differ 
between earlier and more advanced disease settings (Tatsumi, 
Storkus, et al. Introduction, Section 1.2, page 1).
Rev. 2/12 

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2. 
Objectives 
2.1 
Primary Endpoints 
2.1.1 
First Co-primary Endpoint: To evaluate recurrence-free survival (RFS) 
between patients randomized to receive post-operative adjuvant 
ipilimumab given at either 10 mg/kg (high dose ipilimumab; HIP) or 3 
mg/kg (low dose ipilimumab: LIP) versus those randomized to receive 
HDI utilizing a hierarchical design assessing HIP versus HDI first and 
LIP versus HDI second (if the first comparison is significant). 
2.1.2 
Second Co-primary Endpoint: To evaluate overall survival (OS) 
between patients randomized to receive post-operative adjuvant 
ipilimumab given at either 10 mg/kg (HIP) or 3 mg/kg (LIP) versus 
those randomized to receive HDI utilizing a hierarchical design 
assessing HIP versus HDI first and LIP versus HDI second (if the first 
comparison is significant). 
2.2 
Secondary Endpoints 
2.2.1 
To evaluate safety and tolerability of post-operative adjuvant 
ipilimumab therapy given at either 10 mg/kg (HIP) or 3 mg/kg (LIP). 
2.2.2 
Among patients enrolled by CCOPs, to compare the global QOL 
between the ipilimumab arms versus HDI using FACT-G form and to 
evaluate the effect of treatment-related side effects that may have an 
impact on the health-related domains of QOL using FACIT-D and 
FACT-BRM.
Rev. 2/12 
Rev. 2/12 
Rev. 2/12 
Rev. 2/12 

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NCI Update Date: September 6, 2017 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
Only patients with melanoma of a cutaneous origin or unknown primary are 
eligible for this study. Patients with ocular melanoma or melanoma of 
mucosal origin are not eligible. 
3.1 
Eligibility Criteria 
3.1.1 
Age ≥ 12 years. Age __________ 
NOTE: 
Up to 45 patient’s ages 12–17 years will be enrolled on this trial. 
3.1.2 
All patients must have disease-free status documented by a complete 
physical examination and imaging studies within 4 weeks prior to 
randomization. Imaging studies must include a total body PET-CT 
scan (with or without brain) and brain MRI or CT (if MRI is 
contraindicated). If PET-CT cannot be done, CT of neck, chest, 
abdomen, and pelvis should be done. 
If for some reason a CT cannot be done, an MRI may be done 
instead. Any other imaging studies if performed (eg, bone scan) must 
show no evidence of disease. 
Surgically rendered disease-free? Yes _____ No _____ 
Negative margins? Yes _____ No _____ 
Complete physical examination? Yes _____ No ______ 
Date ________ 
Brain MRI/CT scan (if MRI contraindicated)? Yes _____ No ______ 
Date ________ 
Total body PET-CT scan? Yes _____ No ______  
Date ________ 
If PET-CT cannot be done: 
Rev. 9/14,  
9/14 
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CT of neck, chest, abdomen, and pelvis? Yes _____ No _____ 
Date ______ 
3.1.3 
Patients must have primary cutaneous melanoma that belong to one 
of the following AJCC stages (2009 AJCC Melanoma Staging System. 
Also see Appendix XI): 
3.1.3.1 
IIIB  
T1-4b N1a 
M0 
Yes _____ No _____ 
T1-4b N2a 
M0 
Yes _____ No _____ 
T1-4a N1b 
M0 
Yes _____ No _____ 
T1-4a N2b 
M0 
Yes _____ No _____ 
T1-4a N2c 
M0 
Yes _____ No _____ 
3.1.3.2 
IIIC 
T1-4b N1b 
M0 
Yes _____ No _____ 
T1-4b N2b 
M0 
Yes _____ No _____ 
T1-4b  N2c 
M0 
Yes _____ No _____ 
Any T N3 
M0 
Yes _____ No _____ 
3.1.3.3 
IV 
M1a 
 
 
Yes _____ No _____ 
M1b 
 
 
Yes _____ No _____ 
NOTE: 
Patients with stage IV melanoma must have 
normal LDH and either distant skin, 
subcutaneous, lymph node or lung metastases, 
but no other visceral metastases in order to be 
eligible. For patients with resected stage IV 
melanoma, LDH within the institutional upper 
limit of normal (ULN) must be documented 
within 4 weeks prior to randomization. 
LDH: _______ ULN: _______ Date _________ 
3.1.4 
Patients with disease recurrence after adequate surgical excision of 
the original primary cutaneous/unknown primary melanoma are 
allowed even if they don’t fit the strict staging criteria noted in Section 
3.1.3, but only as follows:. 
• 
Recurrence in a regional lymph node basin after a prior complete 
lymph node dissection. Relapsed disease must be completely 
surgically resected with free margins. 
• 
Recurrence in the form of in-transit or satellite metastases or 
distant skin/subcutaneous, nodal or lung metastases that are 
completely surgically resected with free margins.  
• 
Recurrence in a regional lymph node basin. Relapsed disease 
must be completely surgically resected with free margins. 
Recurrence in a regional lymph node basin. Has relapsed disease 
been completely surgically resected with free margins?  
Yes _____ No _____ 
_____
_____ 
_____ 
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Recurrence in a regional lymph node basin after a prior complete 
lymph node dissection and relapse disease is completely surgically 
resected with free margins?  
Yes____ No _____ 
Recurrence in the form of in-transit or satellite metastases or distant 
skin/subcutaneous, nodal or lung metastases that are completely 
surgically resected with free margins.  
Yes _____ No _____ 
Patients with unknown primary melanoma (Tx) who present with 
cutaneous, subcutaneous, nodal and/or lung metastases that are 
completely surgically resected with free margins are allowed. These 
patients are allowed even if they don’t fit the strict staging criteria 
noted in Section 3.1.3. For stage IV patients LDH within the 
institutional ULN must be documented within 4 weeks prior to 
randomization (M1c is not eligible). 
Unknown primary melanoma presenting with cutaneous or 
subcutaneous metastases that are completely surgically resected with 
free margins?   
Yes _____ No _____ 
Unknown primary melanoma presenting with nodal metastases that 
are completely surgically resected with free margins? 
Yes _____ No _____ 
Unknown primary melanoma presenting with lung metastases that are 
completely surgically resected with free margins? 
Yes _____ No _____ 
NOTE: 
All subjects should be classified as IIIB, IIIC, M1a or M1b 
including subjects with disease recurrence after adequate 
surgical excision of the original primary melanoma. That is 
the treating team/physician investigator should review an 
overall TNM status (that includes primary tumor 
presentation and disease recurrence status) and provide a 
designation of IIIB, IIIC, M1a or M1b. For newly diagnosed 
primary cutaneous melanoma, refer to section 3.1.3. For 
subjects with disease recurrence after adequate surgical 
excision of the original primary melanoma or who present 
with an unknown primary melanoma, classify as follows 
(check one): 
1=regional nodal and satellite/in-transit disease _____ IIIC 
2=regional nodal without satellite/in-transit disease _____ IIIB or 
_____ IIIC  
3=regional satellite/in-transit disease without lymph nodes 
involvement _____ IIIB or _____ IIIC 
4=distant cutaneous/nodal disease _____ M1a 
5=distant lung disease  _____ M1b 
Rev. 2/12 
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Unknown primary melanoma (newly diagnosed or recurrent) with: 
1=cutaneous or nodal disease  _____ IIIB or _____ IIIC or _____ M1a 
2=lung disease _____ M1b 
3.1.5 
Patients must be randomized within 84 days (12 weeks) of surgical 
resection. If more than one surgical procedure is required to render 
the patient disease-free, the patient must be randomized within 12 
weeks of the last surgery. 
NOTE: 
Patients with clinically positive lymph nodes for melanoma 
involvement or those with positive lymph nodes identified 
through lymphoscintigraphic and/or dye lymphographic 
techniques in the groin, axilla, or neck should have 
additional lymphadenectomy in those sites. See Section 
5.1 and Appendix VII for suggested guidelines on surgical 
management. The complete lymph node dissection 
procedure would be considered as the last surgery in 
counting the 84 days unless a subsequent surgical 
procedure(s) was clinically required to ensure the disease 
free status. 
Date of Randomization: ________  
Date of last surgical resection _________ 
More than 1 surgery required to render patient disease-free? 
Yes ____ No _____  
Number of surgeries __________  
Dates of surgeries _______, _______, _______, _______ 
3.1.6 
Patients must not have received any adjuvant treatment 
(chemotherapy, biotherapy, or limb perfusion) after the resection(s) 
that make(s) them eligible for this trial. 
NOTE:  
Previous radiation therapy, including after the surgical 
resection, is allowed as long as 21 days have elapsed 
between the radiation and initiation of this adjuvant 
systemic therapy. 
Adjuvant treatment (chemotherapy, biotherapy, limb perfusion) 
received after resection? 
Yes _____ No ______ 
Previous radiation therapy (including after resection)?  
Yes _____ No ______ Date of radiation _____ 
3.1.7 
Prior treatment with anti-CTLA4 monoclonal antibodies or prior CTLA-
4 inhibitor or agonist or  prior CD137 agonist or prior interferon-α is 
not allowed. 
Other forms of prior treatment for melanoma (e.g., IL-2, anti-tumor 
vaccine, chemotherapy) are allowed if given before the resection(s) 
that make(s) the patient eligible for this trial, but these must have 
been completed at least 4 weeks prior to randomization. 
_____
Rev. 8/12 
_____
Rev. 2/12 
_____

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Prior treatment with anti-CTLA4 monoclonal antibodies? 
Yes ____ No ______ 
Prior treatment with CTLA4 inhibitor or agonist? 
Yes ____ No ______ 
Prior treatment with CD137 agonist? 
Yes ____ No ______ 
Prior treatment with interferon-α? 
Yes ____ No ______ 
3.1.8 
Patients must have ECOG performance status of 0-1. 
See Appendix VI. 
ECOG performance status _______ 
3.1.9 
Patients must not have an active infection requiring current treatment 
with parenteral antibiotics. 
Active infection requiring current treatment with parenteral antibiotics? 
Yes _____ No _____ 
3.1.10 
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 with a baseline of frequent diarrhea (e.g. irritable 
bowel syndrome) are not eligible because of the difficulty in 
interpreting later expected GI toxicities that may lead to suboptimal 
management and complications. 
Significant medical, surgical or psychiatric conditions as defined 
above? Yes ____ No _____ 
Condition requiring any medication or treatment as defined above? 
Yes _____ No _____ 
Condition associated with frequent diarrhea? 
Yes _____ No _____ 
3.1.11 
Given that serious adverse events may occur with ipilimumab and 
IFNα and that these may impact a patient’s wellbeing, it is possible 
that the occurrence of other SAEs may seriously impact an underlying 
state of mental depression and lead to suicidal ideation. Therefore, 
patients should be carefully screened for depression at baseline and if 
there are indications or a history of depression it is strongly 
recommended that these patients be closely followed together with 
behavioral health or psychiatric medical support. Patients with an 
established diagnosis of depression that, in the assessment of the 
investigator may make the administration of IFNα or ipilimumab 
hazardous, should not be enrolled on this protocol. The risks and 
benefits of being treated with standard adjuvant IFNα should be 
weighed very carefully in consultation with behavioral health or 
psychiatry. 
_____
_____
_____
_____
Rev. 2/13 
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NCI Update Date: September 6, 2017 
44 
3.1.12 
Patients must not have a documented history of inflammatory bowel 
disease (including ulcerative colitis and Crohn’s disease) or 
diverticulitis (history of diverticulosis is allowed). 
Documented history of inflammatory bowel disease? 
Yes _____ No ______ 
History of diverticulitis? 
Yes _____ No ______ 
3.1.13 
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 (i.e., 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.  
Treatment with systemic corticosteroids (including oral steroids)? 
Yes _____ No ______ 
Continuous use of topical steroid creams/ointments? 
Yes _____ No ______ 
Continuous use of steroid containing inhalers? 
Yes _____ No ______ 
Adrenal insufficiency? 
Yes _____ No ______ 
Date of last dose of steroid containing medicines _____________ 
3.1.14 
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.  
Has the patient had an infectious disease vaccine within the past four 
weeks?  
Yes _____ No _____ Date of vaccine _________ 
_____
_____
_____

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NCI Update Date: September 6, 2017 
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3.1.15 
Patients must not be prisoners or subjects who are compulsorily 
detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (e.g., infectious) illness. This is due to concerns 
about subject safety and compliance with study procedures. 
Is the patient a prisoner or involuntarily incarcerated? 
Yes _____ No _____ 
3.1.16 
Patients who have other current malignancies are not eligible. 
Patients with other malignancies are eligible if they have been 
continuously disease free for > 5 years prior to the time of 
randomization. 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 melanoma in situ are eligible. 
Patients with prior history of basal or squamous skin cancer are 
eligible. Patients who have had multiple primary melanomas are 
eligible.  
Other current malignancies? Yes ___ No _____ 
Type of malignancy _________________ 
Other previous malignancies? Yes ____ No ____ 
Type of malignancy _________________ 
Disease-free? Yes ______ No _____ 
Date of last treatment ______________________ 
3.1.17 
Women must not be pregnant or breast-feeding due to the unknown 
effects of ipilimumab and 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 7.1.5 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 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). 
Post-menopause is defined as: 
Amenorrhea ≥ 12 consecutive months without another cause, or 
For women with irregular menstrual periods and taking hormone 
replacement therapy (HRT), a documented serum follicle stimulating 
hormone (FSH) level ≥ 35 mIU/mL. 
WOCBP must be using an adequate method of contraception to avoid 
pregnancy throughout the study and for up to 26 weeks after the last 
dose of ipilimumab or HDI, in such a manner that the risk of 
_____
_____
_____
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pregnancy is minimized.  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 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. 
WOCBP are not eligible if they satisfy any of the following: 
• 
A positive pregnancy test at baseline 
Pregnant or breastfeeding 
3.1.18 
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  
 
 
WBC count: __________ 
Date _____________ 
• 
ANC ≥ 1500/uL 
 
 
ANC count: __________ 
Date _____________ 
• 
Platelets  ≥ 100 x 103/uL 
 
Platelet count: __________ 
Date _____________ 
• 
Hemoglobin ≥ 10 g/dL 
 
Hemoglobin: __________ 
Date _____________ 
• 
Serum creatinine ≤ 1.5 mg/dl 
Serum creatinine: ________  
Date _____________ 
• 
AST/ALT ≤ 2.5 x ULN  
AST: _________ Date _________ 
ULN: __________ 
ALT: __________ Date ________ 
ULN: __________ 
• 
Serum bilirubin ≤ 1.5 X ULN, (except patients with Gilbert’s 
Syndrome, who must have a total bilirubin less than 3.0 mg/dL) 
Serum bilirubin: __________ Date ________ ULN: __________ 
_____
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3.1.19 
No active or chronic infection with HIV, Hepatitis B, or Hepatitis C due 
to the unknown effects of ipilimumab. Patients must have negative 
testing for HIV, HBV, HCV within 4 weeks prior to randomization. 
Negative HIV serology? Yes _____ No ______ 
Date _________ 
Negative Hepatitis B antigen testing? Yes _____ No ______ 
Date _________ 
Negative HCV serology? Yes _____ No ______ 
Date _________ 
 
 
 
 
 
 
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 
NOTE:  
As of August 15, 2014, adult accrual to Arms A, B, and C has completed. 
Adolescent patients (ages 12 -17) will be randomized to study arms D, E, 
or F. 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
Added to a site roster 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. 
For questions, please contact the RCR Help Desk by email at 
<RCRHelpDesk@nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
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registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and 
applied to the RSS in an automated process. Signatory Institutions must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate 
their intent to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study. 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E1609 protocol page located on the 
CTSU members’ website.  
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E1609 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Requirements for E1609 site registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted ) 
• 
Ipilimumab Investigator Training (please see Section 4.6.4) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org (members’ area)  Regulatory Tab  
 Regulatory Submission 
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When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
Required Protocol Specific Regulatory Documents 
1. 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. 
2. A. CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
C.  IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment: 
Patients must not start protocol treatment prior to registration. 
Treatment should start within 7 working days after registration. 
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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. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam/>) and a 'Registrar' role on either the LPO or 
participating organization roster. Registrars must hold a minimum of an AP registration 
type. 
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study. 
It is integrated with the CTSU Enterprise System for regulatory and roster data. 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. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in 
OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number 
used on the site’s IRB approval. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
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 
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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. An 
eligibility checklist has been appended to the protocol. A confirmation of 
registration will be forwarded by the ECOG-ACRIN Operations Office - Boston. 
4.5 
Stratification Factors 
Patients with surgically resected AJCC stage: 
• 
IIIB 
• 
IIIC 
• 
M1a 
• 
M1b 
4.6 
Additional Requirements  
4.6.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
CCOP institutions are required to present the patient with 
the Quality of Life questionnaires. The CCOP and non 
CCOP versions of the model consent are posted as 
separate documents on the ECOG website. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office - Boston. 
4.6.2 
Pathological materials are to be submitted as indicated in Section 10 
for central diagnostic review (required), and banking (including use for 
research in accordance with patient consent). 
4.6.3 
Blood samples are to be submitted for banking, including use for 
research per patient consent as indicated in Section 11. 
NOTE:  
ECOG-ACRIN requires that biological samples submitted 
from patients participating in E1609 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking 
System (STS). See Section 10.4. 
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 
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 
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titled: E1609 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
2873P  
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 – 5:30pmET Monday through Friday, please 
email the ECOG-ACRIN Ipi Education Team at 
ECOGIpi@ecogchair.org for after hours assistance. 
4.6.5 
Patients must be at least 12 years of age. Patients 12-17 years of age 
must be registered and treated at a COG institution and be presented 
with the "Sample Research Information Consent/Parental Permission 
Form.” 
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 according to the 
instructions in the E1609 Forms Packet. Document the reason for not starting 
protocol treatment on the Off Treatment form. Also report the date and type of 
the first non-protocol treatment that the patient receives. 
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5. 
Treatment Plan 
5.1 
Surgical Considerations 
Refer to Appendix VII for suggested guidelines on surgical management and 
techniques for lymphadenectomy. These are important standard of care surgical 
guidelines and all investigators are strongly urged to consider them in the 
management of their patients. 
5.2 
Administration Schedule 
NOTE: As of August 15, 2014, adult accrual to Arms A, B, and C has 
completed. Adolescent patients (ages 12 -17) will be randomized to 
study arms D, E, or F. 
Patients will be randomized to either Arms A or D (ipilimumab at 10 mg/kg) or 
Arms C or F (ipilimumab at 3 mg/kg) or Arms B or E (HDI). 
5.2.1 
ARMS A,C, D, or F: Patients Receiving Ipilimumab 
5.2.1.1 
Patients must receive their first infusion of ipilimumab 
within 7 days of randomization, and only after complete 
wound healing from surgery. 
5.2.1.2 
Use actual weight when calculating the dose. 
5.2.1.3 
Ipilimumab at 10 mg/kg IV (Arms A, D) or 3 mg/kg (Arm C, 
F) infusion administered as follows: 
Induction Phase 
Ipilimumab 10 mg/kg (Arms A, D) or 3 mg/kg (Arms C, F), 
administered by IV infusion every 3 weeks for a total of 
four doses. 
Maintenance Phase 
Ipilimumab 10 mg/kg (Arms A, D) or 3 mg/kg (Arms C, F), 
administered by IV infusion every 12 weeks (3 months), 
beginning at week 24, then at weeks 36, 48, and 60. 
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). 
5.2.1.4 
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. 
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For example, a patient on Arms A or D (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. 
5.2.2 
ARMS B and E: Patients receiving Interferon Alfa - 2b 
5.2.2.1 
Patients must receive their first injection of IFN Alfa - 2b 
within 7 working days of randomization. 
5.2.2.2 
Use actual weight when calculating body surface area. 
5.2.2.3 
Induction Phase 
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. 
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. 
5.2.2.4 
Days 2-5 of interferon 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 week 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. Home Health Agencies (HHA) may be used to 
treat patients, if the HHA is under the supervision of a 
Theradex approved institution and the nurse treating the 
patient is supervised by an approved doctor. 
5.2.2.5 
Self Administration of Subcutaneous Doses  
Patients who are deemed competent to self administer the 
subcutaneous maintenance 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 with 
instructions to reconstitute with 1 ml of diluent to reach a 
final concentration of 10:1. See Appendix X for directions 
and patient IFN information guide. Patients must complete 
the E1609 Patient Diary -Interferon (Appendix IV). 
5.2.2.6 
Corticosteroids and other immunosuppressive medications 
are contraindicated during IFN Alfa-2b therapy because of 
immune suppressive effects. No systemic treatment with 
steroids (including creams) is permitted. Exception: 
patients may receive antihistamines and inhaled steroids 
may be permitted at dosages that are not systematically 
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immunosuppressive if there is no alternative medication. 
Also, steroids (topical, inhaled or systemic) may be used to 
treat adverse events or toxicities if there is a clear clinical 
indication. 
5.2.3 
Treatment at Recurrence 
A patient on E1609 ipilimumab treatment arms who experiences 
disease recurrence but was still considered surgically operable and 
can be rendered disease free by surgery should be reported as 
disease recurrence. However, in the absence of limiting toxicities per 
protocol criteria, such a patient may be offered additional ipilimumab 
therapy on protocol that must be captured on the usual forms 
(including treatment forms, toxicity forms, long term follow up for 
subsequent recurrence). In such a case the patient would re-start 
ipilimumab treatment at the next scheduled dose when medically 
cleared by his treating physician investigator. 
5.3 
Adverse Event Reporting Requirements 
5.3.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E1609 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting.  
5.3.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
An investigational agent is a protocol drug administered under an 
Investigational New Drug Application (IND). In some instances, the 
investigational agent may be available commercially, but is actually 
being tested for indications not included in the approved package 
label. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
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Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: 
Identify the type of event:  The descriptions and grading 
scales found in the Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be 
utilized for AE reporting. The CTEP Active Version of the 
CTCAE is identified and located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_app
lications/ctc.htm. All appropriate treatment areas should 
have access to a copy of the CTEP Active Version of 
CTCAE. 
Step 2: 
Grade the event using the Active Version of the NCI 
CTCAE. 
Step 3: 
Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
Step 4: 
Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or 
the severity of the event is NOT listed in:  
• 
Arms A and D (ipilimumab at 10 mg/kg) and Arms C and F 
(ipilimumab at 3 mg/kg)  – the current NCI Specific Protocol 
Exceptions to Expedited Reporting (SPEER) 
• 
Arms B and E – the drug package insert or protocol 
NOTE: 
The NCI Specific Protocol Exceptions to Expedited 
Reporting (SPEER) is included in section 5.4 of the 
protocol. The SPEER is presented in the last column of the 
CAEPR and identified with bold and italicized text.  FOR 
THIS PROTOCOL, events listed in the SPEER column 
should be considered EXPECTED if the grade being 
reported is the same or lower than the grade noted in the 
parentheses next to the AE in the SPEER. Events listed in 
the SPEER column should be considered UNEXPECTED 
if the grade being reported exceeds the grade noted in 
parentheses next to the AE in the SPEER." 
Step 5: 
Review the ”Additional instructions, requirements, and 
exceptions for protocol E1609” table in section 5.3.6 for 
protocol and/or ECOG-ACRIN specific requirements for 
expedited reporting of specific adverse events that require 
special monitoring.   
NOTE: 
For general questions regarding expedited reporting 
requirements, please contact the CTEP-AERS Help Desk:  
301-897-7497. 
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5.3.3 
Reporting procedures 
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 AE Team at ECOG-ACRIN (617-632-3610)  
for Arms A, B, C, D, E, and F 
• 
the NCI (301-897-7497) for Arms A and D, and Arms C and F 
• 
the FDA (800-332-1088) for Arms B and E 
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 faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 230-0159) for Arms A, 
C, D and F and FDA (800-332-0178) for Arms B  and E 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. 
5.3.4 
When to report an event in an expedited manner 
Some adverse events require 24-hour notification (refer to Section 
5.3.6). Please complete a 24-Hour Notification Report via CTEP's 
website (http://ctep.cancer.gov) within 24 hours of learning of the 
event.  The full CTEP-AERS report must be completed and submitted 
via CTEP-AERS within 5 calendar days. 
If the CTEP-AERS system is down, a 24-hour notification call must be 
made to ECOG-ACRIN (617-632-3610) and to NCI (301-897-7497).  
Once the system is restored, a 24-hour Notification Report must be 
entered into the CTEP-AERS system by the original submitter of the 
report at the site. 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.3.6. 
NOTE: 
Adverse events that meet the reporting requirements in 
Section 5.3.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
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requirements in Section 5.3.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
5.3.5 
Other recipients of adverse event reports 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to 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 must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
5.3.6 
Expedited reporting for investigational agents 
NOTE: 
Although Arms B and E contain only commercially 
available agents, all arms will follow the investigational 
adverse event reporting requirements for this protocol. 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND: CTEP-
AERS Expedited Reporting Requirements for Adverse Events 
That Occur Within 30 Days1 of the Last Dose of Investigational 
Agent [Ipilimumab] in this Study (Arms A, C, D, or F) OR Within 
30 Days of the Last Dose of Any Protocol Treatment (Arms A, B, 
C, D, E, or F). 
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NOTE: 
All deaths on study require both routine and expedited reporting regardless of causality.  Attribution to treatment or other 
cause should be provided. 
• 
Expedited AE reporting timelines: 
 24 Hours; 5 calendar days – The investigator must initially report the AE via CTEP-AERS within 24 hours of 
learning of the event followed by a complete CTEP-AERS report within 5 calendar days of the initial 24-hour 
report. 
 10 calendar days – A complete CTEP-AERS report on the AE must be submitted within 10 calendar days of the 
investigator learning of the event. 
Attribution 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
10 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of treatment with an agent under 
a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in the table. 
    
Please see additional information below under section entitled “Additional instructions, requirements, and exceptions for protocol E1609” 
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• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization* (or prolongation of 
existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with 
the exception of any events identified as protocol-specific expedited adverse event reporting exclusions. 
• 
Any event that results in persistent or significant disability/incapacity, congenital anomaly, or birth defect must 
be reported via CTEP-AERS if the event occurs following treatment with an agent under a CTEP IND 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all reports. 
* Hospitalizations are defined as lasting 24 hours or longer and these events must be reported via CTEP-AERS. 
Additional instructions, requirements and exceptions for protocol E1609 
1. Additional Instructions: 
 With respect to determining the specific day by which the event must be reported, the day the reporter learns of the 
adverse event constitutes “Day 0” 
 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 Help Desk at 301-897-7497 or aemd@tech-
res.com. 
2. ECOG-ACRIN and Protocol Specific expedited reporting requirements: 
The adverse events listed below also require expedited reporting for this trial: 
ECOG-ACRIN specific expedited reporting requirements: 
 Hospitalizations:  Any grade 1 or 2 adverse event with precipitates a hospitalization lasting ≥ 24 hours (or prolongs 
hospitalization) 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.   
Protocol specific expedited reporting requirements: 
 Bowel Perforation: Any grade 3 or higher bowel perforation 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. 
 Immune Related Adverse Events: Any grade 2 or higher immune related adverse event (see section 5.5.1.3 for 
definition), excluding skin reactions, that occurs within 70 days of the last day of protocol treatment 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). In addition, any 
grade 2 or higher IRAE, excluding grade 2 or 3 skin reactions, that occurs greater than 70 days after the last dose of 
protocol treatment with an attribution of possible, probable, or definite must also be reported via CTEP-AERS within 10 
calendar days of learning of the event. Any questions regarding if an event qualifies as an IRAE can be directed to the 
study chair. 
Rev. 2/14 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
62 
5.3.7 
Reporting second primary cancers 
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: 
• 
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. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
• 
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. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
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. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report should not be 
used to report recurrence or development of metastatic disease. 
Rev. 2/12, 4/14 

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63 
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 Primary Form. 

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NCI Update Date: September 6, 2017 
64 
5.4 
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. 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: 
FOR THIS PROTOCOL, events listed in the SPEER column should 
be considered EXPECTED if the grade being reported is the same or 
lower than the grade noted in the parentheses next to the AE in the 
SPEER. Events listed in the SPEER column should be considered 
UNEXPECTED if the grade being reported exceeds the grade noted 
in parentheses next to the AE 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/hypophysit
is)2 
 
 
Endocrine disorders - 
Other (testosterone 
deficiency)2 
 
 
Hyperthyroidism2 
Hypothyroidism2 
Rev. 10/11, 11/13, 
3/16 
Rev. 2/12 
Rev. 2/12 
Rev. 10/14 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
65 
 
 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%) 
 
EYE DISORDERS 
Eye disorders - Other 
(episcleritis)2 
 
 
Uveitis2 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Colitis2 
Colitis (Gr 3) 
Colonic perforation3 
Constipation 
Diarrhea 
Diarrhea (Gr 3) 
Enterocolitis 
Esophagitis 
Ileus 
Nausea 
Nausea (Gr 3) 
Pancreatitis2 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Chills 
Fatigue 
Fatigue (Gr 3) 
Fever 
Fever (Gr 2) 
Infusion related reaction 
Multi-organ failure 
HEPATOBILIARY DISORDERS 
Hepatobiliary disorders - 
Other (hepatitis)2 
 
 
IMMUNE SYSTEM DISORDERS 
Autoimmune disorder2 
 
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 
 
 

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NCI Update Date: September 6, 2017 
66 
 
 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%) 
 
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 
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. 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
67 
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. 
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 

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NCI Update Date: September 6, 2017 
68 
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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NCI Update Date: September 6, 2017 
69 
5.5 
Dose Modifications 
All toxicities should be graded according to 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 web site (http://ctep.cancer.gov). 
NOTE: 
Per Addendum #7, the dose modification plan for Arms A and D 
(ipilimumab 10 mg/kg) has been modified to become stricter due 
to a higher incidence of severe toxicities observed on Arms A 
and D than seen in Arms C and F. Arms C and F dose 
modification guidelines continue to be the same, with minor 
changes. 
5.5.1 
ARMS A and D and Arms C and F: Patients Receiving Ipilimumab 
5.5.1.1 
Dose and Schedule Modifications for Arms A and D 
(Ipilimumab 10 mg/kg) 
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 skipping doses or dose discontinuation. Some of 
these adverse events may be consistent with potentially 
drug-related immune-mediated phenomena; termed IRAEs 
(Appendix XIII-Appendix XVII). 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 certainly, 
probably, or possibly related to ipilimumab treatment 
unless otherwise specified. The following criteria will be 
used to determine dosing delay, restarting doses, or 
discontinuing ipilimumab. For an adverse event, review the 
following criteria in a stepwise manner: First, assess the 
dose delay criteria and decide whether a scheduled dose 
should be delayed. 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 ipilimumab. 
Rev. 2/12, 11/13 
9/14 
Rev. 11/13 
9/14 

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NCI Update Date: September 6, 2017 
70 
5.5.1.1.1 
Criteria to delay/skip one dose of 
ipilimumab on Arms A or D (ipilimumab 
10 mg/kg) 
Delay ipilimumab dosing for any of the 
following certainly, probably, or possibly 
treatment related adverse events, unless 
otherwise specified: 
• 
Grade ≥ 1 diarrhea and/or colitis 
regardless of attribution.  Grade ≥ 2 
diarrhea and/or colitis, certainly, 
probably, or possibly related to 
ipilimumab, requires permanent 
discontinuation (Section 5.5.1.1.3). 
• 
Any other ≥ Grade 2 non-skin related 
adverse event (including IRAEs) except 
for laboratory abnormalities. 
• 
Grade ≥ 2 laboratory abnormalities that 
are secondary to an immune-related 
adverse event or autoimmune 
phenomenon (e.g., Grade ≥ 2 TSH 
associated with a CTCAE v.4 grade 2 
thyroid dysfunction induced by 
ipilimumab, anemia, neutropenia, 
amylase, lipase, CPK, hyperglycemia, or 
elevated LFTs) should also lead to an 
ipilimumab dosing delay/skipping. 
• 
Any other ≥ Grade 3 laboratory 
abnormality. 
• 
Any ≥ Grade 3 skin-related adverse 
event (including IRAEs) regardless of 
attribution. 
5.5.1.1.2 
Criteria to resume ipilimumab treatment 
on Arms A or D (ipilimumab 10mg/kg) 
Ipilimumab may not be restarted while the 
patient is being treated with oral or 
intravenous  corticosteriods for the 
management of immune related adverse 
events except for patients on stable doses 
of hormone replacement therapy for adrenal 
insufficiency such as hydrocortisone.  In 
addition, patients must be off and have no 
requirement for oral/I.V. corticosteroids for 
at least 1 week and meet the other criteria 
for retreatment as outlined below. 
Restart ipilimumab dosing if/when the 
adverse event(s) resolve(s) to ≤ Grade 1 

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NCI Update Date: September 6, 2017 
71 
severity or returns to baseline within 3 
weeks of last dose administration: 
• 
If the adverse event has resolved (to ≤ 
Grade 1 severity or returns to baseline), 
restart ipilimumab dosing at the next 
scheduled time point per protocol. 
• 
If the adverse event has not resolved in 
the protocol-specified dosing window (3 
weeks [+/- 3 days], the next scheduled 
dose will be omitted. 
• 
Patients with Grade 1 diarrhea and/or 
colitis who require steroid therapy must 
have resolution to grade 0 (baseline) 
before resuming dosing with ipilimumab. 
Patients with Grade ≥ 2 related diarrhea 
and/or colitis must have ipilimumab 
permanently discontinued (Section 
5.5.1.1.3). 
5.5.1.1.3 
Criteria for permanent discontinuation of 
ipilimumab for Related Adverse Events 
on Arms A or D (ipilimumab 10mg/kg) 
Ipilimumab administration must be 
permanently discontinued for any of the 
following certainly, probably, or possibly 
treatment related adverse events, unless 
otherwise specified:  
• 
Any ≥ Grade 2 eye pain or reduction of 
visual acuity that does not respond to 
topical therapy and does not improve to 
≤ Grade 1 severity within 2 weeks of 
starting therapy, OR, requires systemic 
treatment. 
• 
Any ≥ Grade 2 diarrhea and/or colitis 
related to ipilimumab. Any ≥ Grade 2 
diarrhea/colitis should be considered 
RELATED unless immune related colitis 
is definitely ruled out (including by 
endoscopy and biopsy.) 
• 
Any ≥ Grade 2 hypophysitis, 
pneumonitis, nephritis, and/or sarcoid-
like lesions. 
• 
Any new motor or sensory neurologic 
toxicity ≥ Grade 2 regardless of 
attribution (including Guillain-Barré 
syndrome and myasthenia gravis). 
• 
Any ≥ Grade 3 bronchospasm or other 
hypersensitivity reaction. 
Rev. 2/14 

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NCI Update Date: September 6, 2017 
72 
• 
Any other ≥ Grade 3 non-skin adverse 
event with the exception of events listed 
under “Exceptions to Permanent 
Discontinuation” (Section 5.5.1.1.4). 
• 
AST or ALT > 5 x ULN. 
• 
Total Bilirubin > 3 x ULN.  
• 
Any other ≥ Grade 4 laboratory 
abnormalities except for specified 
exceptions (Section 5.5.1.1.4). 
• 
Any other ≥ Grade 4 adverse event. 
• 
Stevens-Johnson syndrome, toxic 
epidermal necrolysis, or rash 
complicated by full thickness dermal 
ulceration or necrotic, bullous, or 
hemorrhagic manifestations. 
• 
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. 
• 
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 
Guidelines/Algorithms should have 
ipilimumab permanently discontinued. 
5.5.1.1.4 
Exceptions to permanent 
discontinuation of ipilimumab on Arms A 
and D (ipilimumab 10mg/kg) 
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. 
• 
Laboratory abnormalities that are rapidly 
reversible, not life threatening, do not 
reflect underlying organ system 
dysfunction, and are not related to the 
study treatment, such as transient 
elevations of uric acid, hypocalcaemia, 
hypophosphatemia. 

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NCI Update Date: September 6, 2017 
73 
• 
Hospitalization for ≤ Grade 2 adverse 
events (not including Grade 2 events 
that require permanent discontinuation 
as listed under Section 5.5.1.1.3) where 
the primary reason for hospitalization is 
to expedite the clinical work-up. 
• 
Patients with the following conditions 
where in the investigator’s opinion 
continuing study drug administration is 
justified: 
− Ocular toxicity that has responded to 
topical therapy and has improved to 
≤ Grade 1 severity within 2 weeks of 
starting therapy. 
− Patients without a diagnosis of 
hypophysitis who have Grade 2 
hypothyroidism, Grade 2 low 
testosterone or Grade 2 adrenal 
insufficiency where clinical 
symptoms are controlled with 
appropriate hormone replacement 
therapy.  
5.5.1.2 
Dose and Schedule Modifications for Arms C and F 
(Ipilimumab 3 mg/kg) 
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 skipping doses or dose discontinuation. Some of 
these adverse events may be consistent with potentially 
drug-related immune-mediated phenomena; termed IRAEs 
(Appendix XIII-Appendix XVII). 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 
certainly, probably, or possibly related to ipilimumab 
treatment unless otherwise specified. The following criteria 
will be used to determine dosing delay, restarting doses, or 
discontinuing ipilimumab. For an adverse event, review the 
following criteria in a stepwise manner: First, assess the 
dose delay criteria and decide whether a scheduled dose 
should be delayed. 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 
Rev. 8/12 
Rev. 11/13, 
9/14 

ECOG-ACRIN 
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NCI Update Date: September 6, 2017 
74 
have had any infectious disease vaccination 
(e.g., standard influenza, H1N1 influenza, 
pneumococcal, meningococcal, tetanus toxoid) 
4 weeks before or after any dose of ipilimumab.   
5.5.1.2.1 
Criteria to delay/skip one dose of 
ipilimumab on Arms C and F (ipilimumab 
3 mg/kg) 
Delay ipilimumab dosing for the following 
certainly, probably, or possibly treatment 
related adverse events, unless otherwise 
specified: 
• 
Any ≥ Grade 2 non-skin related adverse 
event (including IRAEs) except for 
laboratory abnormalities. 
• 
Grade ≥ 2 laboratory abnormalities that 
are secondary to an immune-related 
adverse event or autoimmune 
phenomenon (e.g., Grade ≥ 2 TSH 
associated with a CTCAE v.4 grade 2 
thyroid dysfunction induced by 
ipilimumab, anemia, neutropenia, 
amylase, lipase, CPK, hyperglycemia, or 
elevated LFTs) should also lead to an 
ipilimumab dosing delay/skipping. 
• 
Any other ≥ Grade 3 laboratory 
abnormality. 
• 
Any ≥ Grade 3 skin-related adverse 
event (including IRAEs) regardless of 
attribution. 
5.5.1.2.2 
Criteria to resume ipilimumab treatment 
on Arms C and F (ipilimumab 3mg/kg) 
Ipilimumab may not be restarted while the 
patient is being treated with oral or 
intravenous corticosteriods for the 
management of immune related adverse 
events except for patients on stable doses 
of hormone replacement therapy for adrenal 
insufficiency such as hydrocortisone.  In 
addition, patients must be off and have no 
requirement for oral/I.V. corticosteroids for 
at least 1 week and meet the other criteria 
for retreatment as outlined below. 
Restart ipilimumab dosing if/when the 
adverse event(s) resolve(s) to ≤ Grade 1 
severity or returns to baseline within 3 
weeks of initial dose administration: 
Rev. 2/12, 
9/14 
Rev. 9/14 

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• 
If the adverse event has resolved (to ≤ 
Grade 1 severity or returns to baseline), 
restart ipilimumab dosing at the next 
scheduled time point per protocol. 
• 
If the adverse event has not resolved in 
the protocol-specified dosing window (3 
weeks [+/- 3 days], the next scheduled 
dose will be omitted. 
• 
Patients with Grade 2 diarrhea/colitis 
must have resolution to Grade 0 
(baseline) severity and must have a 
follow-up colonoscopy to document 
endoscopic (with or without pathologic) 
resolution of inflammation before 
resuming dosing with ipilimumab. 
5.5.1.2.3 
Criteria for permanent discontinuation of 
ipilimumab for Related Adverse Events 
Ipilimumab administration must be 
permanently discontinued if any of the 
following Related Adverse Events occurs:  
• 
Any ≥ Grade 2 eye pain or reduction of 
visual acuity that does not respond to 
topical therapy and does not improve to 
≤ Grade 1 severity within 2 weeks of 
starting therapy, OR, requires systemic 
treatment. 
• 
Any ≥ Grade 2 hypophysitis. 
• 
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 
5.5.1.2.4). 
• 
Any ≥ Grade 4 laboratory abnormalities, 
except for specified exceptions (Section 
5.5.1.2.4). 
• 
For AST, ALT, or Total Bilirubin, then as 
follows: 
o AST or ALT > 5 x ULN. 
o Total Bilirubin > 3 x ULN. 
• 
Any other ≥ Grade 4 adverse event 
except for specified exceptions (Section 
5.5.1.2.4). 
• 
Stevens-Johnson syndrome, toxic 
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complicated by full thickness dermal 
ulceration or necrotic, bullous, or 
hemorrhagic manifestations. 
• 
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 or sensory neurologic toxicity 
≥ Grade 3 regardless of attribution. 
• 
Diagnosis with Guillain-Barré syndrome 
or myasthenia gravis (any grade). 
• 
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 
Guidelines/Algorithms should have 
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. 
5.5.1.2.4 
Exceptions to permanent 
discontinuation of ipilimumab on Arms C 
and F (ipilimumab 3mg/kg) 
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. 
• 
Laboratory abnormalities that are rapidly 
reversible, not life threatening, do not 
reflect underlying organ system 
dysfunction, and are not related to the 
study treatment, such as transient 
elevations of uric acid, hypocalcaemia, 
hypophosphatemia. 
• 
Hospitalization for ≤ Grade 2 adverse 
events (not including Grade 2 events 
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that require permanent discontinuation 
as listed under Section 5.5.1.2.3) where 
the primary reason for hospitalization is 
to expedite the clinical work-up. 
• 
Patients with the following conditions 
where in the investigator’s opinion 
continuing study drug administration is 
justified: 
− Ocular toxicity that has responded to 
topical therapy and has improved to 
≤ Grade 1 severity within 2 weeks of 
starting therapy. 
− Patients without a diagnosis of 
hypophysitis who have Grade 2 
hypothyroidism, Grade 2 low 
testosterone or Grade 2 adrenal 
insufficiency where clinical 
symptoms are controlled with 
appropriate hormone replacement 
therapy.  
NOTE: 
A patient on E1609 ipilimumab 
treatment arms ( Arm A and 
Arm C or Arm D and Arm F, 
respectively) who experiences 
disease recurrence but was still 
considered surgically operable 
and can be rendered disease 
free by surgery should be 
reported as disease recurrence. 
However, in the absence of 
limiting toxicities per protocol 
criteria, such a patient may be 
offered additional ipilimumab 
therapy on protocol that must be 
captured on the usual forms 
(including treatment forms, 
toxicity forms, long term follow 
up for subsequent recurrence). 
In such a case the patient would 
re-start ipilimumab treatment at 
the next scheduled dose when 
medically cleared by his treating 
physician investigator. 
5.5.1.3 
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, 
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and hypopituitarism were drug-related, presumptive 
autoimmune events, now termed irAEs, noted in previous 
ipilimumab studies. 
For the purposes of this study, an irAE is defined as an AE 
of unknown etiology associated with drug exposure and 
consistent with an immune phenomenon. Efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin or 
other etiologic causes prior to labeling an AE an irAE. 
Serological, immunological, and histological (biopsy) data 
should be used to support the diagnosis of an immune-
mediated toxicity. Suspected irAEs must be documented 
on an AE or SAE form.  
Patients should be informed of and carefully monitored for 
evidence of clinically significant systemic irAE (e.g., 
systemic lupus erythematosus-like diseases) or 
organ-specific irAE (e.g., rash, colitis, uveitis, hepatitis or 
thyroid disease). If an irAE is noted, appropriate work-up 
(including biopsy if possible) should be performed, and 
steroid therapy may be considered if clinically necessary. 
See Appendix XIII for suggested work-up and treatment of 
irAEs. 
It is unknown if systemic corticosteroid therapy has an 
attenuating effect on ipilimumab activity. However, clinical 
anti-tumor responses have been maintained in patients 
treated with corticosteroids and discontinued from 
ipilimumab. If utilized, corticosteroid therapy should be 
individualized for each patient.  
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. 
Prior experience suggests that diarrhea and/or colitis that 
is persistent or severe requires corticosteroid treatment. 
See Appendix XIV for GI Management Algorithm for 
additional details. 
5.5.1.4 
Supportive care considerations for ipilimumab 
administration 
5.5.1.4.1 
Treatment of infusion reactions 
associated with ipilimumab 
Since ipilimumab contains only human 
protein sequences, it is less likely that any 
allergic reaction will be seen in patients. 
However, it is possible that infusion of 
ipilimumab will induce a cytokine release 
syndrome that could be evidenced by fever, 
chills, rigors, rash, pruritus, hypotension, 
hypertension, bronchospasm, or other 
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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 50 mg IV 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 
IV. 
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 
physician, ipilimumab infusion may 
be resumed at one half the initial 
infusion rate, then increased 
incrementally to the initial infusion 
rate. 
o If symptoms develop after 
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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). 
5.5.1.4.2 
Treatment of Ipilimumab-Related Isolated 
Drug Fever 
In the event of isolated drug fever, the 
investigator must use clinical judgment to 
determine if the fever is related to the 
ipilimumab or to an infectious etiology. If a 
patient experiences isolated drug fever, for 
the next dose, pre-treatment with 
acetaminophen or non-steroidal anti-
inflammatory agent (investigator discretion) 
should be instituted and a repeated 
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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. 
5.5.1.5 
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 XVII.   
Gastrointestinal (diarrhea) and skin (rash)-related toxicities 
are the most common irAEs reported in previous studies 
with ipilimumab. Suggested evaluation procedures for 
suspected irAEs of the GI tract, liver, skin, eye, pituitary, 
and adrenal gland are described in the current version of 
the IB. When symptomatic therapy is inadequate or 
inappropriate, an irAE should be treated with systemic 
corticosteroids followed by a gradual taper. 
5.5.1.5.1 
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. Subjects should be 
advised to inform the investigator if any 
diarrhea occurs, even if it is mild. An 
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diarrhea or suspected colitis is provided in 
Appendix XIV and the IB.  
Corticosteroid therapy is strongly 
recommended for ipilimumab related  
≥ Grade 3 diarrhea/colitis and should be 
slowly tapered according to symptomatic 
response over at least 1 month. Subjects 
with ipilimumab related Grade 2 
diarrhea/colitis may be initially treated 
conservatively, but should be immediately 
switched to corticosteroids if symptoms 
persist or worsen. For more severe 
symptoms in patients with grade 1 or 2, 
prednisone 60 mg or equivalent may be 
required to control initial symptoms, and the 
dose should be gradually tapered over at 
least a 1-month 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 IV administration) be the 
corticosteroids of choice in the treatment 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. It is strongly recommended that 
these patients be hospitalized for I.V. 
corticosteroids and inpatient work-up. All 
subjects with confirmed colitis should also 
have an ophthalmologic examination, and a 
slit-lamp exam should be considered, to rule 
out uveitis. Also consider testing for stool 
calprotectin and stool WBCs as outlined in 
Appendix XIV. 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. 
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5.5.1.5.2 
Hepatotoxicity 
Liver function tests should always be 
performed and reviewed prior to 
administration of all ipilimumab doses. In 
addition, subjects presenting with right 
upper quadrant abdominal pain, 
unexplained nausea, or vomiting should 
have LFTs performed immediately and 
reviewed before administering the next dose 
of study drug. A Hepatotoxicity 
Management Algorithm is provided in 
Appendix XV 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 rising LFTs, ipilimumab dosing should 
be held according to the dose 
delay/permanent discontinuation guidelines. 
For AST/ALT > 5x the ULN or total bilirubin 
> 3x the ULN, the following should be done: 
(1) ipilimumab should not be administered; 
(2) LFTs should be repeated every 24 hours 
until stabilization or improvement; and (3) 
therapeutic intervention with high dose 
steroids should be strongly considered (e.g., 
methylprednisolone 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 
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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. The most current experience with 
immune-related hepatitis has allowed 
further development of this management 
algorithm (see flow chart in Appendix XV 
and current IB) to include recommendations 
for treatment. 
For rising LFTs with AST/ALT> 5X ULN or 
total bilirubin >3X the ULN or suspected 
immune-mediated hepatitis: 
a. Admit subject to hospital for evaluation 
and close monitoring.  
b. Stop any further ipilimumab dosing per 
protocol (Section 5.5.1.2.3 of protocol).  
c. Start at least 2 mg/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 1g 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 immunosuppressive therapy per 
institutional guidelines and in 
consultation with hepatology. 
h. Continue to check LFTs daily for at least 
2 weeks to monitor sustained response 
to treatment. 
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5.5.1.5.3 
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.  
5.5.1.5.4 
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 (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., 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 
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5.5.1.5.5 
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. 
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 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 
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. 

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Patients diagnosed with hypophysitis should 
be permanently discontinued from additional 
ipilimumab therapy. 
Please see Appendix XVI and the current IB 
for the Endocrinopathy Management 
Algorithm. 
5.5.1.5.6 
Eye 
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. On this 
study, the last dose of ipilimumab will be at 
approximately week 60. Ophthalmologic 
examination is strongly recommended at 6 
and 18 months after start of treatment, to be 
performed by an ophthalmologist. If 
melanoma recurrence occurs before these 
time points, the ophthalmological 
examination should still be done if clinically 
indicated.  
5.5.1.5.7 
Neuropathies 
Isolated cases of motor neuropathy of an 
autoimmune origin have been reported 
among patients treated with ipilimumab. 
Three cases have been diagnosed as 
Guillain-Barre syndrome (GBS), two of 
which were considered study related. In 
both cases, the GBS was atypical in nature 
and more clinically resembled  polyneuritis. 
As of 30 June 2009, 27 cases of neuropathy 
SAEs have been reported. 
Of these, 22 were assessed as unrelated to 
study therapy because alternative 
etiologies, including brain metastases, 
spinal cord compression, arterial 
thrombosis, or platinum-based 
chemotherapy were identified in almost 
every case. Please see Appendix XVII and 
the current IB for the Neuropathy 
Management Algorithm. 
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5.5.2 
ARMS B AND E: Patients receiving Interferon Alfa - 2b 
Induction therapy by the IV route in the first 4 weeks shall be 
evaluated separately from Maintenance in weeks 5-52; a patient 
requiring dose modification(s) in the first month will therefore 
commence month 2 without prejudice, at full 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), 
treatment must first be held. The first modification then requires a 
33% reduction of dosage (to 13.3 MU/m²) and the second modification 
requires a 66% reduction of dosage (to 6.6 MU/m²). A patient who 
requires a third dose modification will be removed from treatment. 
Dose re-escalation will not be attempted following resolution of toxicity 
that required dose interruption or attenuation. Please see the table 
below. 
 
Full 
Treatment 
Dose Mod 1 
Dose Mod 2 Dose Mod 3 
Arm B or E Induction (Weeks 1-4): 
High Dose IFN Alfa - 2b 
20 MU/m²   
13.3 MU/m² 
6.6 MU/m² 
Off 
Arm B or E Maintenance (Weeks 
5-52): High Dose IFN Alfa - 2b 
10 MU/m²  
6.6 MU/m²  
3.3 MU/m² 
Off 
PLEASE NOTE: If a patient experiences any of the toxicities listed 
below, the patient must have a dose modification as 
follows: treatment must be held until the toxicity 
returns to institution’s normal limits, patient’s baseline, 
or normal limits per Common Toxicity Criteria or as 
listed in the table under Section 5.5.2.8, then reduced 
per above.  
EXCEPTIONS: For Grade 3 proteinuria without 
Creatinine or BUN elevation, dose 
should be held until return to Grade 
2 toxicity. For Grade 2 weight loss 
observed over a period of one 
month, dose should be held until 
weight gain or stabilization. 
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. 
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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. 
5.5.2.1 
Constitutional Toxicity 
Fever, chill, myalgia/arthralgia, fatigue, headache: these 
constitutional toxicities of the interferons and other 
biologics 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 higher toxicities.   
5.5.2.2 
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. 
5.5.2.3 
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 bilirubin, AST, ALT or alkaline phosphatase 
require dosage modification. Please refer to table under 
Section 5.5.2.8. 
5.5.2.4 
Nephrotoxicity 
Acute kidney injury of Grade 1 (CTCAE v.4) is an 
indication for dose modification and elevations of Grade 2 
require withdrawal of therapy. 
5.5.2.5 
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 
psychologist).  
5.5.2.6 
Cardiopulmonary 
Cardiac arrhythmia has been reported as a complication of 
interferon therapy, and the  appearance of signs or 
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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. 
5.5.2.7 
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. 
5.5.2.8 
HDI Dose Modification and Discontinuation Guidelines 
(please also see sections 5.5.2.1-5.5.2.7) 
 
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 
 
 
Granulocytopenia 
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 
 
Thrombocytopenia 
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 

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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 
 
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 
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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 
 
 
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. 
5.6 
Supportive Care  
5.6.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study.  
5.6.2 
Patients requiring chemotherapy or radiation therapy will be taken off 
study treatment. Any exceptions must be discussed with the study 
chair. 
5.6.3 
Additional Prohibited and Restricted Therapies During the Study 
5.6.3.1 
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 
• 
Immunosuppressive agents 
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• 
Chronic systemic corticosteroids 
• 
Any non-oncology vaccine therapies used for the 
prevention of infectious diseases (for up to 30 days 
prior to or after any dose of study drug). 
5.6.3.2 
Precautions 
Caution is advised when considering treatment with high-
dose IL-2 in patients who have previously been 
administered ipilimumab, particularly in patients who 
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. 
5.6.4 
Please see Section 5.5.1.4 that provides additional supportive 
care considerations for ipilimumab administration. 
5.7 
Duration of Therapy  
5.7.1 
The duration of therapy for Arms A and D and Arms C and F 
(ipilimumab) patients is approximately 60 weeks (See Section 5.5.1 
for dose and schedule delay criteria). For Arms B and E (HDI) patients 
the duration of therapy is 52 weeks. 
5.7.2 
 Patients who develop any recurrent melanoma will be removed from 
study treatment, unless they fit the criteria in Section 5.2.3. They will, 
however, continue to be followed for survival. In addition, data on 
salvage patterns post recurrence will be collected. 
5.7.3 
Patients will be discontinued from treatment because of excessive or 
unexpected toxicity (see Section 5.5), pregnancy, change in medical 
condition or noncompliance with the study protocol that in the opinion 
of the investigator, necessitates removal of patient from treatment. 
5.7.4 
Withdrawal of consent will automatically remove a patient from study 
treatment. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression and for survival for 20 years 
from the date of registration. All patients must also be followed through 
completion of all protocol therapy. 
5.9 
Quality of Life Evaluations 
Aspects of quality of life (QOL) will be measured for adult patients enrolled by 
CCOPS to arms A, B, and C utilizing the FACT-G and FACT-BRM health 
questionnaires and the FACIT-D (Diarrhea assessment). QOL data will be 
collected at baseline, every 12 weeks (+/- 2 weeks) while on treatment, at 
completion of treatment, and every 24 weeks (+/- 2 weeks) while off-treatment for 
one year. Patients who go off treatment early due to excessive toxicity or 
progressive disease should complete QOL measures at the specified time points. 
The calendar should not be reset. Baseline measures are necessary to draw 
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conclusions about the impact of therapy despite the fact that they will have 
already been altered from predisease levels. They will serve as a comparison for 
each patient's responses after therapy. The follow-up assessments are included 
at regular intervals to observe changes in quality of life as treatment unfolds and 
to determine whether quality of life returns to baseline following the completion of 
treatment. 
5.9.1 
FACT-G has four areas of measurements—physical well-being, 
social/family well-being, emotional well-being, and functional well-
being—all on a scale of 0 to 4. FACT-BRM has two additional 
sections addressing physical and mental QOL aspects. 
5.9.2 
Since colitis/diarrhea is one of the main toxicities of ipilimumab, 
FACIT-D form will be used to assess QOL- related from 
colitis/diarrhea.  FACIT-D form has five areas on physical well-being, 
social/family well-being, emotional well-being, functional well-being, 
and additional concerns with a scale of 0 to 4.    The last section on 
additional concerns has detailed questions pertaining to diarrhea.   
The data items collected in this section will be carefully reviewed.   
The changes between before and after treatment (for each area and 
summary of all five areas) will be compared between the two 
treatment arms.  
5.9.3 
The main comparison will be the change before and after the 
treatment between the two treatment arms.  Longitudinal regression 
models will also be used to address the overall change over time 
during which the QOL data is collected. 
5.9.4 
Every study patient enrolled by a CCOP will be expected to complete 
the QOL assessment. All patients will be informed at the time of 
enrollment that they will be asked to complete the quality of life 
assessment at the specified timepoints. This will also be noted on the 
Informed Consent. Patient calendars will reflect the dates of the 
quality of life assessment and will be given to patients at the time of 
enrollment. 
5.9.5 
All quality of life measures will be administered to the patient as self-
report assessments. CRAs will inform patients that the quality of life 
assessment will require about 5 to 15 minutes to complete, and the 
CRA will provide the patient a quiet place to complete the 
questionnaires. Patients will be instructed to read all instructions at 
the top of the quality of life assessment. After the patient’s 
understanding of the instructions has been confirmed, he/she should 
be instructed to complete every item in order without skipping any 
items on any measure, except where directed. If family members 
prefer to remain with the patients while completing the quality of life 
assessment, CRAs will encourage patients to answer the questions 
on their own (i.e., without the influence of family members). 
5.9.6 
If patients are unable to complete any of the quality of life measures 
independently, because language, literacy or physical condition is a 
barrier, the measures should be administered by a trained staff 
member. Any time that additional assistance is provided, it should be 

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documented on the patient form or the Assessment Compliance Form 
before submitting it to the ECOG-ACRIN Operations Office - Boston. 
5.9.7 
If patients are unable to come to the clinic, the quality of life measures 
will be mailed to them with a request to complete and return them to 
the appropriate person (institutional quality of life coordinator, CRA or 
physician) using a self-addressed stamped envelope. This request 
should be followed by a telephone call by the CRA to assist the 
patient and further completion. 
5.9.8 
Patients should be encouraged to respond to all of the items on all 
measures even those that may not seem pertinent to their situation. 
While patients are still in the clinic, the nurse must check each quality 
of life measure for completeness and encourage the patient to 
complete any uncompleted items. However, patients have the option 
to refuse and the CRA should note the reasons in the margin why an 
item was left unanswered. 
5.9.9 
If a patient fails to complete an assessment for any reason, it will be 
documented on the Assessment Compliance Form. The patient will 
still be asked to complete the remaining quality of life assessments. 
5.9.10 
Each CCOP institution will designate an individual who will ensure the 
timely completion of the quality of life assessments. 

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6. 
Measurement of Effect 
6.1 
Local, Regional Recurrence  
The development of a local or regional recurrence of cancer. 
6.2 
Distant Recurrence  
The development of a distant recurrence of cancer. 
6.3 
Recurrence-Free Survival  
Date of randomization to the date of first treatment failure (recurrence or death 
before recurrence). 
6.4 
Survival  
Date of randomization to date of death. 
6.5 
Histological or cytological evidence of recurrence should be attempted in all 
cases except for brain metastases. Strong consideration should be given to 
resection of solitary brain lesions in the absence of other systemic disease. 
6.6 
Documentation of recurrence will require specification of all sites involved to 
establish the pattern of recurrence. 
6.7 
The following criteria of treatment failure constitute the only acceptable evidence 
of disease recurrence. 
6.7.1 
Lung 
Positive cytology or biopsy in the presence of a single new lesion or 
the appearance of multiple lesions consistent with metastatic disease. 
6.7.2 
Liver 
Positive cytology or biopsy in the presence of a single new lesion or 
the appearance of multiple lesions consistent with metastatic disease. 
6.7.3 
Central Nervous System 
A positive brain CT or MRI scan or CSF cytology. 
6.7.4 
Cutaneous, Subcutaneous and Lymph Node Recurrence 
Positive cytology or biopsy in the presence of a single new lesion or 
the appearance of multiple lesions consistent with metastatic disease. 
6.7.5 
Bone and Other Organs 
Positive cytology or biopsy in the presence of a single new lesion or 
the appearance of multiple lesions consistent with metastatic disease 
identified on two different radiologic studies: i.e., positive nuclear bone 
scan or PET scan and contrast GI series or ultrasound, X-ray or CT of 
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7. 
Study Parameters 
7.1 
 Therapeutic Parameters for all arms 
7.1.1 
All patients must have disease-free status documented by a complete 
physical examination and imaging studies within 4 weeks prior to 
randomization.  
7.1.2 
Pre-study CBC (with differential and platelet count), chemistries and 
other laboratory studies required in Section 3 (Selection of Patients) 
should be done within 4 weeks before randomization. On-study 
procedures (both safety and research related) including laboratory 
studies should be followed per the following study calendars. This 
applies also to patients who go off study treatment for toxicity or other 
reasons but have not had disease recurrence. Patients who have 
disease recurrence should have research blood collected at that time 
point then followed for safety, survival and post-progression salvage 
therapy patterns and other requested follow up data per protocol and 
study forms.     
7.1.3 
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 on the ipilimumab arms (Arms A and D, and 
Arms C and F). It should also be done monthly (-/+ 72 hours) on the 
HDI arm (Arms B and E) starting within 72 hours of the first dose of 
HDI and ending on the first day of month 12 (-/+ 72 hours) or with the 
discontinuation of HDI if earlier than month 12. 
7.1.4 
The follow-up imaging schedule in this protocol is identical for both 
study arms. 
7.1.4.1 
Total body PET-CT and Brain MRI (or CT brain with 
contrast if MRI cannot be done) at baseline. If PET-CT 
cannot be done, CT of neck, chest, abdomen and pelvis 
should be done. If for some reason a CT cannot be done, 
an MRI may be done instead. Any other imaging studies if 
performed (e.g., bone scan) must show no evidence of 
disease. 
7.1.4.2 
Follow up imaging studies on both arms, will be done every 
3 months (-/+ 2 weeks) if patient is < 2 years from study 
entry, then 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. 
7.1.4.3 
Follow-up imaging studies will consist of CT (or MRI if CT 
cannot be done) neck/chest/abdomen/pelvis at follow up 
assessment time points for all patients (A PET-CT is not 
required, but is acceptable if done). MRI/CT brain or other 
imaging studies may be done as clinically indicated but are 
not required in the absence of clinical indications. 
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7.1.5 
Pathologic/cytologic confirmation for melanoma recurrence: 
7.1.5.1 
Required for recurrence in (a) solitary or in doubtful 
lesions, (b) cutaneous, (c) subcutaneous, (d) lymph node 
lesions. 
7.1.5.2 
Should be attempted in all cases (if possible) except for 
brain metastases. 
7.1.5.3 
Date of relapse is the date of first documented recurrence 
(by imaging or physical examination). 
7.1.6 
Radiologic follow up imaging of recurrence is required at least 4 
weeks following first documentation of recurrence and before initiation 
of subsequent salvage therapy (given the known mechanism of action 
and reported progression/response patterns of ipilimumab). 
NOTE: 
A 4-week "wash out" period is expected to be required in 
most cases on subsequent salvage clinical trials, but it will 
be important to capture any subsequent disease regression 
on E1609, which would be an indication to hold salvage 
therapy and either observe or resume E1609 therapy. 
Physician investigators are encouraged to resume E1609 
therapy in patients who experience disease regression at 
follow up imaging following first documented melanoma 
recurrence. 
7.1.7 
During treatment, patients should be closely monitored for the onset 
of neuropsychiatric symptoms. Specific questions should be 
incorporated into the routine evaluation conducted at each patient visit 
so as to allow for early detection of neuropsychiatric symptoms. 
 
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7.2 
Arms A,C, D, and F: Patients Treated with Ipilimumab at 10 mg/kg (Arm A and D) or 3 mg/kg (Arm C and F) 
 
Test/ Assessment 
Within 4 
weeks  
(28 days) of 
starting 
study drugs, 
unless 
stated 
otherwise  
Induction Phasea 
Week 
12 
± 2 
weeks 
Maintenance Phasea 
(Until 12 weeks after 
the last ipilimumab 
dose or until relapse) 
End of Study 
Assessmentn 
Follow 
Upl 
 
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  
± 2 Weeks 
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 
 
Immunologic labso 
 
 
 
 
 
See Footnote o 
 
 
 
 
Urinalysise 
 
 
 
 
 
See Footnote e 
 
 
 
 
Pregnancy test (b-HCG)f 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
HIV, HBV, HCVg 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic examinationh 
Xh 
 
 
 
 
 
Xh 
 
 
Xh 
 
Ipilimumab infusion 
 
X 
X 
X 
X 
 
X 
 
 
 
 
Hormonal studiesi 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Adverse events assessmentj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Imaging studiesk 
Xk 
 
 
 
 
Xk 
Xk 
 
Xk 
 
QOL evaluationsm 
X 
 
 
 
 
X 
X 
 
X 
X 
 
Biological sample submissions 
  See Section 7.4 
 
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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 Section 5.5.1.1 Dose and Schedule Modifications for Ipilimumab and Section 5.5.2.8 HDI Dose Modification and 
Discontinuation Guidelines. 
b. For first infusion only, vital signs to be collected prior to dosing, every 15 minutes during dosing and 30 - 60 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 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. The CBC differential includes enumeration of neutrophils, lymphocytes, eosinophils, monocytes, basophils 
and any abnormal blood cells. 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 unless clinically indicated for safety purposes as per the standard of care for these patients. 
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 unless clinically indicated for safety 
purposes as per the standard of care for these patients. 
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 HBsAg (hepatitis B 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. 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 at 6 and 18 months (± 4 weeks) after start of treatment 
especially in patients who experienced diarrhea or colitis, to be 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 timepoints if 
clincially indicated.  
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Rev. 8/12 
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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. 
j. 
Until 70 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. 
k. Baseline imaging studies: should be done within 4 weeks prior to randomization. These must include a total body PET-CT scan (with or 
without brain) and brain MRI or CT (if MRI is contraindicated). If PET-CT cannot be done, CT of neck, chest, abdomen and pelvis should be 
done. If for some reason a CT cannot be done, an MRI may be done instead. Any other imaging studies if performed (e.g., bone scan) must 
show no evidence of disease. During treatment and on follow-up: CT (or MRI if CT cannot be done) neck/chest/abdomen/pelvis will be 
done every 3 months (-/+ 2 weeks) if patient is < 2 years from study entry, then 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 20 years. A PET-CT is not required, but is acceptable 
if done. Brain MRI/CT or other imaging studies may be done as clinically indicated but are not required in the absence of clinical indications. 
l. 
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 20 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 70 days after the last 
study drug administration. 
m. QOL data will be collected for adult patients enrolled by CCOPs at baseline, every 12 weeks (+/- 2 weeks) while on treatment, at completion of 
treatment, and then every 24 weeks (+/- 2 weeks) while off-treatment for one year. Pediatric patients will not participate in the QOL 
evaluations. 
n. End of Study Assessment will be done within 6 weeks (-/+ 1 week) of the discontinuation of study treatment. 
o. 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). These labs must be 
completed even if the patient goes off treatment early for any reason other than recurrence. 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 
(TOTAL). 
Rev. 8/12 
Rev. 2/12,  
      2/13 
Rev. 2/12, 
2/13
Rev. 2/12 
Rev. 2/12, 
       2/13 
Rev. 8/12 
Rev. 8/12 
Rev. 2/13, 
9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
102 
7.3 
Arm B and E: Patients treated with interferon-α2b: 
Rev. 2/12 
Test/ Assessment 
Within 4 weeks 
(28 days) of 
starting study 
drugs, unless 
stated 
otherwise (eg. 
randomization) 
Induction Phasea 
 
Day 29 
(Start 
of 
mainte
nance) 
Maintenance Phasea 
(Until 4 Weeks after the 
last IFN-α2b dose or until 
relapse) 
End of Study 
Assessmentl 
Follow 
UpJ 
Day 1 
(Week 1) 
Day 8 
(Week 2) 
Day 15 
(Week 
3) 
Day 22 
(Week
4) 
Every 4 
Weeks ±1 
Week for 
2 months 
Every 6 
Weeks ±1 
Week (after 
2 months) 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
History/Physical/ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight/Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rev. 2/12 
Corticosteroid 
immunosuppressant, hormone 
Meds Log 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
Hematology Labsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry Labsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunologic labsm 
 
 
 
 
 
 
See 
Footnote 
m 
 
 
 
 
Urinalysisd 
 
 
 
 
 
 
See 
Footnote d 
 
 
 
 
Pregnancy Test (b-HCG)e 
X 
 
 
 
 
 
See 
Footnote e 
 
 
 
 
HIV, HBV, HCVf 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
Hormonal studiesg 
 
X 
 
 
 
X 
X 
 
X 
 
 
Adverse Events Assessmenth 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rev. 2/12 
Imaging studiesi 
Xi 
 
 
 
 
 
Xi 
 
Xi 
 Rev. 2/13, 
2/14 
QOL evaluationsk 
X 
 
 
 
 
 
 
 
X 
X 
 
Biological Sample Submissions 
See Section 7.4 
Rev. 9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
103 
a. All Study procedures, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 3 days prior to 
dosing. Baseline pregnancy exam must be performed within 3 days of beginning IFN-α2b treatment and determined to be negative. NOTE: for 
Days 8, 15, 22 and 29 if IFN-α2b was delayed per the dose delay/scheduling criteria or if a visit had to be delayed due to major circumstances 
(such as a health emergency, family/personal  emergency, transportation difficulties, scheduling difficulties; a visit date falls on a holiday), the 
study assessments scheduled for these dates will be delayed. 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 Section 5.5.1.1 Dose and Schedule Modifications for 
Ipilimumab and Section 5.5.2.8 HDI Dose Modification and Discontinuation Guidelines. 
b. 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. The CBC differential includes enumeration of neutrophils, lymphocytes, eosinophils, monocytes, basophils 
and any abnormal blood cells. 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 unless clinically indicated for 
safety purposes as per the standard of care for these patients. 
c. Chemistry laboratory analysis includes albumin, creatine kinase (CPK), 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. 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 unless clinically indicated for safety purposes as per the standard of 
care for these patients. 
d. 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. 
e. 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 should also be done within 72 hours of the first dose of HDI, then during HDI therapy every 4 weeks  x3 (-/+ 1 week), 
then every 6 weeks (-/+ 1 week) and ending with the discontinuation of HDI. At HDI discontinuation, a negative pregnancy test within the 
preceding 6 weeks is sufficient.  A pregnancy test should also be done at anytime if there are clinical concerns for possible pregnancy. 
f. At screening, testing should be performed for HIV antibody, hepatitis C antibody, and HBsAg (hepatitis B 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. 
g. Hormonal studies: To be done at the indicated visits and when clinically indicated. These include TSH, free T4. 
h. Until 70 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 points specified on the forms. 
i. Baseline imaging studies: should be done within 4 weeks prior to randomization. These must include a total body PET-CT scan (with or 
without brain) and brain MRI or CT (if MRI is contraindicated). If PET-CT cannot be done, CT of neck, chest, abdomen and pelvis should be 
done. If for some reason a CT cannot be done, an MRI may be done instead. Any other imaging studies if performed (e.g., bone scan) must 
show no evidence of disease. During treatment and on follow-up: CT (or MRI if CT cannot be done) neck/chest/abdomen/pelvis will be 
done every 3 months (-/+ 2 weeks) if patient is < 2 years from study entry, then 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 20 years. A PET-CT is not required, but is acceptable 
if done. Brain MRI/CT or other imaging studies may be done as clinically indicated but are not required in the absence of clinical indications. 
Rev. 8/12 
Rev. 8/12 
Rev. 8/12 
Rev. 2/13 
Rev. 2/13 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
104 
j. Follow up period will start 12 weeks after the last interferon 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 20 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 70 days after the last 
study drug administration. 
k. QOL data will be collected for patients enrolled by CCOPs at baseline, every 12 weeks (-/+ 2 weeks) while on treatment, at completion of 
treatment, and then every 24 weeks (-/+ 2 weeks) while off-treatment for one year.  Pediatric patients will not participate in the QOL 
evaluations. 
l. End of Study Assessment will be done within 6 weeks (-/+ 1 week) of discontinuation of study treatment. 
m. 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). These labs must be 
completed even if the patient goes off treatment early for any reason other than recurrence. 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 
(TOTAL). 
Rev. 2/12, 
      2/13 
Rev. 2/12, 
       8/12 
Rev. 2/12, 
2/13 
Rev. 2/13 
Rev. 2/13 
Rev. 9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
105 
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 II (Pathology Submission Guidelines). 
2. Pathology samples for banking should be submitted as outlined in Section 
10 per patient consent. 
3. Blood samples for banking 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) (see Section 10.4) for 
purposes of monitoring compliance. 
NOTE:  
An informed consent must be signed prior to the submission of any 
samples, including mandatory diagnostic reviews and banking for 
research in accordance with the patient consent. Samples for banking 
should be submitted only from patients who have given written 
consent for the use of their samples for these purposes. 
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. 
Biological Materials 
Baseline1 
After 3 weeks 
(Arms A/D, and 
C/F) / 4 weeks 
(Arms B/E) of 
Initiating 
Treatment12 
After 12 
weeks of 
Initiating 
Treatment2 
48 
weeks2 
Progression/ 
Relapse8 
MANDATORY for Central Diagnostic Review 
Pathology Samples6 
X9 
 
 
 
X8 
From patients who answer “YES” to “I agree to provide additional blood for research.” 
Peripheral Blood (ten 10cc 
green top heparin tubes)4,5,7 
X 
X 
X 
X 
X2,3 
Peripheral Blood (three 10cc 
red top tubes)4,5,7 
X 
X 
X 
X 
X2,3 
PAXgene RNA Tube (1)4,5,7 
X 
X 
X 
 
 
Peripheral Blood, (one 10cc 
yellow ACD top tube)4,5,7 
X 
 
 
 
 
1. Prior to start of treatment. 
2. ± 2 weeks. 
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 11.1.2.1 for instructions. 
5. Please completely fill all blood tubes as full as possible. 
Rev. 2/12,
8/12
Rev. 2/12,  
8/12, 9/14 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
106 
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 have tissue submitted for research. 
9. Mandatory submission for central review. 
10. [Deleted in Addendum #5] 
11. [Deleted in Addendum #5] 
12. On the day of the scheduled administration of the second dose of ipilimumab (day 22 -/+ 
3 days) and before administering the second dose of ipilimumab on Arms A, C, D, 
and F (up to one week prior to the scheduled administration of the second dose is 
acceptable if not possible on the same day). On the day of initiation of maintenance 
subcutaneous IFN (day 29 -/+ 3days) on Arm B or E (up to one week prior to initiation of 
maintenance subcutaneous IFN is acceptable if not possible on the same day). If the 
study treatment was delayed or discontinued for that day due to adverse events the 
blood specimen should still be collected. 
Rev. 8/12, 
9/14 
Rev. 3/15 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
107 
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) 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). Completed Clinical Drug Requests (NIH-986) should be submitted to the 
PMB by fax 240-276-7893 or mailed to the Pharmaceutical Management Branch, CTEP, 
DCTDC, NCI, 9000 Rockville Pike, EPN, Rm. 7179, Bethesda, M.D. 20892. The NCI 
Clinical Drug Request form is available on the NCI home page (http://ctep.info.nih.gov) 
or by calling the PMB at 240-276-6575.  
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. 
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 
Rev. 2/14 
Rev. 2/14 
Rev. 2/14 
Rev. 2/14 
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ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
108 
Ipilimumab has two manufacturing processes- ongoing trials have 
been using substances manufactured using Process B. This trial, 
E1609, 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 Tcells. 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. 
 
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. 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
109 
8.1.6 
Dose Specifics  
Induction Phase: 
Ipilimumab 10 mg/kg (Arms A and D) or 3 mg/kg (Arms C and F), 
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 (Arms A and D) or 3 mg/kg (Arms C and F), 
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 Arms A and D 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. 
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 
Rev. 2/12, 
9/14 
Rev. 2/12, 
9/14 
Rev. 2/12 
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ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
110 
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 a total volume of 90 mL in 
0.9% sodium chloride.  
• 
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. 
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 5.4(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 womenand women with known or suspected pregnancy 
should not take ipilumumab. 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
111 
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 
can not 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 
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. 

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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 
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.  
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. 
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 
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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. 
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 E1609 Patient Diary - Interferon, Appendix 
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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 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. 
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 
Updated Final Analysis Plan: 
As information for the primary endpoint was accumulating slower than anticipated, the 
pattern of information-time accumulation was reviewed by the study team from ECOG-
ACRIN, CTEP and BMS on July 13, 2018. Dr. Edward Korn (NCI CTEP) and Dr. 
Catalano (independent ECOG-ACRIN statistician) concluded that it is not likely to obtain 
the required number of events with a longer follow-up time. This conclusion was 
obtained using the pattern of information-time accumulation, the survival-curve 
assumptions in the protocol, and the published survival results with ipilimumab in a 
similar setting (Eggermont, et al. Lancet Oncol. 2015 May;16(5):522-30). The vast 
majority of the deaths were expected to occur in the first 4.5 years. Dr. Korn and Dr. 
Catalano recommended that the study team conduct the final analysis 4.5 years after the 
date the last patient was accrued on study arms A, B, or C, (which was August 15, 
2014). Therefore, the recommended date of the final analysis would be February 15, 
2019. The Z-value for declaring statistical significance at this final analysis can be 
calculated (in the usual way) from the remaining type I error not already spent from the 
interim analyses prior to February 15, 2019, using the correlation between the interim-
analyses test statistics and the final analysis test statistic.  The regularly scheduled 
interim analysis for the DMSC in the Fall 2018 was recommended to proceed as usual, 
with the trial amended for the new final analysis date soon after the Fall DSMC meeting. 
A total of four interim analyses have been conducted as of September 2018 and 
following this recommendation, the final analysis will be conducted using the data as of 
February 15, 2018.  This will alter the interim analysis plan stated in section 9.6. The 
analysis based on the data as of February 15, 2019 will be the planned final analysis for 
all comparisons and the hierarchical testing plan described in sections 9.4 and 9.5 will 
still be followed. 
9.1 
Previous Study Design 
Initially this study was designed to compare the high-dose (10mg/kg) ipilimumab 
(Ipi) vs. HDI. The study was activated on May 25, 2011. Subsequently the 
importance of the low-dose Ipi (3mg/kg) in this patient population was discussed 
based on the results of the MDX010-20 trial and the FDA approval of ipilimumab 
at 3 mg/kg in the treatment of metastatic melanoma, leading to the addition of the 
3 mg/kg arm to this trial as of January 2012. Since then patients are randomized 
to three treatment arms: High dose interferon-alfa (HDI), high dose ipilimumab 
(HIP) and low dose ipilimumab (LIP).  
With the addition of low dose ipilimumab (LIP) arm, a two-step hierarchical 
approach was adopted. In the first step, the high-dose Ipi was to be compared 
with HDI. If the high-dose Ipi is significantly better than HDI, then the low-dose Ipi 
was to be compared with HDI as a second step. However, the order of the 
comparison has been revised to the low-dose Ipi vs. HDI first then to the high-
dose Ipi vs. HDI in February 2015. This revision was made since the low-dose Ipi 
has become the standard of care in the treatment of metastatic melanoma. Since 
no formal interim analysis had been conducted prior to this revision, this change 
did not affect the overall type I error rate of the study design.   
Rev. 2/12 
Rev. 5/15 
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9.2 
Primary Objective 
This is a randomized phase III study of high-dose Ipi (HIP) vs. low-dose Ipi (LIP) 
vs. HDI in patients with resected high-risk melanoma. Approximately 1500 
patients will be randomized equally among the three treatment arms, stratified by 
the AJCC stage (IIIB, IIIC, M1a, M1b). The stratified randomization will be based 
on the permuted block method. 
This study has a two-step hierarchical approach. In the first step, the low-dose Ipi 
will be compared with HDI. If the low-dose Ipi is significantly better than HDI, then 
the high-dose Ipi will be compared with HDI as a second step.  When comparing 
the two investigational treatment groups, the primary comparison will be an intent 
to treat (ITT-defining groups by assigned treatment) analysis of recurrence free 
survival (RFS; First Co-primary Endpoint) and overall survival (OS; Second 
Co-primary Endpoint) in all patients compared to HDI. Both of these endpoints 
will be used as co-primary endpoints in the sense that the study will be 
considered a positive study if it meets either one of these 2 endpoints (see 
Section 1.7.1). That is, in the first step of comparing the low-dose Ipi vs. HDI, it 
will be a positive study if the low-dose Ipi has better RFS or OS outcome. Then 
the comparison will proceed to the second step where the high-dose Ipi will be 
compared to HDI. In each comparison, patients concurrently randomized to the 
two arms being compared will be included in the analysis. . If high-dose Ipi leads 
to a better RFS or OS outcome than the HDI, it will be considered as a positive 
study with respect to the second comparison. 
9.3 
Sample Size and Accrual 
Approximately 1500 patients will be enrolled over 3.3 years. Accrual rate is 
expected to be 38 per month.  Note that the low-dose Ipi arm will be added in 
January 2012 and the low-dose Ipi arm will need a concurrent HDI arm as control 
group. Each group has a sample size of about 500 cases. After the low-dose ipi 
is added, patients will be still randomized equally to three treatment arms. 
Accrual to high-dose Ipi arm will be suspended when it reaches 500 cases. For 
the other two arms (low-dose Ipi and HDI), accrual will continue until each arm 
has 500 cases since the time of adding the low-dose Ipi arm. This will lead to a 
slightly larger sample size (> 500) for the HDI arm. However, it is expected that 
the overall accrual period necessary for completion of the 3mg/kg dose arm and 
concurrent HDI accrual will not be more than several months due to this 
adjustment.  Every effort will be made to shorten the accrual duration with active 
intergroup participations. With additional follow up time, a total duration of study 
is expected to be less than 6 years. The primary comparisons of RFS and OS will 
be performed using the log-rank test stratified on AJCC stage. 
Per amendment #10, approximately 45 adolescent patients (ages 12-17) will be 
enrolled. If accrual to the adult population reaches its goal before 45 adolescent 
patients enroll to this study, the study will remain open only to the adolescent 
population until 2016. If the adolescent population reaches its accrual goal of 45 
before the adult population reaches its accrual goal, adolescent accrual will be 
closed. With the data from a small group (45 or less) of adolescent population, 
analysis will be mostly descriptive and exploratory. 
As of August 15, 2014, adult accrual to Arms A, B, and C has completed. 
Adolescent patients (ages 12 -17) will be randomized to study arms D, E, and F. 
Rev. 9/14 
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9.4 
First Step: Comparison of Low-dose Ipi vs. HDI 
9.4.1 
RFS 
The recurrence-free survival (RFS) is defined from the time from 
randomization to the time of disease recurrence or death from any 
cause.   
Since a moderate percentage of long-term cures have been observed in 
melanoma patients on previous melanoma study, E4697, we have used a 
model proposed by Berkson and Gage (1952) and Goldman (1984). This 
model specifies that the target population is a mixture, with proportion p 
who will be cured, and (1 – p) who will fail according to an exponential 
distribution with rate β. The RFS function D(t) for the HDI arm (A) and the 
Ipi arm (B) is expressed as: 
DA(t) = p + (1 - p) exp(- β t) 
DB(t) = {p + (1 - p) exp(- β t)}ө 
where ө represents a hazard ratio under the proportional hazards 
alternative. For  RFS, it was assumed that the cure rate is 29% and 
the median survival time for those not cured is 0.487 years in patients 
randomized to the HDI arm. Under the proportional hazards 
alternative, we hypothesize that Ipi will reduce the hazard by 25% 
(hazard ratio ө=0.75). The full information is 655 events in high-dose 
Ipi and HDI groups. This design provides at least 80% power at a one-
sided type I error rate of 0.003. An ITT analysis using the stratified 
log-rank test will be performed. 
9.4.2 
OS 
Based on E4697 data, the cure rate model is appropriate for this 
endpoint. This model specifies that the target population is a mixture, 
with proportion p who will be cured, and (1 – p) who will fail according 
to an exponential distribution with rate β. The survival function S(t) for 
the HDI arm (A) and the Ipi arm (B) is expressed as:  
SA(t) = p + (1 - p) exp(- β t) 
SB(t) = {p + (1 - p) exp(- β t)}ө 
where ө represents a hazard ratio under the proportional hazards 
alternative. For the primary endpoint, OS, it was assumed that the 
cure rate is 35% and the median survival time for those not cured is 
2.44 years in patients randomized to the HDI arm. Under the 
proportional hazards alternative, we hypothesize that Ipi will reduce 
the hazard by 25% (hazard ratio ө=0.75). This design requires a total of 
1000 patients. The full information corresponds to 416 deaths in low-
dose Ipi and HDI  groups. This design will provide 80% power to detect 
the above difference at a one-sided type I error rate of 0.022. An ITT 
analysis using the stratified log-rank test will be performed. 
9.5 
Second Step: Comparison of High-dose Ipi vs. HDI 
The second step comparison will only occur if the first step comparison described 
in Section 9.4 is significant for either RFS or OS endpoint.  In such case, the 
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patients enrolled after the low dose ipi arm is added will be included. The same 
design considerations in Section 9.4 will be applied in the second step. 
9.6 
Interim Analysis 
First with respect to the first step comparison of low-dose Ipi vs. HDI, interim 
analyses of RFS and OS will be performed for all semi-annual DMC meetings 
beginning when approximately 50% of the planned full information (416 deaths 
among patients treated with low-dose Ipi and HDI) has occurred. The data from 
both of these co-primary endpoints will be reviewed, however an early stopping 
of the study will be considered only based on the OS endpoint. It is expected to 
have 6 interim analyses at .5, .62, .72, .81, .89, .96 information time and 1 final 
analysis. To preserve the overall type I error rate, critical values at the interim 
analyses will be determined using a truncated version of the Lan-DeMets 
spending function corresponding to the O'Brien-Fleming boundary. Boundary 
values at a nominal significance less than 0.0005 will be truncated at 0.0005, 
with the boundary also adjusted to preserve the overall one-sided type I error 
rate of 0.022 for the OS endpoint.   This study will also be monitored for early 
stopping in favor of the null hypothesis. In particular, at each scheduled interim 
analysis, we will compute the conditional power of rejecting the null hypothesis at 
full information. If the conditional power is less than 10%, an early termination of 
the study will be considered. 
For the RFS endpoint, interim analysis will begin when the OS endpoint has 
reached 50% information time and will be repeated every 6 months. The 
expected information at the first interim analysis is about .83 for the RFS 
endpoint. Interim analysis of RFS will be presented to the DSMC at the time of 
OS interim analyses, but the study does not have stopping rules based on the 
RFS endpoint. The primary analysis for RFS will take place when the full 
information (655 events) is reached. If a treatment benefit is indicated in the RFS 
endpoint at this time, this study will be considered as a positive study regardless 
of the OS result at this time. 
The interim analyses for the second step comparison (high-dose ipi vs. HDI) will 
begin only when the interim analysis for OS or full-information analysis for RFS 
indicates significantly better result in the low-dose Ipi arm in comparison to the 
HDI arm. 
To preserve overall type I error rates for both RFS and OS endpoints, the 
hierarchical testing will be implemented separately for RFS and OS endpoints. 
Interim analyses of low dose Ipi vs. HDI for RFS will begin once low dose Ipi vs. 
HDI is significant for RFS (and only if it is) and interim analyses of high-dose Ipi 
vs. HDi for OS will begin once low dose Ipi vs. HDI is significant for OS (and only 
if it is).  
Similarly during the final analysis, if low dose Ipi vs. HDI is significant for RFS at 
the 0.3% level, then we will compare RFS between high dose Ipi vs. HDI at the 
0.3% level. If low dose Ipi vs. HDI is significant for OS at the 2.2% level, then we 
will compare high dose Ipi vs. HDI at the 2.2% level. These two decisions will be 
made separately and if only RFS is significant for low dose Ipi vs. HDI, then only 
RFS will be compared for high dose Ipi vs. HDI.  Similarly if only OS is significant 
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The futility analysis based on the OS will start at the same time as the first step 
OS comparison and will continue. At each scheduled interim analysis, we will 
compute the conditional power of rejecting the null hypothesis at full information, 
If the conditional power is less than 10%, an early termination of the study will be 
considered. If the low-dose Ipi arm is suspended due to the futility analysis, the 
high-dose Ipi vs. HDI comparison will still continue. 
9.7 
Secondary Objectives 
9.7.1 
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) v.4.0 of the Common Terminology Criteria for Adverse Events 
(CTCAE). 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. 
Expected toxicity data for ipilimumab treated patients, based on the 
BMS four phase II studies utilizing the 10 mg/kg dose with 325 
patients, is as follows. Overall 32.6% experienced the worst 
treatment-related AEs of grade 3/4/5. Immune-related AEs were 
experienced in 72.3% of patients. Of these, 25.2% were Grade 3/4 
and occurred in the following 4 main types: i) Gastrointestinal: e.g., 
colitis, diarrhea (12.3%), ii) Liver: e.g., transaminase elevation (6.8%), 
iii) Skin: e.g., rash pruritis (2.8 %), iv) Endocrine: e.g., hypophysitis, 
thyroiditis (2.5%). Other complications, i.e., bowel perforations, liver 
failure were minor (~1%). In addition there were 5 treatment-related 
deaths: 4 immune-related: multi-organ failure, abnormal hepatic 
function, and acute glomerulonephritis, hypovolemic shock and 1 not 
immune-related: acute myeloid leukemia. The toxicity data from all 
treated patients will be reviewed carefully by the ECOG-ACRIN DMC. 
In the early part of the study, when 50 patients and then 100 patients 
are treated with each of the ipilimumab doses, toxicity incidence data 
will be summarized and presented to DMC. All treatment-related 
toxicity data will be presented along with a summary on the worst 
grade. A particular attention will be given to the specific toxicity types 
mentioned above. Toxicity incidence rate and 95% confidence interval 
for each type will be presented. Upon DMC’s review, if there are major 
issues, this will be communicated with the CTEP. 
In the MDX010-20 trial (ipilimumab 3 mg/kg), 97-98% patients 
experienced any adverse event and approximately 46% experienced 
grade 3/4/5 adverse events. (Hodi et al. NEJM 2010) The most 
common adverse events related to the study drugs were immune-
related events, which occurred in approximately 60% of the patients 
treated with ipilimumab. The frequency of grade 3 or 4 immune 
related adverse events was 10 to 15% in the ipilimumab groups. The 
most common immune-related adverse event was diarrhea, which 
occurred at any grade in 27 to 31% of the patients in the ipilimumab 
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in the ipilimumab/gp100 and ipilimumab/placebo arms respectively 
was as follows:  dermatologic (2.4% and 1.5% of patients), GI (5.8% 
and 7.6%), endocrine (1.1% and 3.8%), hepatic (1.1% and 0%). 
Death due to irAE occurred in 1.3% and 1.5% respectively. 
Interim toxicity monitoring and analysis will be performed separately 
for the high dose ipilimumab (HIP) and low dose ipilimumab (LIP) 
arms. If one arm meets criteria for discontinuation due to toxicity the 
other arm will continue enrolling patients and continue to be monitored 
per protocol monitoring criteria. For example, if HIP arm was 
discontinued due to toxicity, LIP arm will continue per protocol unless 
LIP meats criteria for discontinuation as well. 
9.7.2 
Quality of Life 
General hypothesis: There are no clinically relevant differences 
between the two arms using global QOL scale at the assessed 
intervals (every 3 months while on treatment and every 6 months off-
treatment for one year). There may be a later advantage to the 
ipilimumab arm if disease progression occurs, thereby leading to a 
better global QOL. 
Primary hypothesis (for sample size calculation): Ipilimumab is 
superior to HDI using global QOL scale at 12 weeks following the 
initiation of therapy (after completion of the ipilimumab induction 
phase). 
The primary objective for the QOL study is to evaluate if patients 
treated with ipilimumab will have a better global QOL. This component 
of the protocol will be open to patients enrolled by Community Clinical 
Oncology Programs (CCOPs). 
FACT-G will be collected at baseline, every 3 months while on 
treatment and every 6 months off-treatment for one year. The main 
time point for the comparison of global QOL between the two 
treatment arms will be at 3 months following the initiation of therapy 
(after completion of the ipilimumab induction phase).  
FACT-G has four areas of measurements (physical well being, 
social/family well-being, emotional well-being and functional well-
being) with a scale of 0-4. The changes between before and after 
treatment for each area and summary of all four areas will be 
compared between the two treatment arms. We do not have the 
preliminary QOL data to justify the sample size calculation. We plan to 
perform the QOL study in all patients enrolled by CCOPs, projected to 
be about a third of the patients (450 total patients, 150 per arm).  We 
will use the baseline and 3 months data to compare the change 
before and after the treatment between the two treatment arms (high-
dose Ipi vs. HDI and low-dose Ipi vs. HDI).  If the standardized 
difference (difference in means / sd) is at least 0.4, this analysis will 
have at least 80% power for each comparison. Given the exploratory 
nature of this analysis, no adjustments for the multiple comparisons 
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This is based on one-sided type I error rate of 0.025. While the study 
is open to accrual, the proportion of patients from CCOP institutions 
will be monitored. If the QOL accrual target cannot be met by CCOPs 
alone, a plan to expand the QOL component to other institution types 
will be considered. 
The secondary objective of QOL study is to evaluate the effect of 
adjuvant ipilimumab and HDI on the various symptoms and 
functioning scales as treatment related side effects that may have an 
impact on the health-related domains of QOL. FACT-BRM and 
FACIT-D forms will also be collected on the same schedule as the 
FACT-G form. FACT-BRM has two additional sections addressing 
physical and mental QOL aspects. FACIT-D has a section addressing 
colitis and diarrhea related issues.  
For both QOL objectives, ITT analysis in all patients (from two 
treatments) will be conducted. The changes between before and after 
treatment will be compared between the two treatment arms. The two-
sample t-test will be used to compare continuous measurements and 
Chi-square test will be used to compare the categorical outcomes 
between the two treatment groups. Longitudinal regression models 
will also be used to address the overall change over time during which 
the QOL data is collected. 
9.8 
Statistical Analysis Plan 
9.8.1 
Primary analysis 
RFS is defined as the time from randomization to the time of disease 
recurrence or death from any cause.  OS is defined as the time from 
randomization to the time of death due to any cause. Both RFS and 
OS will serve as co-primary endpoints in this study.  When 50% 
information time (208 deaths among patients treated with low dose Ipi 
or HDI) is reached for OS, the first interim analysis will begin. To 
preserve overall type I error rates for both RFS and OS endpoints, the 
hierarchical testing will be implemented separately for RFS  and OS 
endpoints. Interim analyses of high dose Ipi vs. HDI for RFS will begin 
once low dose Ipi vs. HDI is significant for RFS (and only if it is) and 
interim analyses of high-dose Ipi vs. HDi for OS will begin once low 
dose Ipi vs. HDI is significant for OS (and only if it is).  
Similarly during the final analysis, if low dose Ipi vs. HDI is significant 
for RFS at the 0.3% level, then we will compare RFS between high 
dose Ipi vs. HDI at the 0.3% level. If low dose Ipi vs. HDI is significant 
for OS at the 2.2% level, then we will compare high dose Ipi vs. HDI at 
the 2.2% level. These two decisions will be made separately and if 
only RFS is significant for low dose Ipi vs. HDI, then only RFS will be 
compared for high dose Ipi vs. HDI.  Similarly if only OS is significant 
to low dose ipi vs. HDI, then only OS would be compared for the high 
dose arm.   
The primary comparison will be an ITT analysis including all cases as 
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log-rank test.  Kaplan-Meir plot will be generated and two-sided p-
values will be reported. 
During the interim analysis, data available as of the data cut-off date 
for a specified interim analysis will be included. Specific guidelines 
outlined in section 9.6 will be used.  Briefly, for the efficacy analysis, 
the type I error rate will be allocated per truncated O’Brien-Fleming 
boundary (equivalent to O’Brien-Fleming boundary in our case since 
the first analysis will not begin until 50% information time).  For the 
futility analysis, the conditional power will be calculated.  Hazard ratio 
will be estimated and repeated confidence intervals will be generated 
for OS and RFS.  
 At the final analysis, all cases will be included.   If the proportional 
hazard assumption is appropriate, multivariate Cox proportional 
hazard models for RFS and OS will be developed at the final analysis.  
Prognostic factors such as age, gender, stage, ulceration, etc will be 
included. For the stratified log-rank test and Cox proportional hazards 
regression model, sensitivity analysis will be conducted at the final 
analysis based on analyzable(eligible and treated) patients only.  
At the final analysis, if the low-dose Ipi vs. HDI is significant and high-
dose Ipi vs. HDI is significant for OS then OS will be compared for the 
low-dose Ipi vs, high-dose Ipi arms.  Similarly, if  the low-dose Ipi vs. 
HDI is significant and high-dose Ipi vs. HDI is significant for RFS then 
RFS will be compared for the the low-dose Ipi vs, high-dose Ipi arms.  
It is likely this comparison will be underpowered.  
9.8.2 
Toxicity data analysis  
Adverse events (AE) data will be summarized based on the data 
collected in ECOG CRFs as well as the data reported via CTEP-
AERS.  Individual toxicity type AE and categorized AE data (by 
autoimmune disorders, endocrine, GI, liver, nervous system, 
pancrease, psychiatric disorders, skin, thromboemblic disorders) will 
be summarized by grade and treatment arm.  The percentages of 
patients experiencing the worst degree toxicities (highest grade event 
per AE type per patient) will be evaluated and the distribution of the 
worst degree toxicities will be compared among the treatment arms.   
The proportion of patients with worst degree toxicities with 3 or higher 
will be summarized and compared  among the treatment arms.  Chi-
square test will be used for AE comparisons.   For the AE data, any 
patient who received treatment will be included. 
9.8.3 
Other secondary analyses 
The QOL study is open to patients enrolling from CCOPs. FACT-G, 
FACIT-D and FACT-BRM forms will be collected every 3 months while 
on treatment and every 6 months off-treatment for one year. 
The main comparison for all forms will be the change in QOL 
measurements between the baseline and 3 month time point by 
treatments (high-dose Ipi vs, HDI or low-dose ipi vs. HDI).  Descriptive 
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will be used for each comparison and two-sided p-values will be 
reported. ITT analysis on all cases with QOL data will be conducted.  
At the final analysis, subgroup analyses of the treatment effects on 
RFS and OS will be conducted. Subgroups by age, sex, ECOG PS, 
AJCC stage (IIIB, IIIC, M1a, M1b), ulceration status of the primary, 
type of lymph node involvement (microscopic / macroscopic), extent 
of lymph node involvement (1 vs 2-3 vs ≥ 4 positive LN) will be 
considered in the ITT patient population. This analysis will be 
summarized using the forest plots with HRs and 95% CIs. 
In the event of missing data, it will be assumed that the data will be 
missing at random and no imputation will be performed.  
9.9 
Gender and Ethnicity 
Based on previous data from E4697 and E1694, the anticipated accrual in 
subgroups defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
6 
8 
Not Hispanic or Latino 
567 
925 
1492 
Ethnic Category: Total of all subjects 
569 
931 
1,500 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
2 
2 
Black or African American 
3 
3 
6 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
566 
926 
1492 
Racial Category: Total of all subjects 
569 
931 
1,500 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual 
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9.10 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC 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 DSMC 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 DSMC. Any DSMC 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 DSMC Policy can be 
obtained from the Coordinating Center. 
9.10.1 
Arm A Toxicity Monitoring  
Grade 5 AE data reported via CTEP-AERS system has been 
reviewed by ECOG-ACRIN DSMC. Based on the data as of 9/23/13, 
there had been 8 grade 5 AEs potentially treatment-related in arm A. 
At that time, there were 405 patients who were treated with 10mg/kg 
Ipi dose. While AE data was being reviewed by ECOG-ACRIN DSMC, 
accrual to arm A was suspended and treatment for the patients 
randomized to arm A was held. Upon reopening the arm A for accrual 
and grade 5 AE data will be reviewed carefully. When there is a new 
grade 5 AE event in arm A, a study statistician will be alerted. The 
rate of grade 5 potentially treatment-related AE will be estimated by 
dividing the total number of cases with grade 5 potentially treatment-
related AEs by (total accrual in arm A – cases never started therapy). 
If this rate is greater than or equal to 2.5%, ECOG-ACRIN DSMC will 
be notified and this matter will be discussed. If this rate is reached, it 
will require suspension of accrual to arm A while the review is 
conducted. 
For a cutoff rate of 2.5%, the rule would be 11 events in 440 or fewer 
treated patients, 12 events in 480 or fewer patients, or 13 in > 480 
(assuming < 520 entered). Given that we already have observed 8 
potentially treatment-related grade 5 AE events in 405 patients, the 
conditional power for the proposed rule can be estimated by: the 
probability of 3 or more (to reach 11) in 35, plus the probability of 4 or 
more in 75 given < 3 in the first 35, plus the probability of 5 or more in 
95 given < 3 in the first 35 and < 4 in the first 75. Then the conditional 
power is 3.7% for a true grade 5 AE rate of 1.5%, 8.5% for a true 
grade 5 AE rate of 2.0%, 15.3% for a true rate of 2.5%, 23.6% for a 
true rate of 3.0%, 32.9% for a true rate of 3.5%, 42.5% for a true rate 
of 4.0%, and 60.4% for a true rate of 5.0%. Conditional power is not 
particularly high given that we have already observed 8 cases with 
grade 5 AEs out of 405 treated patients. However this toxicity 
monitoring rule will provide some guidance for a formal review by 
ECOG-ACRIN DSMC. 
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9.11 
Adolescent Patients 
As of amendment #10 activation, E1609 age eligibility criteria will be expanded to  
allow adolescent patients ages 12–17 years old. This is based on preliminary 
safety and tolerability data reported in study NCI 7458. UP to 45 patients will be 
randomized into the 3 study arms as follows: up to 15 patients on Arm D 
(ipilimumab 10 mg/kg), up to 15 patients on Arm E (HDI) and up to 15 patients on 
Arm F (ipilimumab 3 mg/kg). This patient sample size of 45 will be in addition to 
the approximately 1500 adult patients planned to be enrolled on this trial. The 
primary study objective for the adolescent patient population is safety. This 
includes the frequency of study treatment related adverse events with a focus on 
the frequency and severity of ipilimumab induced immune mediated adverse 
reactions in adolescent patients with resected high risk melanoma (Stage IIIB, 
IIIC, M1a, M1b) as the primary endpoint in this study population. Further, the 
plans for the adult population study analysis will not be impacted by the accrual 
in the adolescent population part of the study. 
 
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10. 
Pathology Review 
NOTE:  
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 10.4.  
NOTE: 
An informed consent must be signed prior to the submission of any samples, 
including mandatory diagnostic reviews and banking. 
10.1 
Pathology samples must be submitted for review and classification (baseline 
only) and banking. 
The submitting pathologist and clinical research associate should refer to 
Appendix II (Pathology Submission Guidelines) for guidelines and summary of 
submission requirements. 
10.2 
Materials Required For This Protocol 
10.2.1 
Forms (must be submitted with all tissue submissions) 
• 
A copy of the surgical pathology report 
• 
Immunologic studies, if available 
• 
Sample Tracking System Shipping Manifest (see Section 10.4) 
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.  
10.2.2 
Pathology Submissions (Mandatory for Central Diagnostic Review) 
10.2.2.1 
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. 
10.2.2.2 
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: 
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 
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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). 
10.2.2.3 
Resected in-transit or satellite metastases, or cutaneous 
metastases, or lymph node metastases, or lung 
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.  
NOTE:  
Sections of surgical margins of skin, unless 
positive for tumor, are not required.  A surgical 
pathology report is sufficient. 
NOTE: 
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 stating this to the ECOG-ACRIN 
Central Biorepository and Pathology Facility. 
10.2.3 
Progression/Relapse Biopsy (if performed, for banking for future 
research 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. 
10.3 
Shipping Procedures  
Log the samples into the ECOG-ACRIN Sample Tracking System (STS) the day 
of shipment. If the STS is unavailable, an 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.   
Ship using the CBPF’s FedEx account via the FedEx on-line ship manager. 
 Access to the FedEx shipping account for specimen shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained by logging 
into fedex.com with an account issued by the ECOG-ACRIN CBPF. For security 
reasons, the account number will no longer be given out in protocols, over the 
phone, or via email. If your site needs to have an account created, please contact 
the ECOG-ACRIN CBPF by email at eacbpf@mdanderson.org . 
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10.3.1 
Submission Schedule  
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.  
10.3.2 
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. 
10.3.3 
Central Biorepository and Pathology Facility: Processing and Routing  
Diagnostic materials will be forwarded to Dr. Uma Rao for central 
review. 
10.4 
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. 
10.4.1 
Study Specific Notes 
An Generic Specimen Submission Form (#2891) will be required only 
if STS is unavailable at the time of sample submission. Notify the 
laboratory of the shipment by FAXing a copy of the completed form to 
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the laboratory. Indicate the appropriate laboratory on the submission 
form: 
• 
ECOG-ACRIN Central Biorepository and Pathology Facility 
• 
ECOG-ACRIN Immunologic Monitoring and Cellular Products 
Laboratory 
o The day of shipment, notify the IMCPL ECOG-ACRIN study 
coordinator by FAX (412-623-6625) using the Specimen 
Shipment/Requisition Form (Appendix IX).  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. 
10.5 
Banking  
The residuals and/or derivatives of the blocks/slides submitted will be retained at 
the ECOG-ACRIN Central Repository for possible use in future ECOG-ACRIN 
approved studies. Any residual blocks will be available for purposes of individual 
patient management on specific written request. If future use is denied or 
withdrawn by the patient, the samples will be removed from consideration for use 
in any future study. 
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11. 
Correlative Studies 
NOTE: 
An informed consent MUST be signed prior to the submission of any sample, 
including banking for research. 
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. 
NOTE:  
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System.  An STS 
shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.4.  
11.1 
Blood Sample Collection 
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.   
Please refer to Appendix XIX for the full description of the laboratory research 
studies being performed. 
11.1.1 
Sample Submission Schedule 
Blood should be collected as specified below for each tube type at 
baseline (prior to start of treatment), after three (Ipilimumab Arms A, D 
and C, F) / four (IFN Arm B, E) weeks of initiating study treatment, 
after twelve (12) weeks of initiating treatment, at 48 weeks or at 
disease relapse (if relapse occurs earlier than the specified time 
point).  No further blood samples are to be submitted after the relapse 
blood is sent. 
Blood samples should be shipped the day they are drawn. 
Instructions to order kits are outlined below. 
Questions are to be directed to the Immunological Monitoring and 
Cellular Products laboratory (IMCPL) ECOG-ACRIN study coordinator 
at (412) 624-0078. 
11.1.2 
Sample Preparation Guidelines 
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). 
2. At Baseline, after three (Ipilimumab Arms A, D and C, F) / four 
(IFN Arm B, E) weeks, and after twelve (12) weeks of initiating 
treatment ONLY, please submit the following: 
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• 
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) 
Please completely fill all blood tubes as full as possible 
and collect the correct number and tube type as outlined 
above: 
Each tube must be clearly labeled to include: 
• 
ECOG-ACRIN protocol number E1609 
• 
ECOG-ACRIN five-digit patient sequence number 
• 
Patient initials 
• 
Originating institution/investigator name  
• 
Date and time drawn 
• 
Collection time point 
11.1.2.1 
Shipping Kits 
Specimen shipping kits are available to order for the 
collection of the blood samples and must be requested 
from the IMCPL. Kits will contain the supplies and 
instructions for collecting, processing, and shipping the 
blood samples. Please fax the request using the Shipping 
Kit Request Facsimile Form (Appendix VIII) to (412) 623-
6625 or call the IMCPL at (412) 624-0078. Please allow 
ten working 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 the 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 
11.2 
Shipping Procedures  
Log the samples into the ECOG-ACRIN STS the day of shipment. If the STS is 
unavailable, an 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.   
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If the STS is unavailable, notify the IMCPL ECOG-ACRIN study coordinator by 
fax (412-623-6625) using the Specimen Shipment/Requisition Form (Appendix 
IX). 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. 
 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 2-8oC. Shipments must be timed to arrive during 
normal working hours and should be shipped in one box. 
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, Suite L 1.26 
ECOG-ACRIN Study Coordinator 
Hillman Cancer Center 
5117 Centre Avenue 
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. 
NOTE: 
Blood should NOT be collected on Fridays. 
11.2.1 
Federal Guidelines for the Shipment of Blood Products: Sites should 
follow IATA regulations for Packaging UN3372 shipments. Please 
refer to FedEx guidelines. 
11.3 
Banking 
Blood samples collected will be retained at the UPCI-IMCPL for use in future 
ECOG-ACRIN approved studies. If future use is denied or withdrawn by the 
patient, the samples will be removed from consideration for use in any future 
study. 
11.4 
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.  
11.5 
Lab Data Transfer Guidelines 
The data collected or generated on the above mentioned correlative studies will 
be submitted electronically via secure data portal to the ECOG-ACRIN 
Operations Office – Boston by the central laboratory. 
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12. 
Records to Be Kept 
Please refer to the E1609 Forms Packet for the forms submission schedule and copies 
of all forms. The E1609 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
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 
any source documents. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. 
Balch, C.M., et al., Final version of the American Joint Committee on Cancer 
staging system for cutaneous melanoma. J Clin Oncol, 2001. 19(16): p. 3635-48. 
2. 
Manola, J., et al., Prognostic factors in metastatic melanoma: a pooled analysis of 
Eastern Cooperative Oncology Group trials. J Clin Oncol, 2000. 18(22): p. 3782-
93. 
3. 
Kirkwood JM, A.S., Systemic cytotoxic and biologic therapy melanoma., in Cancer 
Principles and Practice of Oncology. 1993. p. 1-16. 
4. 
Clemente, C.G., et al., Prognostic value of tumor infiltrating lymphocytes in the 
vertical growth phase of primary cutaneous melanoma. Cancer, 1996. 77(7): p. 
1303-10. 
5. 
Hakansson, A., et al., Tumour-infiltrating lymphocytes in metastatic malignant 
melanoma and response to interferon alpha treatment. Br J Cancer, 1996. 74(5): p. 
670-6. 

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6. 
Mihm, M.C., Jr., C.G. Clemente, and N. Cascinelli, Tumor infiltrating lymphocytes 
in lymph node melanoma metastases: a histopathologic prognostic indicator and 
an expression of local immune response. Lab Invest, 1996. 74(1): p. 43-7. 
7. 
Moschos, S.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(19): p. 3164-71. 
8. 
Tatsumi, T., et al., Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T 
cell responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell 
carcinoma or melanoma. J Exp Med, 2002. 196(5): p. 619-28. 
9. 
Tatsumi, T., et al., Disease stage variation in CD4+ and CD8+ T-cell reactivity to 
the receptor tyrosine kinase EphA2 in patients with renal cell carcinoma. Cancer 
Res, 2003. 63(15): p. 4481-9. 
10. Kirkwood, J.M., 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): p. 7-17. 
11. Kirkwood, J.M., 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): p. 2370-80. 
12. Kirkwood, J.M., 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): p. 
2444-58. 
13. Kirkwood, J.M., et al., A pooled analysis of eastern cooperative oncology group 
and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer 
Res, 2004. 10(5): p. 1670-7. 
14. Ives, N.J., Chemotherapy compared with biochemotherapy for the treatment of 
metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin 
Oncol, 2007. 25(34): p. 5426-34. 
15. Wheatley, K., et al., Interferon-à as adjuvant therapy for melanoma: an individual 
patient data meta-analysis of randomised trials. Proceedings of the American 
Society of Clinical Oncology, 2007. 
16. Kirkwood, J.M., et al., High-dose interferon alfa-2b does not diminish antibody 
response to GM2 vaccination in patients with resected melanoma: results of the 
Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin 
Oncol, 2001. 19(5): p. 1430-6. 
17. Wheatley, K., et al., Does adjuvant interferon-alpha for high-risk melanoma provide 
a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev, 
2003. 29(4): p. 241-52. 
18. Wheatley K, I.N., Eggermont A, KirkwoodJM. INTERFERON-ALFA AS ADJUVANT 
THERAPY FOR MELANOMA: AN INDIVIDUAL PATIENT DATA META-ANALYSIS 
OF RANDOMISED TRIALS. in ASCO Annual Meeting. 2007. Chicago. 
19. Creagan, E.T., et al., Phase II trials of recombinant leukocyte A interferon in 
disseminated malignant melanoma: results in 96 patients. Cancer Treat Rep, 1986. 
70(5): p. 619-24. 

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20. Creagan, E.T., et al., Recombinant leukocyte A interferon (rIFN-alpha A) in the 
treatment of disseminated malignant melanoma. Analysis of complete and long-
term responding patients. Cancer, 1986. 58(12): p. 2576-8. 
21. Creagan, E.T., et al., Phase I study of recombinant leukocyte A human interferon 
combined with BCNU in selected patients with advanced cancer. J Clin Oncol, 
1986. 4(3): p. 408-13. 
22. Creagan, E.T., et al., Phase II study: the combination DTIC, BCNU, actinomycin D, 
and vincristine in disseminated malignant melanoma. Med Pediatr Oncol, 1986. 
14(2): p. 86-7. 
23. Lenschow, D.J., T.L. Walunas, and J.A. Bluestone, CD28/B7 system of T cell 
costimulation. Annu Rev Immunol, 1996. 14: p. 233-58. 
24. Schwartz, R.H., Costimulation of T lymphocytes: the role of CD28, CTLA-4, and 
B7/BB1 in interleukin-2 production and immunotherapy. Cell, 1992. 71(7): p. 1065-
8. 
25. Chen, L., et al., Costimulation of antitumor immunity by the B7 counterreceptor for 
the T lymphocyte molecules CD28 and CTLA-4. Cell, 1992. 71(7): p. 1093-102. 
26. Townsend, S.E. and J.P. Allison, Tumor rejection after direct costimulation of 
CD8+ T cells by B7-transfected melanoma cells. Science, 1993. 259(5093): p. 368-
70. 
27. Townsend, S.E., et al., Specificity and longevity of antitumor immune responses 
induced by B7-transfected tumors. Cancer Res, 1994. 54(24): p. 6477-83. 
28. Allison, J.P., A.A. Hurwitz, and D.R. Leach, Manipulation of costimulatory signals 
to enhance antitumor T-cell responses. Curr Opin Immunol, 1995. 7(5): p. 682-6. 
29. Linsley, P.S., et al., CTLA-4 is a second receptor for the B cell activation antigen 
B7. J Exp Med, 1991. 174(3): p. 561-9. 
30. Thompson, C.B. and J.P. Allison, The emerging role of CTLA-4 as an immune 
attenuator. Immunity, 1997. 7(4): p. 445-50. 
31. Walunas, T.L., et al., CTLA-4 can function as a negative regulator of T cell 
activation. Immunity, 1994. 1(5): p. 405-13. 
32. Kearney, E.R., 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(3): p. 1032-6. 
33. Krummel, M.F. and J.P. Allison, CD28 and CTLA-4 have opposing effects on the 
response of T cells to stimulation. J Exp Med, 1995. 182(2): p. 459-65. 
34. Krummel, M.F., T.J. Sullivan, and J.P. Allison, 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(4): p. 519-23. 
35. Tivol, E.A., et al., 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(5): p. 541-7. 
36. Waterhouse, P., et al., Lymphoproliferative disorders with early lethality in mice 
deficient in Ctla-4. Science, 1995. 270(5238): p. 985-8. 
37. Chambers, C.A., T.J. Sullivan, and J.P. Allison, Lymphoproliferation in CTLA-4-
deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. 
Immunity, 1997. 7(6): p. 885-95. 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
136 
38. Hamid O. Dose effect of ipilimumab in patients with advanced melanoma: Results 
from a phase II, randomized, dose-ranging study. in J Clin Oncol 26: 2008 (May 20 
suppl; abstr 9025). 2008. 
39. Weber J. Safety and efficacy of ipilimumab with or without prophylactic budesonide 
in treatment-naive and previously treated patients with advanced melanoma. in 
Clin Oncol 26: 2008 (May 20 suppl; abstr 9010). 2008. 
40. O'Day, S., J. Weber, and C. Lebbe. Ipilimumab Treatment may be Associated with 
a Long-term Survival Benefit : 18-month Survival Rate of Patients with Advanced 
Melnaoma Treated with 10 mg/kg Ipilimumab in Three Phase II Clinical Trials. 
Abstract ID 9033. in ASCO Annual Meeting. 2009. 
41. Kirkwood, J.M., et al., Mechanisms and management of toxicities associated with 
high-dose interferon alfa-2b therapy. J Clin Oncol, 2002. 20(17): p. 3703-18. 
42. Asim Amin, A., De Pril, V., Hamid, O., et al. Systemic Corticosteroids for the 
Treatment of Immune-Related Adverse Events (irAEs) Do Not Impact the 
Development or Maintenance of Ipilimumab Clinical Activity. [Poster presentation: 
#9037]. Presented at the 2009 American Society of Clinical Oncology Annual 
Meeting; May 29-June 2, 2009. Orlando, FL, USA. 
43. Blansfield, J. A., Beck, K. E., Khoi, T., et al. Cytotoxic Tlymphocyte-associate 
antigen-4 blockage can induce autoimmune hypophysitis in patients with 
metastatic melanoma and renal cancer. J Immunother 2005;28(6): 593-598. 
44. Jaber S.H., Edward W., et al. Skin reactions in a subset of patients with stage IV 
melanoma treated with anti-cytotoxic Tlymphocyte antigen 4 monoclonal antibody 
as a single agent. Arch Dermatol 2006;142:166-172. 
45. Robinson, M. R., Chi-Chao C., Yang J. C., et al. Cytotoxic Tlymphocyte-associate 
antigen-4 blockage in patients withmetastatic melanoma: A new cause of uveitis. J 
Immunother 2004;27(6):478-479]. 
46. Hodi. Engl J Med, 2010. 363(8): p. 711-23 
47. Compassionate Use Trial for Unresectable Melanoma With Ipilimumab 
http://www.clinicaltrials.gov/ct2/results?term=ipilimumab 
48. Yurkovetsky ZR, Kirkwood, JM, et al. Multiplex analysis of serum cytokines in 
melanoma patients treated with interferon-alpha2b. Clin Cancer Res. 2007 Apr 
15;13(8):2422-8. 
 

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Dose Interferon a-2b for Resected High risk Melanoma 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials 
(English Language) [Deleted in Amendment #6] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in amendment #6 and is posted as 
a separate document on the ECOG website. This was removed from the protocol to 
comply with NCI formatting guidelines 
 
 

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Version Date: October 22, 2018 
 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
Appendix I-A 
 
Informed Consent Template for Cancer Treatment Trials 
(English Language, Non-CCOP Institutions) [Deleted in Amendment #6] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I-A was removed from the protocol document in amendment #6 and is posted 
as a separate document on the ECOG website. This was removed from the protocol to 
comply with NCI formatting guidelines 
 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix II 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
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 E1609 
4.  ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
Rev. 3/15 

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NCI Update Date: September 6, 2017 
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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. If any other reports are required, they should be obtained from the appropriate 
department at this time. 
3. 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. 
4. 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 email at eacbpf@mdanderson.org . 
Rev. 3/15 

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List of Required Material 
E1609: A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus 
High-Dose Interferon α-2b for Resected High-Risk Melanoma 
Baseline (submit within one month of patient randomization) 
1. STS shipping manifest or 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. 
• 
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). 
• 
Resected in-transit or satellite metastases, or cutaneous metastases, or lymph 
node metastases or lung 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. 
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. STS shipping manifest or ECOG-ACRIN Generic Specimen Submission Form 
(#2981) 
Rev. 2/12 

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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. 

 
143 
MEMORANDUM 
TO:  
___________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
___________________________________________ 
SUBJECT: 
Submission of Pathology Materials for E1609: A Phase III Randomized 
Study of Adjuvant Ipilimumab ANTI-CTLA4 Therapy Versus High-Dose 
Interferon α-2b for Resected High-Risk Melanoma 
 
A 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 
banking (for research studies in consenting patients and only in accordance with 
the patient consent). 
Keep a copy for your records and return the completed Submission Form, the surgical 
pathology report(s), the slides and/or blocks and any other required material (see List of 
Required Material) to the Clinical Research Associate (CRA). The CRA will forward all 
required pathology material to the ECOG-ACRIN Central Biorepository and Pathology 
Facility. 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN 
Central Repository for future studies.  Blocks will be returned for purposes of patient 
management care upon request. 
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at 1-844-744-2420 or 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 
144 
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 
Rev. 3/15 

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Version Date: October 22, 2018 
 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix III 
 
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. 4/14 

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Version Date: October 22, 2018 
 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix IV 
 
Patient Interferon Diary (for patients who self-administer Interferon) 
 
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 
 
 
 
 
 
 
 
 
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AM  PM 
 
2 
 
 
 
 
 
 
 
 
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AM  PM 
 
3 
 
 
 
 
 
 
 
 
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AM  PM 
 
4 
 
 
 
 
 
 
 
 
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ECOG-ACRIN 
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Version Date: October 22, 2018 
 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix V 
 
E1609 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. 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: 
Jan M. Casadei, Ph.D., 
Cheif, Regulatory Affairs Branch 
Cancer Therapy Evaluation Program 
Cancer Therapy Evaluation Program  
Division of Cancer Treatment and Diagnosis, NCI 
9609 Medical Center Drive 
Room 5-W532, MSC 9740 
Bethesda, MD 20892-9740 [if US Postal Service] 
Rockville, MD 20850 [if non-USPS/private carrier] 
Tel 240-276-6125 
E-mail:  casadeij@mail.nih.gov E-mail:  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. 
 
Rev. 9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
150 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix VI 
 
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. 
 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix VII 
 
Suggested Surgical Considerations and Techniques for Lymphadenectomy 
Surgical Considerations - Surgery is to be completed prior to randomization. 
Stage IIIB, IIIC (except in-transit or satellite metastasis)  
Primary Excision: All patients with initial presentation of melanoma T1-4 are preferably 
treated by wide excision of the primary after the initial biopsy.  Biopsy for initial 
documentation may be performed by punch biopsy, or excisional biopsy, at the discretion 
of the treating dermatologist, surgeon, or physician. 
It is important that definitive surgery will include wide excision of the primary and 
lymphadenectomy according to the guidelines below.   
For patients with known primary cutaneous melanoma lesion and no history of wide local 
excision of that primary lesion, an adequate wide excision of the primary lesion  is 
recommended. Patients with nodal relapse after an inadequate primary excision should 
undergo wide excision at the time of complete lymphadenectomy. The recommendation 
for adequate wide excision is the same for patients enrolled at the time of lymph node 
recurrence as for those enrolled at the time of initial treatment of the primary. 
Wide excision with a minimum 1 cm margin surrounding the primary lesion or biopsy scar 
is important for local surgical control. For lesions whose Breslow's thickness is > 1 mm, a 
2 cm minimum margin is preferred when anatomically feasible (i.e., for lesions of the trunk 
and proximal extremity).  For subungual melanoma, a distal interphalangeal amputation 
with histologically negative margins constitutes an adequate wide excision. 
The specimen should be excised to include skin and all subcutaneous tissue down to the 
muscular fascia.  Fascia may be included at the discretion of the operating surgeon.  
Closure of the defect may be via primary closure, split thickness skin graft, or flap rotation 
flap at the discretion of the surgeon. 
Regional Lymphadenectomy: Note: For patients undergoing sentinel node mapping and 
lymphoscintigraphic and dye lymphographic identification of regional nodal drainage, the 
minimum number of nodes may be less than the mandatory minimum numbers of 5/groin, 
10/axilla, and 15/cervical node dissection. Patients with clinically positive nodes in the 
groin, axilla, or neck should have full lymphadenectomy in those sites. 
Staging lymphadenectomies: 
Head and Neck Lesions  
a. 
Face, ear, and anterior scalp Modified radical neck or radical neck dissection.  
Parotidectomy to be included if lymphoscintigram indicates flow to the area (to yield a 
minimum of 15 nodes). 
b. Submandibular and anterior neck:  Modified radical or radical neck dissection (to yield 
a minimum of 15 nodes). 
c. 
Posterior scalp, posterior neck and uppermost trunk (areas that drain to posterior 
cervical triangle): Modified posterior triangle neck dissection with subocccipital nodes 
(to yield a minimum of 8 nodes). 
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Upper Extremity (to yield a minimum of 10 nodes) 
Axillary node dissection to include at least 10 nodes taken from levels I, and II.  Level III 
nodes should be dissected if they are clinically involved.  The pectoralis minor muscle 
may be divided or sacrificed at the surgeon's discretion. 
Lower Extremity (to yield a minimum of 5 nodes) 
Superficial inguinal node dissection to be performed.  A deep inguinal node dissection will 
be at the discretion of the surgeon, but if performed, the established guidelines should be 
followed as closely as possible. 
Lymphadenectomy for Nodal Recurrence: Regional node recurrences to be treated using 
the appropriate lymphadenectomy as described above.  Whenever possible, diagnosis of 
regional node recurrence to be made using fine needle aspiration technique to avoid 
contaminating the region with tumor.   
Sentinel Node (SLN) Dissection and Nodal Staging 
Patients with recurrent nodal disease (grossly palpable) or a positive SLN must undergo a 
complete node dissection to be eligible for the trial. 
Patients should have pre-operative lymphoscintigraphy prior to the nodal staging 
procedure. If drainage is to 2 or fewer basins, all basins need to be dissected or sampled 
with SLN biopsy techniques. 
The SLN to be examined by making at least 5 sections of the node and staining with H&E 
and S-100 immunohistochemical stain. A 2 mm² sample may be submitted to a central 
laboratory after snap freezing for mRNA isolation and RT-PCR analysis.  
At a minimum, the SLN will be examined with step sections and immunohistochemical 
staining with S-100. In those institutions who do not have mapping capability, 3 lymph 
nodes from each level of the dissection can be examined with S-100 
immunohistochemistry. 
Stage IV: M1a, M1b 
All patients must have disease that is completely surgically resected in order to be eligible. 
Patients must have been surgically rendered free of disease with negative margins on 
resected specimen.  
In-transit or satellite metastasis 
All patients must have disease that is completely surgically resected in order to be eligible. 
Patients must have been surgically rendered free of disease with negative margins on 
resected specimen. 
Consideration should be given to performing lymphatic mapping and a SLN biopsy in 
patients with small volume in transit disease. The identification of regional lymph node 
involvement should be followed by regional lymphadenectomy. While there is no 
consensus about the utilization of SLN biopsy in this setting, the technique is similar to 
that described for patients with primary melanoma. SLN biopsy is best reserved for 
individuals who have only one to two lesions that are close together and where there is a 
clearly defined optimal site to inject the radionucleotide or dye for SLN localization. This 
site should be next to the in transit disease.

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
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Surgical Techniques 
1. Axillary Lymphadenectomy: Complete axillary lymph node dissection will be performed 
including nodes at levels, I, and II. Level III nodes should be dissected if they are 
clinically involved. The boundaries of the dissection should include the axillary vein 
superiorly beginning at the thoracic outlet and coursing to the latissimus dorsi tendon. 
The lateral border of the dissection is the anterior edge of the latissimus dorsi muscle. 
The posterior boundary is the subscapular muscle. The anterior border of the resection 
is the pectoralis major group. The inferior boundary of the dissection should be the 
juncture of the latissimus dorsi and the serratus anterior muscles. 
The contents within these boundaries should be completely removed with the 
exception of the long thoracic nerve and the thorocodorsal nerve which should be 
identified during the dissection and preserved throughout. As stated, the pectoralis 
minor muscle may be divided or sacrificed with the specimen at the discretion of the 
surgeon. Care should be exercised that in the superior part of the dissection, the 
medial pectoral nerve is not injured. The preferable approach to the axilla is through a 
horizontal incision in the line of the skin crease, 3 or 4 cm below the apex of the skin 
fold of the axilla. 
2. Inguinal Lymphadenectomy: A superficial femoral node dissection should be 
performed by excising all of the nodes inferior to the inguinal ligament and bounded by 
the medial border of the Sartorius muscle in the lateral border of the adductor magnus 
muscle. The fatty and lymphatic tissues should be dissected carefully off of the femoral 
vessels and nerves all the way up to the inguinal canal and for 3 cm superior to the 
inguinal ligament. Care should be exercised and the obdurator nerve should be 
spared. Ideally, this area should be entered through a curvilinear incision starting 
laterally over the inguinal ligament and curving medially and inferiorly ending over the 
mid-point of the adductor magnus muscle. 
3. Deep Inguinal and External Iliac Node Dissection: This can be most easily approached 
by incising the abdominal wall musculature 3 or 4 cm superior to the inguinal ligament. 
This incision is taken down through the external oblique, internal oblique and 
transversus muscles and the surgeon at that point stays extraperitoneally as in the 
approach to the iliac vessels for renal transplantation. With this approach, the external, 
internal and common iliac arteries are exposed and the lymphatics coursing among the 
iliac vessels are excised. 
4. Radical Neck Dissection: Classic or modified radical neck dissection may be 
performed for patients with melanoma of the head and neck. As noted above, patients 
with melanoma located on the ear and anterior scalp and face will require superficial 
parotidectomy along with a radical neck procedure. The boundaries of the radical neck 
dissection are inferiorly the clavicle; the mandible, the mastoid and the tail of the 
parotid gland superiorly; the anterior border of the trapezius muscle posteriorly; and 
the strap muscle of the larynx anteriorly. The sternocleidomastoid muscle may be 
sacrificed or preserved at the surgeon's discretion. For posterior lesions the radical 
neck incision must be extended posteriorly or a second incision must be make so that 
the sub-occipital nodal group can be sampled. 

ECOG-ACRIN 
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NCI Update Date: September 6, 2017 
154 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix VIII 
 
Shipping Kit Request Facsimile Form 
ECOG-ACRIN – PROTOCOL E1609 
 
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: __________________________________ 
 
Shipping Address: 
 
 
 
_______________________________________ 
 
 
 
 
_______________________________________ 
 
 
 
 
________________________________________ 
 
 
 
 
________________________________________ 
 
 
 
 
_________________________________________ 
 
PLEASE ALLOW 10 WORKING DAYS FOR RECEIPT OF SHIPPING KITS 
NOTE: 
To order collection and shipping kits for E1609, patients must be registered to 
or in the process of being worked up for the E1609 trial. Due to funding 
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. 
Rev. 2/12 
Rev. 2/12 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
155 
restrictions institutions cannot order multiple collection and shipping kits in 
advance. 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix IX 
 
Specimen Shipment Requisition Form 
ECOG-ACRIN – PROTOCOL E1609 
It is required that samples submitted from patients participating in E1609 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (see Section 10.4). 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 
 
 
Call the IMCPL ECOG-ACRIN Study Coordinator at 412-624-0078 with questions on 
collection and shipping. 
 
Please complete the following information and include this form in the shipment. 
 
Specimen  
 
 
 
 
Specimen 
Collection Date __ __/__ __/__ __ 
 
Collection Time: ____ ____:____ ____ 
 
                   mm    dd        yy  
 
 
 
 
 (24 hour clock) 
 
 
Ship specimens by FedEx Priority 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. 
ECOG Patient Sequence Number:  ______________________ ECOG Patient Initials: _________ 
 
 
 
 
 
 
 
 
 
 
        Last    First 
 
Clinical Site:____________________________   Site Contact: ____________________________ 
 
Telephone Number:  _______________________  Fax Number: __________________________ 
 
Federal Express® Air Bill No.: _________________________ Date of Shipment: _____________ 
 
Rev. 2/12, 9/14 
Rev. 2/12, 9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
156 
Time Points (check one): 
 
 Baseline 
Three (3) red top tubes, Ten (10) green top tubes, One (1) PAXgene  
 
RNA tube and One (1) yellow top tube 
 
 3 weeks (Arms A/D, C/F) 
4 weeks (Arm B, E) Three (3) red top tubes, Ten (10) green top tubes, one (1) PAXgene  
 
RNA tube 
 
 12 weeks 
Three (3) red top tubes, Ten (10) green top tubes, One (1) PAXgene  
 
RNA tube  
 
 48 weeks 
Three (3) red top tubes and Ten (10) green top tubes 
 
 
[Deleted in Addendum #5] 
 
 Relapse 
Three (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. 
 
____ [Deleted in Addendum #4] 
 
____ 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. 
 
 
____ [Deleted in Addendum #4] 
 
 
 
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. 
Rev. 2/12 
Rev. 2/12 
Rev. 2/12 
Rev. 8/12, 
9/14 
Rev. 8/12 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
157 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix X 
 
Administration of Interferons (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. 
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 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
158 
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. 
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. 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected 
High risk Melanoma 
 
Appendix XI 
 
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. 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
160 
 
 
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. 
 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix XII 
 
General Recommendations for immune-related Adverse Events (IrAEs) 
Section 5.5.1.3 
Rev. 2/14 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
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A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High 
Dose Interferon a-2b for Resected High risk Melanoma 
 
Appendix XIII 
 
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. Effective Amendment #7, the 
dose delay and discontinuation criteria have been made stricter on Arms A or D (ipilimumab 10 
mg/kg) than on Arms C or F (ipilimumab 3 mg/kg) due to a higher incidence of severe toxicities 
observed on Arms A and D compared to Arms C and F. 
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 XIV. 
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 and possibly other 
immunosuppressants as noted in the E1609 study protocol (Sections 5.5.1.3, 5.5.1.5) and 
Appendix XIV.  
Liver: Elevation of LFTs from baseline should instigate an investigation into the underlying 
etiology for suspected IRAEs, in accordance with Sections 5.5.1.3, 5.5.1.5 and Appendix XV. 
Neoplastic, concurrent medications, viral hepatitis, and toxic etiologies should be considered 
and addressed, as appropriate. Imaging of the liver, gall bladder, and bile duct should be 
performed to rule out neoplastic or other causes for the increased LFTs. An ANA, pANCA, and 
anti-smooth muscle antibody test should be performed if an autoimmune etiology is considered. 
Consultation with a hepatologist is appropriate for a suspected liver IRAE and a biopsy should 
be considered. 
Rev. 11/13 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
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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 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. Please see Sections 5.5.1.3, 5.5.1.5 and Appendix XVIII. 
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. 
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 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
164 
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. Please see Sections 5.5.1.3, 5.5.1.5 and Appendix XVI. 
Suspected irAEs should be documented in the patient’s medical record.
Rev. 11/13 

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E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
165 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected 
High risk Melanoma 
Appendix XIV 
GI Management Algorithms 
 
 
 
PLEASE NOTE:  THERE ARE TWO (2) SEPARATE E1609 GI MANAGEMENT ALGORITHMS. ONE IS TO BE USED FOR 
ARMS A AND D PATIENTS ONLY, AND THE OTHER FOR ARMS C AND F PATIENTS ONLY. PLEASE 
REFERENCE THE CORRECT VERSION OF THE ALGORITHM BASED ON THE ARM DESIGNATION OF 
THE PATIENT. THE ALGORITHMS APPEAR ON THE FOLLOWING 2 PAGES. 
 
Rev. 9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
166 
E1609 (Arms A and D) GI Management Algorithm 
Rev. 2/13, 11/13 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
167 
Severity  of diarrhea/
colitis
Rule out 
causes.  If 
cause, treat 
and 
of perforation! Infliximab 
not 
in 
of perforation/sepsis!
Grade 1
Diarrhea: < 4 stools/day over 
baseline;
Colitis: asymptomatic
Grade 2
Diarrhea: 4-6 stools per day 
baseline; IV fluids indicated < 
hrs; not interfering with 
Colitis: abdominal pain; blood 
** Patients on Arm A and Arm D with Grade 1 diarrhea/colitis must have ipilimumab held until resolution to Grade 0 (baseline) before resuming dosing with 
ipilimumab. Patients on Arm A and Arm D with Grade 2 diarrhea/colitis must have ipilimumab permanently discontinued.
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. 
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.
• Close monitoring for worsening 
• Educate patient to report any worsening 
• Hold 
• Symptomatic treatment (dietary 
modifications and loperamide or 
diphenoxylate)
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
• D
• High dose IV steroids 
methylprednisolone 1-2 
• Consider 
• Discontinue 
• Symptomatic treatment 
(dietary modifications and 
loperamide or diphenoxylate)
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:
• Increase steroids (up to methylprednisolone 2 mg/kg/day IV)
• Continue same dose until symptoms are grade 1, then taper 
over at least 1 month
• If no improvement to increased corticosteroid dose, 
consider 1 dose of infliximab (if no contraindication)
*G4 = life-threatening, perforation
 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
168 
E1609 (Arms C and F) GI 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 with Grade 2 colitis who require steroid therapy with resolution to ≤ Grade 1 severity must have a follow-up colonoscopy to document endoscopic 
(with or without pathologic) resolution of inflammation before resuming dosing with ipilimumab.
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. 
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.
• Close monitoring for worsening symptoms
• Educate patient to report any worsening immediately
• Continue ipilimumab
• Symptomatic treatment (dietary 
modifications and loperamide or 
diphenoxylate)
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 
(dietary modifications and 
loperamide or diphenoxylate)
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:
• Increase steroids (up to methylprednisolone 2 mg/kg/day IV)
• Continue same dose until symptoms are grade 1, then taper 
over at least 1 month
• If no improvement to increased corticosteroid dose, consider 
1 dose of infliximab (if no contraindication)
*G4 = life-threatening, perforation
 
Rev. 11/13 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
169 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected 
High risk Melanoma 
Appendix XV 
Hepatotoxicity Management Algorithms 
E1609 (Arms A and D & C and F) 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 < 3.0 x ULN 
and/or 
Total bilirubin < 1.5 x ULN
Grade 2 
AST or ALT 
> 3.0 to < 5.0 x ULN 
and/or 
Total bilirubin 
> 1.5 to 
< 3.0 x ULN
*Ipilimumab may be held/delayed rather than discontinued if AST/ALT < 5 x ULN and Tbili < 3 x ULN. Resume ipilimumab when AST/ALT/Tbili return to grade 1 
and meet protocol specific retreatment criteria.
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.
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. 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.
• Continue monitoring LFT prior to each dose
• Continue ipilimumab
Grade 3-4 
AST or ALT 
> 5.0 x ULN 
and/or
 Total bilirubin 
> 3.0 ULN
• Discontinue ipilimumab if AST or ALT 
> 5 x ULN or total bilirubin > 3 x ULN*
• 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
 
Rev. 2/13, 11/13, 
9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
170 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected 
High risk Melanoma 
Appendix XVI 
Endocrinopathy Management Algorithm 
E1609 (Arms A and D & C and F) Endocrinopathy Management Algorithm 
Rev. 2/13, 11/13, 
9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
171 
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
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 our without 
hormone substitution): 
•
Resume ipilimumab (if no 
diagnosis of hypophysitis)
•
Taper steroids over at least 1 
month*
•
Evaluate endocrine function
•
Consider pituitary scan (e.g. MRI)
•
Consider endocrinology consult
•
Symptomatic with abnormal lab/pituitary scan:
•
Withhold/delay ipilimumab
•
High dose IV steroids (e.g., 1-2 mg/kg/day 
methylprednisolone or dexamethasone 4mg every six hrs 
or equivalent)
•
Initiate appropriate hormone therapy
No abnormal lab/pituitary scan but symptoms  persist:
•
Repeat labs in 1-3 weeks / MRI in 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.Ipilimumab may not be restarted while the patient is being treated with systemic corticosteroids except for patients on stabl e doses of hormone 
replacement therapy such as hydrocortisone.
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
- For patients diagnosed
with hypophysitis,
ipilimumab should be
permanently discontinued.
*- Patients with adrenal insufficiency 
might need to continue steroids with 
mineralcorticoid component as 
substitution
 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
172 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected 
High risk Melanoma 
Appendix XVII 
Neuropathy Management Algorithms 
 
 
PLEASE NOTE:  THERE ARE TWO (2) SEPARATE E1609 NEUROPATHY MANAGEMENT ALGORITHMS. ONE IS TO BE 
USED FOR ARMS A AND D PATIENTS ONLY, AND THE OTHER FOR ARMS C AND F PATIENTS ONLY. 
PLEASE REFERENCE THE CORRECT VERSION OF THE ALGORITHM BASED ON THE ARM 
DESIGNATION OF THE PATIENT. THE ALGORITHMS APPEAR ON THE FOLLOWING 2 PAGES. 
 
Rev. 9/14 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
173 
E1609 (Arms A and D) Neuropathy Management Algorithm 
Rev. 2/13, 11/13 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
174 
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
(Asymptomatic, clinical 
observations only)
Grade 3-4 sensory
(Severe symptoms, 
limiting self-case ADL, life-
threatening 
consequences)
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.Ipilimumab may not be restarted while the patient is being treated with systemic corticosteroids except for patients on stabl e doses of 
hormone replacement therapy such as hydrocortisone.
Continue monitoring the patient. If symptoms worsen,
treat as below.
• Continue ipilimumab
Grade 3-4 motor
(Severe symptoms, 
limiting self-case ADL, 
life-threatening 
consequences)
• 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 regardless of 
relationship
• 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
(Moderate symptoms, 
limiting instrumental 
ADL)
• Discontinue ipilimumab regardless of 
relationship
• Treat symptoms per local guidelines
If symptoms worsen, treat as below.
 

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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
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E1609 (Arms C and F) Neuropathy Management Algorithm 
Rev. 11/13 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
176 
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
(Asymptomatic, clinical 
observations only)
Grade 3-4 sensory
(Severe symptoms, 
limiting self-case ADL, life-
threatening 
consequences)
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.Ipilimumab may not be restarted while the patient is being treated with systemic corticosteroids except for patients on stabl e doses of 
hormone replacement therapy such as hydrocortisone.
Continue monitoring the patient. If symptoms worsen,
treat as below.
• Continue ipilimumab
Grade 3-4 motor
(Severe symptoms, 
limiting self-case ADL, 
life-threatening 
consequences)
• 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 regardless of 
relationship
• 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
(Moderate symptoms, 
limiting instrumental 
ADL)
• Hold/delay ipilimumab
• Treat symptoms per local guidelines
Resume ipilimumab when resolved / grade 1
If symptoms worsen, treat as below.
 

ECOG-ACRIN 
E1609 
Cancer Research Group 
Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
177 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected 
High risk Melanoma 
Appendix XVIII 
Skin Toxicity Algorithm 
E1609 (Arms A and D & C and F) Skin Toxicity 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 (Mild to 
moderate, localized; 
papules/pustules covering 
< 10%–30% of body 
surface)
Grade 3-4 (Intense or 
widespread > 30%; skin 
sloughing < 10%–30% of 
body surface; epidermal or 
mucus membrane 
detachment)
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.Ipilimumab may not be restarted while the patient is being treated with systemic corticosteroids except for patients on stabl e doses of 
hormone replacement therapy such as hydrocortisone.
• Symptomatic therapy, e.g.topical thick moisturizers and oatmeal 
baths, antihistamines, topical steroids
• Continue ipilimumab 
Symptoms resolve / return to grade 1: 
• Taper steroids over at least 1 month
• Resume ipilimumab if grade 3
• 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 persist > 1-2 weeks with topical 
corticostroids:
• Moderate to high dose steroids PO (e.g., 
prednisone 0.5 - 1 mg/kg/day)
• Once controlled, taper steroids over at 
least 1 month
Rev. 9/14 

ECOG-ACRIN 
E1609 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
178 
A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected 
High risk Melanoma 
Appendix XIX 
Biomarkers of the Proinflammatory Response and Elements of Immune Suppression 
 
Study PI: Ahmad A. Tarhini, MD, PhD 
XIX.1 Hypotheses 
1. Based on significant preliminary data generated by our group and others we hypothesize that a baseline and /or early-on 
treatment prognostic biomarker signature in relation to ipilimumab and IFNα can be generated by assessing specific 
markers of the pro-inflammatory immune response and of immunosuppression in both tumor tissue and in circulating 
blood, when evaluated simultaneously due to the common systems biology.  
2. The prognostic biomarker signature generated will have therapeutic predictive value in relation to ipilimumab. 
3. Based on significant preliminary data we hypothesize that clustered genomic variants specific to patients who develop 
immune-related colitis after ipilimumab predict this toxicity.  
 
XIX.2 Objectives 
1. Primary Objective: Generating prognostic biomarker signature for patients treated with Ipilimumab and high dose IFNα 
(HDI). 
a. Aim 1: Testing of specific circulating biomarkers of therapeutically predictive value generated by significant preliminary 
data 
i 
Cellular populations: (1) absolute lymphocyte count; (2) T regulatory  (CD4+CD25hi+Foxp3+, 
CD4+CD25hi+CD39+) and MDSC (monocyte gate HLA-DR+ low/CD14+, monocyte gate Lin1-/HLA-DR-
/CD33+/CD11b+, lymphoid gate Lin1-/HLA-DR-/CD33+/CD11b+); (3) IFNg+CD4+ and IFNg+CD8+ antigen 
specific T cells (gp-100, MART-1, NY-ESO-1 peptides); (4) CD4+ and CD8+ ICOS-hi T cells; (5) 
IFNg+CD8+CXCR3+VLA4+ T cells 
ii 
Serum proteins: CRP, LDH, S100, MIA, YKL40, IL1α, IL1β, IL2, IL2Rα, IL6, IL8, IL10, IL17, IL12p40, TNFα, IFNα, 
MIP1α, MIP1β, TNF-RII, TGF-α, TIMP-1, CXCL10 (IP10), CXCL11, CXCL9, VEGF 
b. Aim 2: Testing of specific biomarkers within the tumor microenvironment (TME) of therapeutically predictive value 
generated by significant preliminary data 
i 
Expression levels of immune related-genes (RNA microarray): CCL2, CCL3, CCL4, CCL5, CD8A, CXCL10, 
CXCL11, CXCL9, IDO, PRF1, GZMB, HLA-DMA, HLA-DOA, CD79B, IGH, IGKC, IGLC1, HLA-DQA1, IGHM, 
CD79A, IGHD, CD3G, CD3D, HLA-DPA1, LAT, VAV1, INPP5D, IL2RB, IGHG1, CIITA, IL21R, STAT1 

ECOG-ACRIN 
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Version Date: October 22, 2018 
 
NCI Update Date: September 6, 2017 
179 
ii 
Tumor infiltrating lymphocytes and immunosuppressive markers (immunohistochemistry): CD3, CD4, CD8, 
FOXP3, PD-L1, IDO, CD45RO 
Using known clinical covariates and the markers identified in Aims 1 and 2, we will use the entire data set to develop and 
validate models capable of identifying which patients belong to different prognostic groups. 
2. Secondary Objectives:  
a. Testing the therapeutic predictive value in relation to ipilimumab of the prognostic biomarker signature identified in the 
primary objective. 
b. If a prognostic biomarker signature could not be generated based on the candidate biomarkers selected under the 
primary objective or if it fails to have a therapeutic predictive value, we will conduct a more comprehensive approach 
aimed at the generation and validation of a therapeutically predictive biomarker signature in relation to ipilimumab and 
HDI. This strategy will be feasible since we plan to conduct TME global RNA microarray studies that will generate 
global gene expression data. This testing approach will allow both global and individual gene expression data 
analysis. 
c. Testing the “immune-related colitis” predictive value of specific genomic variants generated by significant preliminary 
data. 
d. Testing for activating mutations (BRAF, NRAS) in patients without known tumor mutational status as tested in a CLIA 
certified laboratory.  
XIX.3 Choice of Trial  
These correlatives will be utilizing banked biospecimens (pre-treatment and 3-4 weeks post initiation of treatment) in subjects 
previously consenting to the future use of their banked biospecimens for research purposes. E1609 trial that is testing 
adjuvant ipilimumab (at high dose and standard dose) versus IFNα in patients with operable stage IIIB/C and M1a/b 
melanoma who are at high risk for recurrence and death. The large sample size (N ~ 1600) and diverse banked biorepository 
for E1609 make it an ideal platform through which to evaluate these interrelated markers for their prognostic and 
immunotherapeutic predictive value with regard to ipilimumab in reference to IFNα, as assessed individually and in 
combination based on the common systems biology. E1609 will allow the development of a therapeutic predictive model that 
links circulating markers of the pro-inflammatory response and immunosuppression with markers in the tumor 
microenvironment. This trial also allows the evaluation of potentially toxicity-predictive biomarkers, the most devastating of 
which has been autoimmune colitis. 

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XIX.4 Preliminary Data 
Primary Objective: Generating Prognostic Biomarker Signature 
1. Tumor Microenvironment 
Immune related pathways/genes identified through tumor gene expression profiling are significantly associated 
with neoadjuvant ipilimumab clinical benefit (Tarhini et al, AACR 2014) 
Patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab in a previously reported study 
(NCI-ASCO-EORTC Markers in Cancer 2012; PLOS One 2014).1,2 Gene expression profiles of tumors of treated patients 
were investigated for their immunotherapeutic predictive value.  
Methods: Patients were treated with ipilimumab (10mg/kg IV every 3 weeks x 2 doses) bracketing surgery. Tumor 
specimens were obtained at baseline and at definitive surgery (week 6-8).  Gene expression profiling was performed on 
the tumor biopsies of 32 patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene 
chips. Significance Analysis of Microarrays (SAMR) was performed to test the association of each gene with outcome. 
Pathway analysis was performed using Ingenuity Pathway Analysis software. The Benjamini and Hochberg method was 
used to adjust for multiple testing in the pathway analysis.  
Results: Pathway analysis identified biologically relevant pathways enriched with genes that are significantly associated 
with clinical outcome at baseline in relation to progression free survival (PFS) and disease non-progression (NP) as well 
as early on-treatment outcomes (PFS and overall survival, OS). These pathways and the top associated molecules were 
notably immune related and highly statistically significant. Associations with clinical outcome overlapped between baseline 
and on-treatment specimens as well as across clinical endpoints tested. Table 1 summarizes the top canonical pathways 
identified at baseline (PRE) and on-treatment (POST) and their association with PFS, NP and OS.  
Conclusions: Gene expression profiling identified pathways and genes related to inflammation and autoimmunity that 
significantly predict clinical benefit from neoadjuvant ipilimumab at baseline and early on-treatment. These findings 
warrant further investigation in relation to ipilimumab and other immunotherapeutics.  
The genes that belong to the top pathways were selected (22 genes, 49 probe sets). We evaluated correlation with clinical 
outcome (PD, disease progression vs. non-PD). We generated a PD vs. non-PD heatmap using only the probe sets that 
are significantly differentially expressed between the two groups (27 probe sets from 19 genes). Hierachical clustering 
was performed and the PD group was found to have a lower expression of these genes. We noticed a sub-group within 
the non-PD group that has a genomic profile between the PD group and the other non-PD subgroup. As expected, 
because the genes were selected to correlate with outcome, the clusters produced by these genes also associate with 
outcome.  KM curve shows that this subgroup (in gray) has slightly worse PFS than the others (in black). These results 
are shown in Figure 1.  

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Table 1. Pathways identified at baseline and on-treatment and their association with PFS, NP and OS 
Pathways 
PRE/PFS 
(Adjusted P) 
PRE/NP  
(Adj. p) 
POST/PFS 
(Adj. p) 
POST/OS 
(Adj. p) 
Antigen Presentation 
0.0002 
4.22 x10-05 
0.004 
3.08 x10-05 
Cytotoxic T Lymphocyte-mediated Apoptosis of Target Cells 
0.0004 
3.92 x10-07 
0.004 
0.0009 
T Helper Cell Differentiation 
0.001 
0.0005 
0.05 
0.023 
 B Cell Development 
6.98 x10-12 
1.14 x10-13 
2.26 x10-06 
4.26 x10-07 
 iCOS-iCOSL Signaling in T Helper Cells 
0.006 
4.23 x10-07 
0.11 
0.11 
OX40 Signaling 
0.007 
1.29 x10-05 
0.005 
0.0002 
 CD28 Signaling in T Helper Cells 
0.04 
8.3 x10-05 
0.04 
0.15 
IL-4 Signaling 
0.02 
0.0008 
0.06 
0.002 
PKCÎ¸ Signaling in T Lymphocytes 
0.04 
7.97 x10-05 
0.14 
0.04 
Nur77 Signaling in T Lymphocytes 
0.03 
0.0001 
0.03 
0.008 
 SLE Signaling 
1.52 x10-05 
4.27 x10-06 
 
 
Allograft Rejection Signaling 
0.0003 
4.27 x10-06 
0.004 
0.0006 
Autoimmune Thyroid Signaling 
0.004 
4.51 x10-05 
0.021 
0.003 
Genes: HLA-DMA, HLA-DOA, CD79B, IGH, IGKC, IGLC1, HLA-DQA1, IGHM, CD79A, IGHD, CD3G, CD3D, HLA-DPA1, GZMB, LAT, VAV1, 
INPP5D, IL2RB, IGHG1, CIITA, IL21R, STAT1 
 
Figure 1. Prediction of PD endpoint using baseline expression data. Hierachical clustering was performed and the PD group was 
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between the PD group and the other non-PD subgroup. KM curve shows that this subgroup (in gray) has slightly worse PFS than the 
others (in black). 
 
 
 
 
 
Time to event analysis was conducted (49 probe sets from the 22 genes). Supervised Principle Components (SPC) were 
applied to the top genes (probe sets) that are associated with progression free survival (PFS). The plots demonstrated the 
ability to separate the survival curves by dichotomized value of the first SPC. These signatures will require validation on an 
independent data set.   
Recent data generated by other groups support the importance of the pro-inflammatory gene expression profile as a 
potential predictor of immunotherapeutic benefit. Studying melanoma activating mutations and methylation status of 
immune-related genes may complement potential predictive signatures: 
• 
Chemokine expression in melanoma metastases is important for CD8+ T cell recruitment. Affymetrix gene 
expression profiling completed on metastatic melanoma biopsies revealed a major segregation of samples based on the 
presence or absence of T cell–associated transcripts.3 The presence of lymphocytes correlated with the expression of 
defined chemokine genes, and a subset of 6 chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was 
confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that 
contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8+ effector T cells, 
and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8+ effector 
cells in vitro; Chemokine blockade with specific antibodies inhibited migration of CD8+ T cells. These data suggest that 
lack of critical chemokines in melanoma metastases may limit the migration of activated T cells, which in turn could limit 
the effectiveness of antitumor immunity. 
• 
Proinflammatory gene expression signature is associated with survival following GSK MAGE-A3 protein vaccine. 

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A phase II trial of immunization with recombinant MAGE-A3 protein using 2 different immune stimulants as an adjuvant 
(AS15 and AS02B) was conducted by GSK Biologicals in 72 patients with MAGE-A3-positive unresectable stage III or 
stage IV M1a metastatic melanoma. Gene expression and transcriptional profiling by microarray was performed on 
baseline biopsies.4 The predictive gene signature was associated with a significant improvement in median overall 
survival: 16.2 months in signature (-ve) versus 28 months in signature (+ve) patient population. The high expression of 
immune-related cell markers in patients with clinical activity was confirmed by quantitative reverse transcription PCR,4 
which suggests that a subset of melanoma patients have metastatic tumors that contain a pro-inflammatory infiltrate that 
includes T cells and chemokines, and that such individuals are more likely to respond clinically to melanoma vaccines and 
potentially other immunotherapeutic interventions. Further, a phase II study in non-small cell lung cancer evaluated the 
MAGE-A3 recombinant protein in 182 patients with MAGE-A3-positive, completely resected stage IB or II disease. A 
signature of immune-related genes, overlapping with the gene set identified for melanoma, was associated with improved 
outcome from MAGE-A3 treatment,5 which suggests that a Type I immune active tumor microenvironment may have 
therapeutic predictive value for immunotherapy.  
• 
Similar pro-inflammatory gene expression profile on pre-treatment biopsies may be associated with clinical 
response to high-dose interleukin 2 (IL2)  Data presented at the 2009 ASCO Meeting reported a similar pro-
inflammatory tumor microenvironment to be potentially predictive of IL2 clinical responses.{Sullivan, 2009 #23}  
• 
Pro-inflammatory/immune-reactive tumor microenvironment favors clinical response to ipilimumab Affymetrix 
gene expression profiling was performed on tumor biopsies collected from 45 metastatic melanoma patients before and 
3 weeks after the start of treatment in a phase II clinical trial.6,7 Analysis of pre-treatment tumors indicated that patients 
with high baseline expression levels of immune-related genes were more likely to respond favorably. Associated 
genes included: T cell surface markers, such as CD8A, CD2, CD247, CD27, CD38, and CD3; members of the TNF 
receptor family, such as CD40, FAS, and TNFRSF9; cytokines and chemokines, such as CXCL9, CXCL10, CXCL11, 
CCL4, and CCL5; immune receptors, such as IL10RA, IL12RB2, IL15RA, IL21R, CXCR6, and CCR5; cytotoxic factors, 
including perforin 1 and various granzymes; and various types of T cell receptors, MHC molecules, and immunoglobulin 
genes. Pathway analysis of these genes identified the top functional category as “inflammatory response,” with immune-
cell trafficking, proliferation, and activation also among the top functional categories. The top 10 canonical pathways that 
were enriched with the input genes were all associated with the immune system. The most significant pathways were 
“cytotoxic T lymphocyte-mediated apoptosis of target cells” and “antigen presentation pathway.” Among 22 unique genes 
with a minimum 2.5-fold difference in pretreatment expression between the clinical activity and no clinical activity groups, 
most were associated with immune function and had a subcellular localization of plasma membrane or extracellular 
region. Notably, this list included genes encoding for a surface marker for CD8+ cytotoxic T cells (CD8A and cytolytic 
components: GZMB and PRF1); Th1 cytokines and chemokines (CCL4, CCL5, CXCL9, CXCL10, and CXCL11); a 
member of the MHC class II family (HLA- DQA1); and other immune-related genes, such as NKG7, CD38, IGL, and IDO1. 
Most probe sets also had greater mean post-treatment expression in tumor samples from patients in the clinical activity 
group. Furthermore, ipilimumab appeared to induce two major changes in tumors from patients who exhibited clinical 
activity: genes involved in immune response showed increased expression, whereas expression of genes for melanoma-
specific antigens and genes involved in cell proliferation decreased.  These changes were associated with the total 

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lymphocyte infiltrate in tumors, and there was a suggestion of association with prolonged overall survival in these patients. 
Many IFNg-inducible genes and Th1-associated markers showed increased expression after ipilimumab treatment, 
suggesting an accumulation of this type of T cell at the tumor sites, which might play an important role in mediating the 
antitumor activity of ipilimumab.  
• 
The aberrant hypermethylation of CpG islands located within promoter regions has been associated with the 
transcriptional silencing of over 50 genes in melanoma.8 In this context, Project 1 collaborator Maio et al. recently showed 
the relevance of aberrant DNA methylation in impairing immunogenicity and immune recognition of melanoma cells, 
eventually hampering the clinical efficacy of available immunotherapeutic strategies.8,9 They demonstrated that a global 
hypomethylation of genomic DNA significantly associates with increased overall survival in stage IIIC CM patients.10 
Furthermore, they defined different methylation-based classifiers able to assign stage III and sub-stage IIIC patients to 
good or bad prognosis classes, based on the methylation status of specific gene signatures (manuscript in press).  
Neoadjuvant ipilimumab induces significant influx of cytotoxic CD8+ tumor infiltrating lymphocytes (TIL) into tumor 
(Tarhini et al., PLOS One 2014)   
Tumor samples (n=24) obtained at baseline 
and then at definitive surgery and tested by 
immunohistochemistry showed significant 
increase in CD8+ TIL after ipilimumab 
therapy (p=0.02), as shown in Figure 3.1 
There were trends observed in examining the 
change in T reg and clinical benefit 
("CR/PR/SD" vs. “PD”); p=0.09. T reg 
(CD4+CD25hi+ Foxp3+) were higher at week 
6 (mean change=1.5; SD=1.46) in the PD 
group while the opposite was seen in the 
clinical benefit group (“CR/PR/SD”, mean 
change= -0.64; SD=1.83). The change in 
Treg is unlike what we observed in the 
circulation. Ipilimumab was also seen to 
induce T cell activation evidenced by CD69 
without in vitro stimulation. There was an 
increase in the % CD3+/CD8+/CD45RO+/ 
TNFα+ TIL (mean change at Week 6 1.38; SD 1.46, p=0.03) and no change in  
the CD3+/CD8+/CD45RO-/ TNF-α+% TIL (mean change  
at Week 6 0.20; SD 0.41, p=0.4). This induction/potentiation of T cell memory (CD45RO+) but not naïve (CD45RO-) T cells in 
tumor requires further testing as a predictive marker given data by Galon et al. in colorectal tumors.11 
Recent data generated by other groups support the importance of testing PD-L1, IDO, and Tregs in the melanoma 
tumor microenvironment in association with CD8+ T Cells 
Figure 3. Significant invasion of tumor by CD8+ TIL after ipilimumab (p=0.02).
(-) ipi 
(+) ipi 
B. 
A. 

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Spranger et al., have reported that the up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is 
driven by CD8+ T Cells.12 Although infiltrating CD8+ T cells can be found in melanoma, those tumors are immunologically 
tolerated and are not rejected. In their report, they showed that the subset of CD8+ T cell infiltrated tumors showed high 
expression of the three defined immunosuppressive mechanisms (PD-L1, IDO, and Tregs), suggesting that these inhibitory 
pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8+ T cell infiltration. They 
conducted mechanistic studies in mice that revealed that the up-regulated expression of IDO and PD-L1, as well as the 
recruitment of Tregs in the tumor microenvironment depended on the presence of CD8+ T cells. These results support the 
hypothesis that these major immunosuppressive pathways are intrinsically driven by the immune system rather than the 
tumor, and imply that immunotherapy approaches targeting both of these immunosuppressive pathways would best enhance 
cytotoxic T lymphocytes-mediated cytotoxicity. Therefore, because of the multiple immune inhibitory pathways involved 
concurrently to facilitate immune escape, these data also support combination therapeutic strategies to target two or more 
immunosuppressive mechanisms simultaneously. In fact, preclinical data support the idea that combinatorial manipulations of 
two immunoregulatory pathways can work synergistically to enhance immune-mediated antitumor activity in vivo.13-15 These 
data support the notion that the combined inhibition of the immunosuppressive mechanisms mediated through PD1/PDL1 and 
IDO that are known to inhibit T cell activation leading to tumor escape from immune-mediated destruction is a potentially 
superior therapeutic approach than the inhibition of either pathway alone. 
Immunotype of the tumor-infiltrating lymphocytes correlates with clinical outcome in metastatic melanoma and 
various other malignancies and may be best evaluated in conjunction with PDL1 and IDO expression 
A recent report by Erdag et al showed that an immunotype characterized by a diffuse immune cell infiltrate throughout a 
metastatic tumor correlated best with survival in patients with metastatic melanoma. Further, higher densities of CD8+ T cells 
in the tumor microenvironment were the best predictor of improved survival.16 The presence of CD8+ T cells and the ratio of 
CD8+ T cells / FoxP3+ regulatory T cells was also reported to correlate with a favorable prognosis and improved survival in 
metastatic melanoma and other malignancies. 17-19 We and others have also reported that T cell infiltrates within regional 
nodal metastases correlates with improved survival and is significantly induced by neoadjuvant IFNα2b therapy.20-22 Spranger 
et al have also recently reported that the up-regulation of PD-L1, IDO, and regulatory T cells in the melanoma tumor 
microenvironment is driven by CD8+ T cells. 
2. Circulating Biomarkers 
Potential therapeutic predictive value for baseline ALC in metastatic melanoma patients treated with Anti-CTLA4 
antibody and INFα (Tarhini et al, JCO 2012).  In a phase II study of the combination of IFNα-2b and tremelimumab, 37 
patients with stage IV melanoma were treated.23 The best response rate by intent to treat (ITT; N=37) was 24% (4 complete 
response, CR  and partial response, PR lasting 6, 6, 12+, 14+, 18+, 20, 28+, 30, 37+ months). Disease control rate (response 
+ stable disease, SD) by ITT was 62% (90% CI=0.53, 0.79). Median PFS was 6.4 months (95% CI = 3.3 – 13.1 months). 
Median OS was 21 months (95% CI = 9.5 months, -).23 Baseline ALC at ≥1000/uL (N=34 patients) was associated with 
response (CR/PR versus SD/PD; p=0.02) and clinical benefit (CR/PR/SD versus disease progression, PD; p=0.03 by 
Wilcoxon two-sample test).24 No patient ALC<1550/µL had an objective response, and no patient with an ALC<1200/µL had 
either an objective response or stable disease. 

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Significant potentiation of Type I CD4 and CD8 antigen specific T cell immunity by neoadjuvant ipilimumab that may 
play a therapeutic predictive role (Tarhini et al, PLOS One 2014).  Patients with clinically palpable stage IIIB-C melanoma 
were treated with induction ipilimumab (10 mg/kg I.V. every 3 weeks x2 doses) preoperatively and had definitive 
lymphadenectomy (week ≥ 6), followed by 2 maintenance doses of ipilimumab (q 3 weeks).1,25 Serum, PBMC, and RNA were 
collected at baseline, 6 weeks, then at 3, 6, 9, 12 months and/or progression as summarized above.  Multicolor flow 
cytometry utilizing peptide pools (gp-100, MART-1, NY-ESO-1 peptides) showed evidence of spontaneous in vivo cross-
presentation resulting in type I CD4+ and CD8+ antigen specific T cell immunity. Neoadjuvant ipilimumab induced significant 
potentiation of type I CD4 and CD8 (fully activated and IFN-γ producing) antigen-specific T cell immunity. Both CD4+ and 
CD8+ T cells were activated (up-regulated CD69) upon their stimulation with individual antigen peptide pools, and a subset of 
these cells secreted IFN-γ. The most significant increase “3-10 fold” in CD3+/CD4+/INF-γ+ T cells was seen only in patients 
who were progression-free at 6 months, suggesting a potential early on treatment therapeutic predictive value. The potential 
therapeutic predictive value for CD3+/CD4+/INF-γ+ T cells appears to be similar to the observation by Carthon et al. in 
relation to CD4+ICOShi T cells in bladder cancer patients.26  
Significant modulation of circulating Treg and MDSC in high-risk melanoma patients treated with neoadjuvant 
ipilimumab supporting further assessment for a therapeutic predictive value (Tarhini et al, PLOS One 2014) In the 
same trial testing neoadjuvant ipilimumab, a significant increase in the frequency of circulating Treg (CD4+CD25hi+ Foxp3+; 
p=0.02 and CD4+CD25hi+CD39+; p=0.001) from baseline to 6 weeks was observed.25 Significant decreases in circulating 
MDSC were observed in monocytic HLA-DR+/low/CD14+ MDSC (p<0.0001). Greater increases in Treg were associated with 
improved PFS (p=0.034; HR=0.57), supporting further evaluation of Treg and MDSC for their therapeutic predictive value. In 
tumor, Treg (CD4+/CD25hi+, CD4+CD25hi+ Foxp3+) appeared higher at week 6 in the PD group, but the opposite in the 
clinical benefit (CR/PR/SD) group (p=0.09). Figure 4 summarizes early-on treatment impact of ipilimumab on MDSC and 
Treg and the association between increase in Treg and PFS. Interestingly, Walter et al have recently tested 6 predefined 
populations of MDSC in patients with renal cell cancer treated with the IMA901 vaccine (consisting of multiple tumor-
associated peptides) and found 2 to be prognostic for overall survival.27  
 
 
 
 
 
 
 
 
 

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Similar pattern of 
circulating Treg and 
MDSC in metastatic melanoma patients treated with tremelimumab anti-CTLA4 blocking mAb and INFα supports 
evaluation of these as potential predictive markers in E1609 (Tarhini et al, JCO 2012, J Immunotherapy 2012). 
Changes in Treg and MDSC (using the identical markers described above) were compared between baseline, Day 29 
(completion of induction IFNα), and Day 85 (completion of one course of the combination of tremelimumab and IFNα). There 
was a significant increase in the percentage of CD4+CD25hi+CD39+ Treg at Day 85 (p=0.018) but less significant at Day 29 
(p=0.09) compared with baseline.24,25   
In terms of MDSC, there was a significant decrease in the percentage of all MDSC populations at Day 29, most significantly 
for the monocyte gate MDSC (HLA-DR+ low/CD14+) at Day 29 (p<0.0001) and Day 85 (P=0.001). We noted a less significant 
decrease in the percentage of the lymphoid gate MDSC phenotype (Lin1-/HLA-DR-/CD33+/CD11b+) at Day 29 (p=0.055) and 
Day 85 (p=0.07). There was also a decrease in the frequency of the monocyte gate MDSC (Lin1-/HLA-DR-/CD33+/CD11b+) 
at Day 29 (p=0.04). There was a suggested association between a reduction in lymphoid gate MDSC (Lin1-/HLA-DR-
/CD33+/CD11b+) at Day 85 and clinical response (CR/PR vs. SD/PD).24,25  
Clinical benefit from immunotherapy in melanoma appears to arise from the silencing of MDSC and Treg and the 
coordinated activation of CXCR3 ligand chemokine production and VCAM1 (Walter et al, IJC 2011). Our preclinical 
modeling of effective immunotherapies in the setting of solid tumors, including melanoma, suggest that clinical benefit arises 
from the silencing of MDSC and Treg and the coordinated activation of CXCR3 ligand chemokine (CXCL9, CXCL10 (IP-10) 
and CXCL11) production and VCAM1 (an adhesion molecule that binds to the integrin VLA4) expression by vascular 
endothelial cells in the TME.{Rao, 2012 #1059;Bose, 2012 #1060;Bose, 2011 #1061} These alterations allow for the 
recruitment of peripheral CXCR3+VLA4+Type-1 (i.e., cytotoxic) T effector cells that are capable of mediating direct 
tumoricidal activity that is requisite for objective clinical response.{Bose, 2011 #1061} 
CRP, VEGF, and IL-6 are associated with immune suppression, and their levels at baseline are associated with 
clinical outcome in the phase II study testing tremelimumab anti-CTLA4 mAb and IFNα (IFN-Treme) (Tarhini et al, 
JCO 2012, J Immunotherapy 2012).  We examined CRP at the cut-off value of 1.5 ULN (based on the report by Marshall et. 
Figure 5 The probability of survival by baseline CRP 
level (CRP; <=2.7ULN versus >2.7ULN). 
Figure 6. Baseline S100B ≥ 0.15 µg/L significantly 
correlates with OS (P=0.010). 

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al.)28 but did not detect a significant association with clinical response, clinical benefit, survival, or PFS. Since the distribution 
of our data suggested that CRP at 2.7ULN might be a cut-off value, we explored baseline CRP at 2.7ULN and found an 
association with clinical benefit (p=0.05 by Fisher's exact test) and an association with improved probability of survival (p= 
0.003 by log-rank test), as illustrated in Figure 5. We found an association between baseline VEGF and IL-6 and clinical 
benefit (CR/PR/SD versus PD) but with lesser significance.  
Serum S100B protein is a prognostic biomarker that may improve patient selection for adjuvant therapy (Tarhini et 
al, JCO 2009). We reported on serum levels of S100B serving as a potential prognostic marker for patients with high-risk 
melanoma.29 In this study (see E1694 in Progress Report), sera banked at baseline and 3 additional time points were tested 
for S100B in 691 patients from the E1694 trial by using chemiluminescence. S100B ≥ 0.15 µg/L significantly correlated with 
OS (P=0.010) (Figure 6), and a Cox multivariate analysis identified baseline S100B as a significant independent predictor of 
OS (P=0.043) after adjusting for significant prognostic factors and treatment.  
Multiplex analysis of serum cytokines in high-risk melanoma patients treated with HDI in E1694 adjuvant trial 
showed that baseline pro-inflammatory cytokine levels may predict 5-year RFS with HDI but not GMK vaccine 
(Yurkovetsky et al, CCR 2007).   We used Luminex multiplex to simultaneously measure the levels of 29 cytokines, 
chemokines, and angiogenic and growth factors in the sera of 179 patients from E1694 plus sex-matched controls.30-33 Serum 
concentrations of IL1α, IL1ß, IL6, IL8, IL12p40, IL13, G-CSF, MCP1, MIP1α, MIP1ß, IFNα, TNFα, EGF, VEGF, and TNFRII 
were significantly higher among patients with resected high-risk melanoma compared with controls. Serum levels of immune-
suppressive angiogenic/growth stimulatory factors (VEGF, EGF, HGF) were significantly decreased by HDI, while levels of 
anti-angiogenic IP-10 and IFNα were elevated after treatment. Comparing patients according to relapse outcome, the 
pretreatment levels of pro-inflammatory cytokines IL1β, IL1α, IL6, TNFα, and chemokines MIP1α, and MIP1β were 
significantly higher (P<.05) in sera of patients with longer relapse-free survival (RFS) of 1-3 years and > 5 years, compared 
with patients who experienced shorter RFS of < 1 year.  
A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically 
resected melanoma (Tarhini et al, JTM 2014).  E1694 tested GM2-KLH-QS21 vaccine versus high-dose interferon-α2b 
(HDI) as adjuvant therapy for operable stage IIB-III melanoma. We tested banked serum specimens from patients in the 
vaccine arm of E1694 for prognostic biomarkers.  Aushon Multiplex Platform was used to quantitate baseline serum levels 
of115 analytes from 40 patients. . Leave-one-out cross validation was used to avoid over fitting of the data. In each cross 
validation step, we hold one sample out, and use the rest of the sample to fit a Least absolute shrinkage and selection 
operator proportional hazard regression (Lasso PH) model. Markers with coefficients > 0.1 were selected and included in a 
Cox PH model to predict 1 year RFS and 5 year OS. The linear combination of the CoxPH model was used as the risk score. 
The hold out sample’s risk score is predicted using the CoxPH model fitted by the remaining sample. We continue this until 
the all the samples were “left out and predicted” once. The ability of the resulting risk scores (from cross validation) to predict 
1 year RFS (and 5 year OS) was evaluated by the time-dependent ROC curve. Four markers that include Tumor Necrosis 
Factor alpha Receptor II (TNF-RII), Transforming Growth Factor alpha (TGF-α), Tissue Inhibitor of Metalloproteinases 1 
(TIMP-1), and C-reactive protein (CRP) were found to be most informative for the prediction of OS (high levels correlate with 
worse prognosis). 
 

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As expected, because the markers were selected to correlate with outcome, models built from these selected markers 
also demonstrated prognostic ability in the whole dataset; Figure 7. When using the four-marker PH model to predict 5-
year OS, we achieved an area under the curve (AUC) 72% (cross validated). High baseline TNF-RII was also significantly 
associated with worse RFS. The RFS with high (above median) TNF-RII was significantly lower than low TNF-RII 
(p=0.01). Therefore, the biomarker signature consisting of TNFR-II, TGF-α, TIMP-1 and CRP could potentially be used as 
prognostic markers in patients with high-risk melanoma. These preliminary data warrant further investigation.  
Early on-treatment (one month) pro-inflammatory cytokines predict 1-Year RFS with IFNα but not observation in 
E1697 trial (Tarhini et al, SMR 2013). E1697 was a phase III trial that tested observation (Arm A) vs. adjuvant IFN-α2b 
for one month (Arm B) in patients (pts) with resected intermediate risk stage IIA-B and IIIA melanoma. We evaluated the 
levels of candidate serum biomarkers for their therapeutic predictive or prognostic value in Arm B versus Arm A in 268 pts 
with banked biospecimens. Aushon Multiplex Platform was used for serum cytokine tests at baseline and one month.  Cox 
PH modeling and Wald tests were used to test the association of each marker and RFS. Similar leave-one-out cross 
validation strategy described above was used to avoid over fitting of the data. In the multi-marker modeling analysis in 
Arm B, one month IL2Rα, IL-12p40 and IFN levels significantly predicted one year RFS with LOOCV AUC=83%. The risk 
score (linear combination of the 3markers) separated RFS curves of low and high risk groups well (note that the risk score 
is calculated using the whole data, hence over fitted.); Figure 8. This model did not hold for Arm A, indicating a marker-
treatment (IFN) interaction in Arm B, that is consistent with our previously published predictive role of the proinflammatory 
cytokine profile. Therefore, early on-treatment (one month) proinflammatory serum markers (IL2Rα, IL-12p40, IFN) 
significantly predict RFS in pts treated with adjuvant IFN-α2b and warrant further study.  
3. Prediction of Autoimmune Colitis  
Figure 7. Baseline multi-marker (TGF-α, TNF-
RII, TIMP-1, CRP) risk score in GMK  arm is 
prognostic of poor overall survival (OS). 
Figure 8. One month pro-inflammatory 
cytokines (IL2Rα, IL-12p40 and IFN-α ) 
predict  1-Year RFS with IFNα. 

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Clustered genomic variants specific to patients who develop immune-related colitis after ipilimumab may predict 
this toxicity (Tarhini et al, submitted to ASCO 2014) 
Data generated in the context of UPCI 08-144 trial of neoadjuvant ipilimumab and funded by NIH award P50CA121973. 
These data have been submitted for presentation at the 2014 ASCO Annual Meeting (Tarhini et al., Clustered genomic 
variants specific to patients who develop immune-related colitis after ipilimumab may predict this toxicity). We identified a 
genomic signature to predict colitis predisposition among patients undergoing neoadjuvant ipilimumab therapy for 
locally/regionally advanced operable melanoma.  
XIX.5 Tissue/Specimen Type  
1. Tumor tissue: Paraffin Block or Unstained Slides    
2. Body fluids: Serum, Lymphocytes  
3. Derivatives: DNA (genomic) 
The project plans to test specimens from up to 1600 subjects depending on the availability of biospecimens. The tumor tissue 
blocks/slides are banked at the ECOG-ACRIN Central Biorepository and Pathology Facility. The research blood/blood 
products are banked at the ECOG-ACRIN Immune Monitoring and Cellular Products Laboratory (IMCPL) at the University of 
Pittsburgh Cancer Institute (UPCI). 
1. Tumor: 15-17 (5 micron scrolls), or 15-17 (5 micron unstained slides); 70% tumor  
(Any extra tissue would be saved and returned to the ECOG-ACRIN Central Biorepository and Pathology Facility.) 
[These will be used for the testing of (1) gene expression profiling , (2) Immunohistochemistry, (3)  activating mutations by 
targeted sequencing in select patients with unknown mutational status, (4) methylation status of DNA sequences] 
2. PBMC/Serum: 5 vials PBMC and 3 vials serum   
(An extra vial requested would be saved at the IMCPL and used only for unexpectedly low recoveries and running assays 
on different days.) 
3. DNA (genomic): one yellow top tube  
(Remaining specimen would be saved at the IMCPL.)  
[This will be used for the testing of genomic variants potentially predictive of autoimmune colitis induced by ipilimumab] 
 
XIX.6 Laboratory Methods 
1. 
Tumor Microenvironment 
General: These assays will be conducted at the UPCI Cancer Biomarkers Facility (CBF) Genomics Core (Director:  
William LaFramboise, PhD). 
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1.a. Baseline expression of immune-related pathways/genes 
Microdissection of FFPE tumor specimens will be performed manually using an inverted microscope (Nikon Eclipse 
TE200) to obtain a minimum of 90% tumor cells for RNA purification. Dissection involves scraping cells from unstained 
sections of 5 micron thickness on slides aligned in register with serially cut hematoxylin and eosin stained specimens 
including tumor domains demarcated by a surgical pathologist. RNA purification will be performed using the Qiagen 
miRNeasy FFPE Kit and protocol (Qiagen, Valencia, CA) with isolated RNA suspended in nuclease-free water. Inclusion 
in subsequent in vitro amplification (IVT) assays is determined both by spectrophotometric absorption ratio [260/280 > 
1.8 (NanoDrop, Wilmington, DE)] and RIN values (RNA Integrity Index) determined via microchip electrophoretic analysis 
(Agilent Bioanalyzer 2100, Agilent Technologies, Santa Clara, CA). We have previously established that RIN values 
ranging from 5.0 to 8.0 in RNA from FFPE specimens can undergo successful in vitro transcription and amplification 
using a multiple primer approach. Amplification will be performed using the NuGen whole transcription method 
comprising the Ovation FFPE WTA assay (NuGEN, San Carlos, CA) employing random and 3’ primers to eliminate 
amplification bias beginning with 100 ng total RNA. Confirmation of cDNA diversity will be obtained using the Bioanalyzer 
2100 to generate an electrophoretogram for each amplification reaction regarding sample yield, integrity, and size 
diversity compared to a laboratory human RNA standard and a Universal Human Reference RNA (Stratagene, La Jolla, 
CA). Five micrograms of purified cDNA will be incubated with fragmentation buffer (NuGEN, San Carlos, CA) at 37°C for 
30 minutes, then 95°C for 2 minutes. All cDNA samples will undergo hybridization on Affymetrix GeneChip HG U133A 
2.0 arrays which contain overlapping probe sets for transcripts comprehensively representing the functionally 
characterized human genome. Briefly, fragmented cDNAs are mixed in a hybridization cocktail with water to a final 
volume of 220μl. 130ul of hybridization cocktail is hybridized on each array at 45°C for 18 hours. The arrays are then 
washed and stained with streptavidin-phycoerythrin in a GeneChip Fluidics Station 450 (Affymetrix) and scanned using a 
GeneChip Scanner 3000 (Affymetrix). Quality control (QC) parameters and expression intensity data are derived from the 
MAS 5.0 (Microarray Suite) and RMA algorithms (Robust Multi-array Average) of the Expression Console software 
(version 1.2.0.20; Affymetrix). Comparisons of global and individual gene expression data are performed using median 
normalized and log2 values transferred to Partek Genomics Suite v6.5 (Partek Inc, St Louis, MI). Statistical significance 
is performed at a false discovery rate (FDR) of less than 5% (q value) to control for Type 1 errors arising from multiple 
tests. 
1.b. Tumor infiltrating lymphocytes and immunosuppressive markers (immunohistochemistry): CD3, CD4, CD8, 
FOXP3, PD-L1, IDO, CD45RO 
Immunohistochemistry will be conducted at UPMC Shadyside Hospital, Department of Pathology, under supervision of 
Dr Uma Rao (E1609 Pathology Co-chair). Paraffin-embedded tissue sections (5 μm thick) will be scored at × 20 
magnifications by a surgical pathologist (Uma Rao, MD) who will be blinded to patient and treatment status.  
Lymphocytes will be counted in 4 quadrants and added.  The total numbers of intratumoral, peritumoral, and perivascular 
mononuclear cell infiltrates will be enumerated following standard immunohistochemical staining, as previously 
published,34 with FOXP3, CD4, CD8, IDO, PDL1 and CD45RO monoclonal antibodies.  
2. 
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General:  These assays will be conducted at UPCI Immune Monitoring and Cellular Products Laboratory (IMCPL; 
Director: Lisa Butterfield, PhD) which is CAP accredited and CLIA certified.  All assays are run according to SOPs by 
trained and competency tested personnel, and include healthy donor controls.  The laboratory participates in external 
proficiency panels for flow cytometry and Luminex. 
2.a. Circulating Cellular Populations 
Absolute lymphocyte count will be determined by the hospital clinical lab by standard procedures and is being collected 
prospectively on study-specific forms.  All other cellular assays will be tested by flow cytometry in the IMCPL, according 
to existing SOPs.  The flow cytometer (FC500) is QC’d daily and monitored for any change in laser function.  All 
antibodies are tested before use in patient material testing. 
Cellular subpopulations are sequentially gated on, and both MFI and % positive is reported.  Dot plots and histograms 
are reviewed by an experienced supervisor and results inserted in spreadsheets which are sent to the project associated 
biostatistician.  Negative populations are identified by isotype antibodies or negative control cells or unstimulated cells 
(depending on assay or antibody).  Any cell populations with any degree of positive marker expression are listed by the 
specific MFI or % positive value. 
2.b. Circulating Serum Proteins 
Most serum proteins will be analyzed by the multiplex Luminex assay, and analyzed on a BioRad reader.  Concentrations 
are automatically determined based on kit standard curves from the software.  Additional controls include R&D Systems 
Multiplex QC controls which are mixed cytokines with expected yield values.  Large projects use a single lot of kits 
whenever possible.  Analytes requiring non-standard dilutions (like CRP) are run singly.  Analytes not compatible with 
multiplexing are run singly in ELISA format kits.  Results are presented as the pg/ml values reported and results above or 
below the limits of detection are reported as such.  Given the broad range of detection for the Luminex platform, values 
below the LLD are generally considered negative, and values above the ULD are either considered statistically as equal 
to the ULD, or, if a reasonable fraction of samples are over the ULD, those samples are diluted further and re-run. 
3. 
Prediction of Autoimmune Colitis 
3.a. Targeted Deep Sequencing to identify genomic variants specific to patients who develop immune-related colitis 
after ipilimumab therapy.  
General: These assays will be conducted at the UPCI Cancer Biomarkers Facility (CBF) Genomics Core (Director:  
William LaFramboise, PhD). 
We identified a genomic signature to predict colitis predisposition among patients undergoing neoadjuvant ipilimumab 
therapy for advanced melanoma (Tarhini et al., Clustered genomic variants specific to patients who develop immune-
related colitis after ipilimumab may predict this toxicity. Submitted to the 2014 ASCO Annual Meeting). The proposed 
study will extend these findings in a larger patient cohort. Targeted, deep sequencing will focus on a customized 10 
gene/9 SNP panel developed in our laboratory.  PBMC (blood) samples (1 x 106 cells) will be extracted using the 
QIAamp DNA Micro kit (Qiagen, Valencia, CA) and DNA obtained by column purification will undergo QC to identify 
samples (>100 ng/ul) with OD 260/280 >1.8 (Nanodrop ND-1000 spectrophotometer, NanoDrop, Wilmington, DE) and 
fragments ≥300 base pairs (Bioanalyzer 2100: 12000 DNA Chip, Agilent Technologies, Santa Clara, CA) for library 

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construction. Primers for target genes will be used to generate amplicon libraries via PCR selection (Perkin Elmer 9700, 
Bridgeville, PA) (99°C x 2min, 15 cycles at 99°C x 15 sec, 60°C x 8 min, 10°C x hold) followed by enzymatic digestion 
and phosphorylation of the multiplexed amplicons. The amplicons are then indexed (Ion Xpress Barcode Adapters, Life 
Technologies, Grand Island, NY) and adapters ligated for attachment to Ion Spheres (ISP) in micro-reactors for clonal 
amplification using emulsion PCR (One Touch 2 instrument; 60 cycles, PGM 200bp kit v2). Templated ISPs are 
recovered and enriched using biotin labeled primers bound to streptavidin coated metallic beads (DynaBeads C1, Life 
Technologies). The ISPs are then washed, stripped from the streptavidin beads (125mM NaOH; 0.1% Tween 20) and 
sequencing is performed on the Ion Torrent Personal Genome Machine (PGM) using the 200bp sequencing kit v.2 and a 
washed, precalibrated semiconductor chip (318v.1 for 200bp libraries, Life Technologies) on the PGM platform.  
Sequencing comprising 500 flows (125 washes of each of 4 nucleotides) has provided 1000 x base depth of parsed 
barcoded reads aligned to Human Reference Genome HG19 on 10 samples undergoing simultaneous sequencing. BAM 
files (binary format), linked BAI files (indexed files) and variant call files (vcf) (Torrent Suite 4.0) are transferred from the 
Ion Torrent server (Dell Precision T7500, Intel Xeon Quad Core 2.93GHz, Ubuntu 10.04) to the analysis server (MacPro 
5.1, Intel Xeon 6 Core 2.4GHz, OSX 10.8.4; GenomOncology Inc., Westlake, OH). A Galaxy Project plug-in 
(Pennsylvania State University, State College, PA) generates additional vcfs and INDELs using GATK (Genome Analysis 
Toolkit; UnifiedGenotyper v. 2.3), SAMtools (mpileup v. 0.1.18) and a manual variant caller algorithm (variant: ≥5% base 
calls differ from HG19 with ≥ 300 calls at Phred Score=20 or p < 0.01). All variants and INDELs are validated by manual 
curation of the BAM file sequence using the Integrated Genomics Viewer (IGV Broad Institute). All patient samples will be 
compared for commonality of single nucleotide variants and INDELs based on colitis symptoms. 
XIX.7 Facilities & Personnel 
Principal Investigator: 
Name: Ahmad A Tarhini, MD, PhD (UPCI Skin Spore Biomarker Project Co-Leader) 
Institution: University of Pittsburgh Cancer Institute 
Mailing Address: UPMC Cancer Pavilion, 5150 Centre Avenue, Suite 555, Pittsburgh, PA  
Email: tarhiniaa@upmc.edu 
Phone: 412 648 6578 
 
 
Fax: 412 648 6579 
Co-Investigators: 
Name:  
Walter Storkus, PhD (UPCI Skin Spore Biomarker Project Co-Leader) 
Institution: 
University of Pittsburgh 
Mailing Address: University of Pittsburgh, Biomedical Science Tower, 200 Lothrop Street, W1041, Pittsburgh, PA 
Email: storkuswj@upmc.edu 
 
Name:  
John M Kirkwood, MD 
Institution: 
University of Pittsburgh Cancer Institute 
Mailing Address: Hillman Cancer Center Research Pavilion, 5115 Centre Avenue, Suite 1.32, Pittsburgh, PA  
Email: kirkwoodjm@upmc.edu 

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Name:  
Lisa H Butterfield, PhD 
Institution: 
University of Pittsburgh Cancer Institute 
Mailing Address: Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA  
Email: butterfieldl@upmc.edu 
 
Name:  
William LaFramboise, PhD 
Institution: 
University of Pittsburgh Cancer Institute 
Mailing Address: UPCI, Shadyside Hospital, 5230 Centre Avenue, Pittsburgh, PA 
Email: laframboisewa@upmc.edu 
 
Name:  
Uma N.M. Rao, MD 
Institution: 
University of Pittsburgh Cancer Institute 
Mailing Address: UPCI, Shadyside Hospital, 5230 Centre Avenue, Pittsburgh, PA 
Email: raounm@upmc.edu 
 
Biostatistics: 
 
Name:  
Sandra Lee, PhD (ECOG-ACRIN E1609 Biostatistician)  
Institution: 
Dana Farber Cancer Institute 
Mailing Address: 450 Brookline Avenue Boston, MA, 02215 
Email: sjlee@jimmy.harvard.edu 
 
Name:  
Yan Lin, PhD (UPCI Skin Spore Biomarker Project Biostatistician) 
Institution: 
University of Pittsburgh Cancer Institute 
Mailing Address: UPCI, Biostatistics Facility, Sterling Plaza Suite 325, 201 North Craig Street, Pittsburgh, PA  
Email: yal14@pitt.edu 
 
XIX.8 Statistical Design 
Endpoints (outcomes) 
The clinical endpoints are relapse free survival (RFS) and overall survival (OS). RFS is defined as the time from study entry to 
relapse or death, whichever happens first. OS is defined as the time from study entry to death.  
Primary Comparison 
The primary objective of the study is to build a prognostic model using the candidate biomarkers for each study arm. The 
secondary objectives are (a) to test for the therapeutic predictive power of prognostic panels discovered; (b) to search for 

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therapeutic predictive markers to guide the therapeutic choice of either ipilimumab or HDI; (c) to test for association of pre-
specified genetic variants and the occurrence of colitis.  
Case Selection 
We plan to include all subjects accrued in E1609 ipilimumab study arms (A, D and C, F) and HDI study arm. Arms A and D 
treat patients with high dose ipilimumab (HIP), arms B and E with HDI and arms C and F with low dose ipilimumab (LIP). 
Power Justification 
The target accrual for E1609, which was activated in May 2011, is 1600 (600 HDI, 500 HIP, 500 LIP), which will be completed 
by August 2014. Thus, by 2015, we will have at least 1 year of follow-up data for each patient in the trial for analysis and 
validation of potential biomarkers and the development of prediction models for RFS and OS of the patients in each treatment 
arm. 
We currently estimate that biospecimens are available for testing from approximately 80% of subjects enrolled on E1609. We 
expect that these numbers will improve as we continue to follow up with participating sites on biospecimen submission. 
Power for Primary Objective: Prognostic Modeling  
Subjects will be divided into a training set and a validation set (250 each for the LIP and HIP groups, 300 for HDI group). Here 
we demonstrate our power in the development of a prognosis model in one of the Ipilimumab arms. We base our power 
calculation on a test that compares the SN and SP simultaneously35 . Following the E1609 protocol, we expect that the cure 
rate for the ipilimumab arm will be 40% and the median RFS for the uncured patients is 0.48 years. As described above, we 
expect to obtain samples from >=80% of the patients, after accounting for 95% assay success rate, we will have about 76 
cases (patients who had event within 1 year) and 114 controls (patients who are followed up for 1 year without any event).  
We define a minimal useful model to be one with a sensitivity of 75% or higher and a specificity of 75% or higher. If the true 
sensitivity and specificity are 89% and 87% for our model, we will have over 80% power to claim that our model is significantly 
better than the minimal useful model (α=0.05).  
Power for Predictive Modeling 
With limited preliminary data, predictive modeling is our secondary objective. Nevertheless, here we estimate our power for 
validation of a predictive biomarker in the validation set. We base our calculation on the analysis of one of the ipilimumab 
arms (HIP or LIP) and the HDI arm. However, it is very likely that the RFS profiles are very similar between the two 
ipilimumab arms. If this turned out to be the case by the time we analyze the data, we will consider combining the data of 
these two arms. Thus, our power estimate here is a conservative estimate. The goal here is to determine whether there is a 
significant difference between the clinical benefits of patients in different marker strata. That is, we are testing the interaction 
of the dichotomized marker value (we discuss how to dichotomize the marker value in details in our analysis plan in the 
following section) and the treatment group. We calculate our power based on the method by Peterson and George. 36 As 
shown in Table 1, with 418 samples total, we will be able to detect an interaction term with HR between 1.9-2.1 assuming the 
marker stratum 1 proportion is between 50-70% with a two-sided test (α=0.01). Details on the power calculation for the 
predictive modeling is given below.  

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Table 1 Power calculation for test of interaction (
, two-sided) 
 
 
 
XIX.9 Statistical Analysis Plan 
• 
Statistical methods for the main analyses: For the single marker association with PFS and OS, Cox proportional hazards 
(CoxPH) regression will be used. Because some long-term cures have been observed in patients with stages IIB – III 
melanoma treated with HDI and ipilimumab, we will also perform exploratory analyses using a cure-rate model for RFS as 
a supplement to the CoxPH regression analyses proposed above.  For multi-marker prognostic model, both the Lasso 
Cox proportional hazard regression and the Cox proportional hazard regression will be used. And the results will be 
compared.   
• 
Transformations applied to variables: Distribution of data of different types will be checked and appropriate transformation 
will be used when necessary. 
• 
Methods for marker cutpoint determination: For the predictive biomarker, we will follow the recommendation of Janes et al 
2013 and use the marker-by-treatment predictiveness curves to guide the dichotomization of the marker (or risk score for 
multi-marker panel) 37. Specifically, we will dichotomize the marker (or score) around the point where the two predictive 
curves cross.  

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• 
Variable selection procedures: We will use two strategies and compare our results: Cox proportional hazard regression 
with forward regression and Lasso Cox proportional hazard regression. 
• 
List of standard clinical variables to be incorporated into models or other analyses: Clinical variables that we will consider 
to be included in the models are age, sex, Breslow thickness, recurrent disease at study entry, ulceration of the primary 
tumor, lymph-node status, number of positive lymph nodes, completion of lymph node dissection prior to treatment, 
microscopic extranodal extension, and mitotic rate in the primary tumor. 
• 
Multiple-comparisons adjustment methods: To adjust for the multiple testing, the Benjamini and Hochberg’s (BH)38 
method will be used to control the false-discovery rate (FDR) at 5% for all candidate marker analyses. For the whole 
genome scan, we will use the procedure described in Storey 2002 to control the FDR at 5%.39 
• 
For complex studies, methods that will be used to validate the analysis results, or a rationale for not performing a 
validation study: Given the uniqueness of this study population, we do not a compatible independent validation cohort, but 
our study population is large enough that we will randomly split the samples into two groups of equal size, using one of 
them as the training set and the other one as the validation set. However, to avoid over fitting, the validation set will be 
held out till the last stage of the study, where it will be used to validate the final models. 
• 
Any other information necessary for the Committee to understand and evaluate the main analyses you are proposing: The 
detailed analysis plan for our primary objectives is included below. 
Secondary Objectives 
For the predictive biomarker analysis, again we will randomly split the samples into two groups of equal size, using one of 
them as the training set and the other one as the validation set. However, to avoid over fitting, the validation set will be held 
out till the last stage of the study, where it will be used to validate the few (<=5) final biomarkers (or panels). 
Searching for predictive biomarkers 
Based on our and others studies, we have defined a pool of candidate prognostic biomarkers. We expect that some of these 
markers are also predictive. Thus, we would consider these markers as our top tier candidate predictive markers. First, we will 
follow the recommendation by Janes et al, and use the marker-by-treatment predictive curves using 1-year PFS (or 1-year 
OS) as the “response rates” to evaluate the interaction between the marker and the treatment37.  Only the markers with a 
qualitative interaction with the treatment will be further investigated, since they are the only markers that could guide the 
choice of treatments. We will dichotomize marker around the point where the two predictive curves cross.  To test the 
interaction between the marker and treatment, we will fit the Cox proportional hazard model of the following form: λ(t) = λ0(t) × 
exp{β1Md+ β2T +β3T*Md+ ∑βiCovariates}, where Md denotes dichotomized marker value, T denotes treatment (HDI/HIP/LIP), 
the function λ(t) represents the event rate at time t, and λ0(t) represents the corresponding baseline event rate. Likelihood 
ratio test will be used to test the null hypothesis of β3=0. To adjust for the multiple testing, the Benjamini and Hochberg’s (BH) 
38method will be used to control the false-discovery rate (FDR) at 5%. We may also consider the risk score from the 
prognostic models developed above as a continuous marker and analyze them in the same way as described above. Markers 
(and risk scores) that show a significant qualitative interaction with the treatment effect will be further ordered by the 
estimated 1-year RFS (or OS) rate under the marker-policy. The top few (<5) predictive biomarkers may be validated in the 

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validation set. Given the lack of preliminary data on predictive biomarkers, if our search among the top tier markers failed, we 
will consider a genomic scan of gene expression to search for potential predictive biomarkers using the same strategy 
described above in the training dataset.  
We will also consider building a multi-marker prediction model. Given the limited sample size, we will consider only the top 3-5 
markers in the model. We will first fit a CoxPH model with main effects of the markers and the clinical factors:  λ(t) = λ0(t) × 
exp{∑βiM+ ∑βiCovariates}, and test the predictive value of the predicted risk score (the linear combination of this model) as 
described above. 
The top few (<=5) predictive markers (and/or panels) will be validated in the validation set. The same cutoff point will be used 
to dichotomize the marker value (or risk score value). CoxPH models with interaction term between the dichotomized marker 
and the treatment will be fitted. We will compare the direction and magnitude of the interaction term to that obtained in the 
training set. Likelihood ratio tests will be used to test the interaction of each marker and the treatment effects. A p-value of 
0.01 (0.05/5) will be considered statistically significant.  
Testing the association of candidate SNP genotype and “immune-related colitis”  
We will test the association of each variant and the risk of immune-related colitis by logistic regression adjusting for potential 
clinical confounders including age and sex. The Benjamini and Hochberg’s (BH)40 method will be used to control the false-
discovery rate (FDR) at 5%. 
* 
* 
* 
Detailed Analysis Plan for the Primary Objective 
Association of individual markers with clinical outcome. The association of each marker at each time point with the RFS 
will be assessed by Cox proportional hazard regression (CoxPH), adjusted for treatment arm and known prognostic factors 
such as age, sex, Breslow thickness, recurrent disease at study entry, ulceration of the primary tumor, lymph-node status, 
number of positive lymph nodes, completion of lymph node dissection prior to treatment, microscopic extranodal extension, 
and mitotic rate. Schematically, we will fit models of the following form: λ(t) = λ0(t) × exp{β1M+ β2T + βiCovariates}, where M 
denotes marker value (e.g., the absolute lymphocyte count,  ALC), T denotes treatment (HDI/HIP/LIP), the function λ(t) 
represents the relapse rate at time t, and λ0(t) represents the corresponding baseline relapse rate. Because some long-term 
cures have been observed in patients with stages IIB – III melanoma treated with HDI and ipilimumab, we will also perform 
exploratory analyses using a cure-rate model for RFS as a supplement to the CoxPH regression analyses proposed above. 
The cure-rate model assumes that the population being studied is a mixture of two subpopulations: one of which is cured 
(proportion π of the study population), and the other of which is not (proportion 1 – π of the study population).  We represent 
the survival function in this latter subpopulation by S2(t). The survival function S(t) for the entire study population is a simple 
mixture of the two: S(t) = π + (1 - π)S2(t). Similar approaches will be used for the statistical analysis of OS data. To adjust for 
the multiple testing, the Benjamini and Hochberg’s (BH) 38method will be used to control the false-discovery rate (FDR) at 5%. 
Note that this marker-by-marker analysis is not intended for the feature selection of the multi-marker model building 

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described in the next section. This analysis is to test the marginal association of each candidate marker. The feature 
selection step for the model building is included in the cross-validation loop to avoid over-fitting.  
Development and validation of the prediction model. The model development will be carried out at two levels: within each 
Aim (i.e., using markers within the same category) and across Aims (using markers that are discovered in all Aims). The main 
goal is to develop a prognosis model of RFS in the HIP and LIP arms. However, we will also take the advantage of the 
availability of the HDI arm to develop a prognosis model for melanoma patients treated with HDI. Therefore, we will develop a 
prognosis model for each arm of the study. Given the uniqueness of this study population, we do not a compatible 
independent validation cohort, but our study population is large enough that we will randomly split the samples into two 
groups of equal size, using one of them as the training set and the other one as the validation set. However, to avoid over 
fitting, the validation set will be held out till the last stage of the study, where it will be used to validate the final models. The 
small model within each subgroup of the biomarkers will be evaluated through cross-validation within the training set.  
We will first use the Lasso Cox proportional hazard regression (LPHR) to develop a prognosis model for RFS using the 
training set. The Lasso was developed by Tibshirani 199641 and uses an l1 penalty to achieve a sparse solution, which allows 
simultaneous variable selection while fitting the model.  This method has been applied to generalized linear regression41 and 
CoxPH models42. Friedman et al. developed a fast algorithm for these methods and implemented it in a user-friendly R 
package, glmnet 43Lasso has attracted more and more attention on the analysis of high-dimensional data because of its 
capability to perform the regression with outstanding accuracy in a large feature space, while simultaneously selecting the 
features. The tuning parameter will be trained through ten-fold (10x) cross validation within the training set. The linear 
combination score of the resulting model will be used to classify the patients into low-, intermediate-, and high-risk groups 
(cutoff at the 33% and 67% percentiles of the score). Hazard ratios (HRs) between the groups will be calculated. Log rank 
tests will be used to compare the RFS among these groups. The ability of this score to predict 1-year RFS will be evaluated 
using a time-dependent ROC curve 44.The area under the ROC curve (AUROC) will be calculated. An optimal cutoff point, 
which produces the best prediction (highest accuracy), will be chosen, and the corresponding sensitivity (SN), specificity (SP), 
and accuracy will be reported. The moderate number of candidate markers considered in each aim and the relatively large 
number of samples also enables us to use the regular CoxPH regression as a complement method to the LPHR. Markers will 
be evaluated for inclusion in the CoxPH model by forward stepwise selection. We will follow the same approach described 
above to evaluate the predictability of the model. Several popular machine-learning methods have been extended to handle 
right-censored data and predict subject survival status at a specific time point45,46. We will use these methods as alternative 
methods to predict 1-year RFS for these patients and compare the performance of these methods to the LPHR model and 
Cox regression model. Specifically, univariate Cox regression will be used to evaluate the association of each individual 
marker and RFS. The BH method will be used to control the FDR at 5%40. We will apply the random survival forest 46and the 
survival SVM 13 to markers that passed the univariate analysis to generate a prognostic model to predict 1-year RFS. We will 
also use a bootstrap method in combination with the machine learning algorithm in marker selection. We will cross check the 
results of both methods for consistencies. The SN, SP, and accuracy will be calculated for each model and compared by 
McNemar tests between each pair of models. To avoid over fitting of the data, 10x cross validation within the training set will 
be used. In addition, the final models will be validated in the validation set. Specifically, the model parameters estimated 
using the training data will be applied to the validation set. For the survival model, the HR low-, intermediate-, and high-risk 

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groups (cutoff at the 33% and 67% percentiles of the score) will be calculated. The log rank test will be used to compare the 
RFS between the groups. The discrimination ability of the risk score on 1-year RFS will be assessed by time-dependent ROC 
analysis. The same strategies will be used in the analysis of OS.  
Power Calculation for Predictive Modeling 
The goal here is to determine whether there is a significant difference between the clinical benefits of patients in different 
marker strata. That is, we are testing the interaction of the dichotomized marker value (we discuss how to dichotomize the 
marker value in details in our analysis plan in the following section) and the treatment group. We calculate our power based 
on the method by Peterson and George. 36  
We denote the hazard function for each patient subgroup as the following:  
 
Marker stratum 1  Marker stratum 2  
HDI 
 
 
Ipilimumab  
 
 
 where  
 
 is the baseline hazard 
 is the hazard for the Ipilimumab group 
 is the hazard for marker stratum2 and 
 is the hazard for the treatment by marker stratum interaction. 
Denote N the sample size,  fij, the number of subjects in treatment group i and marker stratum j,   and eij, the event probability 
in treatment group i and marker stratum j. Define that 
 , then the power to test the null hypothesis of 
  
can be calculated using the following formula:  
 
  
 
• 
 : we do not intend to validate more than 5 predictive markers (and/or panels) in the validation set, thus, our type I 
error is set at 0.05/5=0.01. All tests will be two-sided.  

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• 
For the purpose of power calculation, we assume the RFS time follows an exponential distribution. 
• 
 N: 250 on the ipilimumab arm + 300 on the HDI arm. We expect that we will be able to obtain samples from 
approximately 80% of the subjects. We expect that the assay success rate is at least 95%. Thus N is estimated to be 418. 
• 
fij: since this is a randomized trial, we assumed that the marker distribution in the two arms are balanced. Thus we may 
estimate 
 where ti and gj are the frequencies of treatment i and marker stratum j. In our data,
, we calculate the power for g1 in the range of 50%-70%. 
• 
eij: with the exponential failure and uniformed accrual assumption, eij is calculated based the accrual rate, minimum follow 
up time and 
 . The accrual rate for E1609 is approximately 40/month, by the time of the analysis we will have at least 1 
year of follow up for all the subjects.  
• 
’s : determine the effect size 
 .Although 
 (hazard rate for patients in treatment arm i marker stratum j, which is 
unknown. However, the hazard rate for treatment arm i, 
 , can be deduced from the E1609 protocol. It was assumed 
that the RFS function follow a curate model of the following form:
  , where p=0.29, and the 
median RFS for the uncured patients on HDI arm is assumed to be 0.487 year. Thus 
 . Set 
 , we estimate that the median survival time for HDI group to be  0.756 year. For the purpose of power 
calculation, we use exponential distribution to approximate the RFS function in each treatment group. Thus, 
 . It was assumed that a HR of 0.75 will be observed between the ipilimumab arm and the HDI 
arm, thus, 
 . We further approximate  
 .  
 
The following table listed the power for different marker stratum 1 frequencies (g1), and different effect sizes. We only 
considered marker with qualitative interaction with the treatment, assuming that patients in marker stratum 1 benefit from 
the Ipilimumab and those in marker will benefit from HDI. Thus, we consider the situations where 
 and 
 
only. We set 
 within the range of 0.7-1.2. The SWOG webtool (http://stattools.crab.org) was used for the power 
calculation. Here we assume the accrual time is 40 months (Accrual=40/12=3.3), minimum follow up is 12 months 
(Follow=12/12=1), Cell Freq Treat1/Strat1=
 , Cell Freq Treat1/Strat2= f12, Cell Freq Treat2/Strat1= f21, Cell Freq 
Treat2/Strat2= f22, Hazard Rate Treat1/Strat1=
, Hazard Rate Treat1/Strat2=
, Haz Ratio T1/T2 STrat1=
, and Haz 
Ratio T1/T2 Strat2=
.  
 
Table 1 Power calculation for test of interaction (
, two-sided) 
 
 

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