DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a Phase III Trial
Phase: PHASE3
Conditions: Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma, Recurrent Melanoma, Unresectable Melanoma
Sponsor: National Cancer Institute (NCI)

 
EA6134 
1 
DREAMseq (Doublet, Randomized Evaluation in 
Advanced Melanoma Sequencing) a Phase III Trial 
STUDY CHAIR: Michael B. Atkins, M.D. 
SWOG CO-CHAIR: Bartosz Chmielowski, M.D. 
STUDY STATISTICIAN: Sandra Lee, ScD 
PATHOLOGY CO-CHAIR: Brent Harris, M.D., Ph.D 
LABORATORY CO-CHAIRS: Katherine Nathanson, M.D. 
 Ryan Sullivan, M.D. 
 Arnold Potosky, Ph.D 
PATIENT OUTCOMESCANCER CONTROL AND 
SURVIVORSHIP COMMITTEECO-CHAIR: 
 
Lynne Wagner, Ph.D 
MELANOMA COMMITTEE CHAIR: John M. Kirkwood, M.D. 
Version Date:  July 30, 2025 
Update Date:  July 13, 2015 
STUDY PARTICIPANTS 
ACTIVATION DATE 
NRG / NRG Oncology Foundation, Inc 
July 13, 2015 
Addendum #16 
ALLIANCE / Alliance for Clinical Trials in Oncology 
Update #1 – Incorporated 
prior to activation 
Addendum #17 
Addendum #18 
SWOG / SWOG 
Addendum #1 – 12/15 
Addendum #19 
 
Addendum #2 – 12/15 
Addendum #20 
 
Addendum #3 – 3/16 
Addendum #21 
 
Addendum #4 – 6/16 
Addendum #22 
 
Addendum #5 – 11/16 
Addendum #23 
 
Addendum #6 – 1/17 
Addendum #24 
 
Addendum #7 – 2/17 
Addendum #25 
 
Addendum #8 – 5/17 
Addendum #26 
 
Addendum #9 – 10/17 
Addendum #27 
 
Addendum #10 
Addendum #28 
 
Addendum #11 
 
 
Addendum #12 
 
 
Addendum #13 
 
 
Addendum #14 
 
 
Addendum #15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
Ipilimumab 
IND#
 
732442 
NCI-Supplied 
Nivolumab 
IND#
 
748726 
NCI-Supplied 
Dabrafenib 
IND#
 
763760 
NCI-Supplied 
Trametinib 
IND#
 
763093 
NCI-Supplied 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
2 
Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 
Research Hypothesis ................................................................................. 8 
1.2 
Disease Background .................................................................................. 8 
1.3 
Ipilimumab .............................................................................................. 10 
1.4 
Nivolumab ............................................................................................... 13 
1.5 
Nivolumab + Ipilimumab Combination ................................................... 14 
1.6 
Dabrafenib Mesylate (GSK2118436B) ..................................................... 15 
1.7 
Trametinib ............................................................................................... 17 
1.8 
Dabrafenib and Trametinib Combination ............................................... 19 
1.9 
Study rationale ........................................................................................ 20 
1.10 Rationale for Tobacco Use Assessment .................................................. 22 
2. Objectives ......................................................................................................... 25 
2.1 
Primary Objective .................................................................................... 25 
2.2 
Secondary Clinical Objectives ................................................................. 25 
2.3 
Secondary Laboratory Objectives ........................................................... 25 
2.4 
Secondary Patient Reported Outcomes Objectives ................................ 26 
2.5 
Exploratory Tobacco Use Objectives ....................................................... 27 
2.6 
Exploratory Correlative Objective ........................................................... 27 
3. Selection of Patients ......................................................................................... 28 
3.1 
Eligibility Criteria Step 1: ......................................................................... 28 
3.2 
Eligibility Criteria Step 2 (Crossover arms): ............................................. 32 
4. Registration and Randomization Procedures ................................................... 35 
4.1 
Randomization (Step 1) ........................................................................... 39 
4.2 
Randomization (Step 2) ........................................................................... 39 
4.3 
Additional Requirements ........................................................................ 40 
4.4 
Instructions for Patients who Do Not Start Assigned Protocol Treatment43 
5. Treatment Plan ................................................................................................. 44 
5.1 
Administration Schedule ......................................................................... 44 
5.2 
Adverse Event Reporting Requirements ................................................. 48 
5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) ........... 58 
5.4 
Dose Modifications ................................................................................. 78 
5.5 
Treatment of Nivolumab Related Infusion Reactions ........................... 102 
5.6 
Treatment of Ipilimumab Related Infusion Reactions .......................... 104 
5.7 
Prohibited and Restricted Therapies During the Study ........................ 105 
5.8 
Supportive Care ..................................................................................... 105 
5.9 
Quality of Life Studies ........................................................................... 105 
5.10 Duration of Therapy .............................................................................. 110 
5.11 Duration of Follow-up ........................................................................... 110 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
3 
6. Measurement of Effect ................................................................................... 111 
6.1 
Antitumor Effect – Solid Tumors-RECIST .............................................. 111 
7. Study Parameters ............................................................................................ 120 
7.1 
Therapeutic Parameters ........................................................................ 120 
7.2 
Biological Sample Submissions ............................................................. 123 
8. Drug Formulation and Procurement ............................................................... 124 
8.1 
Ipilimumab ............................................................................................ 124 
8.2 
Nivolumab (NSC748726) ....................................................................... 128 
8.3 
Dabrafenib ............................................................................................ 131 
8.4 
Trametinib (NSC 763093) ...................................................................... 135 
9. Statistical Considerations ................................................................................ 138 
9.1 
Study Design and Objectives ................................................................. 138 
9.2 
Study Endpoints .................................................................................... 138 
9.3 
Sample Size Considerations and Monitoring Plan ................................ 138 
9.4 
Statistical Analysis Plan ......................................................................... 140 
9.5 
Sex and Ethnicity ................................................................................... 141 
9.6 
Study Monitoring .................................................................................. 141 
9.7 
Correlative Objectives ........................................................................... 141 
9.8 
Patient Reported Outcomes (PROs) Objectives .................................... 142 
10. Biological Sample Submissions ....................................................................... 149 
10.1 Sample Collection and Submission Schedule ........................................ 149 
10.2 Submissions to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) ........................................................................................ 149 
10.3 Submissions to Immunologic Monitoring and Cellular Products 
Laboratory (IMCPL) ............................................................................... 151 
10.4 ECOG-ACRIN Sample Tracking System .................................................. 152 
10.5 Use of Specimens in Research .............................................................. 153 
10.6 Sample Inventory Submission Guidelines ............................................. 154 
11. Correlative Studies .......................................................................................... 155 
11.1 Pathology Review (MANDATORY) ......................................................... 155 
11.2 Association of Inherited Variation with Immune Mediated Adverse 
Events and Response to Ipilimumab/Nivolumab .................................. 155 
11.3 Evaluation of the Utility of Circulating BRAF Levels in Determining the 
Response and Resistance to Either BRAF Directed and/or 
Immunotherapy in Patients with BRAF Mutant Melanoma ................. 159 
11.4 Lab Data Transfer Guidelines ................................................................ 164 
12. Electronic Data Capture .................................................................................. 165 
12.1 Records Retention ................................................................................. 165 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
4 
13. Patient Consent and Peer Judgment .............................................................. 165 
14. References ...................................................................................................... 165 
 Appendix I  Pathology Submission Guidelines...................................................... 169 
Appendix II  Patient Thank You Letter ................................................................... 173 
 Appendix III  Patient Medication Calendar for Dabrafenib/Trametinib ............... 174 
Appendix IV  CRADA/CTA ...................................................................................... 178 
Appendix V  ECOG Performance Status................................................................. 180 
 Appendix VI  Instructions for Reporting Pregnancies on a Clinical Trial .............. 181 
 Appendix VII  Shipping Kit Request Facsimile Form ............................................. 183 
Appendix VIII  Specimen Shipment Requisition Form ........................................... 184 
Appendix IX  New York Heart Association (NYHA) Classification System .............. 185 
 Appendix X  MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND 
SKIN ADVERSE EVENTS .................................................................................... 186 
 Appendix XI  Strong inducers of CYP3A4 or CYP2C8 ............................................ 194 
 Appendix XII  What to do if a patient comes in with possible immunotherapy-
induced Myocarditis?...................................................................................... 195 
 Appendix XIII  Ancillary for Tobacco Use Assessment:  EAQ16T .......................... 197 
 Appendix XIV  Predictive Biomarker Development in Patients with BRAF Mutant 
Melanoma Enrolled on EA6134 ...................................................................... 208 
 Appendix XV  Patient Clinical Trial Wallet Card .................................................... 210 
 Appendix XVI  Assessment of serum based biomarkers of efficacy and adverse 
events due to treatment with immune checkpoint inhibitors ....................... 211 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
5 
 
STUDY CHAIR 
Michael B. Atkins, M.D. 
Georgetown Lombardi Comprehensive Cancer 
Center 
3970 Reservoir Rd NW Research Bldg, Rm 
E501 
Washington, DC 20057 
Phone: (202) 687-2795 
Fax: (202) 687-6402 
Email: mba41@georgetown.edu 
STUDY CHAIR LIAISON (SCL) 
Kellie Gardner MS, FNP-BC, OCN 
Georgetown Lombardi Comprehensive Cancer 
Center 
3800 Reservoir Rd NW Podium B 
Washington, DC 20007 
Phone: (202) 444-8385 
Fax: (202) 444-3655 
Email: 
Kellie.A.Gardner@gunet.georgetown.edu  
STUDY CHAIR LIAISON (SCL) 
Amy Rose RN, BSN, OCN 
Hillman Cancer Center 
5115 Centre Avenue 
Pittsburgh, PA 15232 
Phone: (412) 647-8587 
Email: roseaj2@upmc.edu  
 
Rev. 12/15 
Rev. 11/16 
Rev. 12/15 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
6 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements 
For patient enrollments:  
For study data 
submission: 
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 SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
through Medidata Rave 
and the ECOG-ACRIN 
Systems for Easy Entry of 
Patient Reported 
Outcomes (EASEE-PRO) 
system. Please see the 
data submission section 
of the protocol for further 
instructions. 
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.  Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS.   
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.  
The CTSU Web site is located at https://www.ctsu.org. 
 
Rev. 11/16 
Rev. 5/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
7 
Schema 
STRAT
FACTORS
R
A
N
D
O
M
I
Z
A
T
I
O
N
PD1,2
Step 1:
Step 2:4
ECOG PS
• 0
• 1
Serum LDH
• Normal3
• Elevated3
C
R
O
S
S
O
V
E
R
1. Progressive disease will be determined by RECIST criteria for all arms (See Section 6).
2. Crossover to Step 2 should occur (if possible) no sooner than 1 week following RECIST defined PD (on Arm A or B) or (if possible) no sooner than 1 week following the stoppage of dabrafenib and trametinib 
for those on Arm B crossing over to Arm D prior to RECIST defined PD.
3. Elevated Serum LDH is defined as above ULN for instituation
4. Must meet eligibility criteria in Section 3.2
Arm A
Initial Treatment Immunotherapy:
Investigator can choose between two 
induction Regimens (1 or 2)
Regimen 1 - Nivolumab 1mg/kg IV infusion 
Day 1 and Day 22 of cycles 1 
and 2
Ipilimumab 3 mg/kg IV infusion 
Day 1 and Day 22 of cycles 1 
and 2
Regimen 2 - Nivolumab 3mg/kg IV infusion 
Day 1 and Day 22 of cycles 1 
and 2
Ipilimumab 1 mg/kg IV infusion 
Day 1 and Day 22 of cycles 1 
and 2
Immunotherapy Maintenance:
• Nivolumab 3 mg/kg IV infusion Day 1, 15 
and 29 of cycles 3-14 (max until 84 weeks 
or 72 weeks of maintenance).
L
O
N
G
-
T
E
R
M
F
O
L
L
O
W
-
U
P
Arm B
• Dabrafenib 150mg PO BID days 1-42 of 
each 6 week cycle
• Trametinib 2mg PO QD days 1-42 of each 
6 week cycle
PD1,2
Arm C
• Dabrafenib 150mg PO BID days 
1-42 of each 6 week cycle
• Trametinib 2mg PO QD days 1-
42 of each 6 week cycle
PD1
PD1
Cycle = 42 days
Accrual Goal = 300
Arm D
Initial Treatment Immunotherapy:
Investigator can choose between two 
induction Regimens (1 or 2)
Regimen 1 - Nivolumab 1mg/kg IV infusion 
Day 1 and Day 22 of cycles 1 
and 2
Ipilimumab 3 mg/kg IV infusion 
Day 1 and Day 22 of cycles 1 
and 2
Regimen 2 - Nivolumab 3mg/kg IV infusion 
Day 1 and Day 22 of cycles 1 
and 2
Ipilimumab 1 mg/kg IV infusion 
Day 1 and Day 22 of cycles 1 
and 2
Immunotherapy Maintenance:
• Nivolumab 3 mg/kg IV infusion Day 1, 15 
and 29 of cycles 3-14 (max until 84 weeks 
or 72 weeks of maintenance).
 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
8 
1. 
Introduction 
1.1 
Research Hypothesis 
We hypothesize that initial treatment of patients with BRAFV600 mutant 
melanoma with ipilimumab + nivolumab (+/- followed by dabrafenib + trametinib) 
will maximize their chance for therapeutic benefit and result in greater 2 year 
survival and more durable complete responders than initial treatment with 
dabrafenib + trametinib (+/- followed by ipilimumab + nivolumab).  
It is conceivable, however, that this assumption is false and that either the two 
treatment approaches produce roughly equivalent outcome or that initial therapy 
with dabrafenib + trametinib results in superior 2-year survival outcome. 
Therefore, the study is designed with a two-tailed p value. 
The results of this study will establish a data driven approach to this treatment 
decision for patients with BRAFV600 mutant melanoma that maximizes their 
chance for long-term benefit. Further, information on the relative value of initial 
treatment with immunotherapy vs molecularly targeted therapy may have 
implications for treatment choices with other immunotherapies and targeted 
therapies in melanoma and for other cancer types where both immunotherapy 
and targeted therapies have shown efficacy (e.g. RCC, NSCLC etc). Measuring 
the severity, duration, and overall impact of CTCAE compiled and patient-
reported toxicities, symptoms and function for each treatment sequence will 
provide additional guidance for treatment decision-making and complement the 
primary endpoint of overall survival. 
1.2 
Disease Background 
Melanoma is currently the 5th and 7th most common cancer in American men 
and women, respectively.1 Although early stage patients can be treated 
successfully with surgical resection in the majority, many will develop 
disseminated disease. The prognosis for patients with metastatic melanoma 
receiving treatments available prior to 2011 had been dismal, with an overall 5-
year mortality rate exceeding 95%.  
Recently, treatment options for patients with advanced melanoma have 
expanded greatly with the FDA approval in 2011-2013 of the CTLA4 blocking 
antibody, ipilimumab and the highly selective inhibitors of BRAFV600E, 
vemurafenib and dabrafenib. In addition, the MEK inhibitor, trametinib, also 
received FDA approval in 2013 for the treatment of patients with BRAFV600E 
mutant melanoma. Finally, the combination of dabrafenib and trametinib received 
FDA approval in 2014 based on a randomized Phase II study in which the 
combination showed superior efficacy relative to dabrafenib alone. 
Ipilimumab has been shown to produce two year survival of 24% and prolonged 
median overall survival in two randomized phase III trials.2,3 A composite analysis 
of 12 clinical studies confirmed the potential long-term survival impact of 
ipilimumab. In this series, 1,257 patients were pretreated and 604 were 
previously untreated for metastatic disease. The dose of ipilimumab was 3 mg/kg 
for 965 patients and 10 mg/kg for 706 patients. The median overall survival for 
the whole patient population was 11.4 months. Most important, the survival curve 
reached a plateau of 22% at 3 years, which persisted to 10 years, and it was 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
9 
independent of the dose.4 Ipilimumab activity has been seen across a broad 
spectrum of prognostic groups including patients with CNS metastases5 and 
does not appear to be influenced by the BRAF mutational status of the patient’s 
tumor.6,7 Recent data has shown that the combination of ipilimumab and the anti-
PD1 antibody nivolumab when administered concurrently shows highly promising 
antitumor activity with 53% of patients treated at the optimal dose and schedule 
exhibiting tumor responses, the majority of which were > 80% tumor shrinkage 
observed within 12 weeks of treatment initiation.8 While long-term follow-up data 
remains preliminary, these results suggest that as many as 88% of these patients 
will be alive at 2 years.22 The combination of ipilimumab and nivolumab is 
currently being examined in comparison to ipilimumab or nivolumab alone in a 
BMS sponsored randomized phase III registration trial. 
The BRAF inhibitors vemurafenib and dabrafenib have been shown to produce 
objective tumor responses in 40-60% of patients with advanced melanoma 
containing BRAFV600E mutations.9,10 Median overall survival in the phase II 
second line trial of vemurafenib was 15.9 months.9 Twenty-five percent of 
patients were shown to be alive at 2 years.30 Furthermore, in a randomized 
Phase III trial vemurafenib produced significant prolongation in progression free 
(HR 0.26) and overall survival with HR 0.37 on the initial analysis, and HR 0.76 
on the longer follow-up relative to dacarbazine.11,12 Dabrafenib has shown similar 
antitumor activity to vemurafenib. In the pivotal phase III trial, in which 250 
patients were randomly assigned in a 3:1 ratio to either dabrafenib or 
dacarbazine, dabrafenib significantly increased PFS compared with dacarbazine 
(median 5.1 versus 2.7 months, HR 0.33, 95% CI 0.20-0.54). Based upon 
independent review of the data, the PFS was similarly increased (6.7 versus 2.9 
months, HR 0.35, 95% CI 0.20-0.61).10 Overall survival favored patients treated 
with dabrafenib (HR 0.76), but was not statistically significant due to extensive 
(57%) cross-over of patients initially treated with dacarbazine to dabrafenib, likely 
obscuring the overall benefit produced by the initial dabrafenib therapy. However, 
despite the major breakthrough provided by BRAF inhibitor therapy, the median 
PFS for patients with BRAFV600E melanoma treated with vemurafenib or 
dabrafenib is only 5-7 months.9-12 Furthermore, few patients experience complete 
response and most patients exhibit disease progression (in many cases rapid) 
following discontinuation of therapy. 
Several mechanisms of resistance to BRAF inhibitors have been described, and 
they are generally divided into MEK dependent and MEK independent 
resistance. Therefore, clinical trials have been conducted with a combination of 
BRAF and MEK inhibitors in patients with metastatic melanoma who were naïve 
to BRAF inhibitors as well as in patients who progressed after a BRAF inhibitor. 
The combination of dabrafenib 150 mg twice daily and trametinib 2 mg once daily 
in BRAF inhibitor-naive patients showed responses in 41 of 54 (76%) patients 
compared with 29 of 54 (54%) given dabrafenib monotherapy, and longer median 
progression-free survival compared with dabrafenib alone (9 vs 5 months).13 
These results led to the FDA approval of combination dabrafenib + trametinib as 
standard therapy for patients with BRAF V600 mutant melanoma in 2014. Recent 
updates for patients enrolled in the full dose dabrafenib + trametinib cohort 
showed a median overall survival of 25 months and a 2 year survival of 75% 
(56%-86%) for patients with a normal LDH compared with 18% (6%-36%) for 
patients with an elevated LDH.25 In addition, it appears that the combination 
treatment was well tolerated. In particular, a significant decrease in the number of 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
10 
cutaneous squamous cell carcinomas (7% vs 19%) and other skin toxicity was 
noted relative to dabrafenib alone. A large phase 3 randomized clinical trial of 
dabrafenib plus trametinib versus dabrafenib plus placebo (Combi-d) confirmed 
the superior efficacy of dabrafenib and trametinib over dabrafenib alone). PFS for 
the combination was 9.3 months vs 8.8 months for dabrafenib alone [HR 0.75; 
95% CI (0.57-0.99)] and overall response rate 67% for the combination vs 51% 
for the single agent. On preliminary analysis, overall survival was improved with 
the combination (HR 0.63, 95% CI 0.42-0.94) although these results were not 
statistically significant, as they did not cross the predefined boundary for early 
stopping.23 These results further support the use of this combination in patients 
with BRAF mutant melanoma. 
While the combination treatment appears to be more efficacious and similarly 
well tolerated, as with treatment with a BRAF inhibitor alone, complete responses 
were infrequent (8% in the phase II study) and continued response off treatment 
did not occur. Consequently many patients are either unable to stop BRAFi (+/- 
MEKi) therapy or to receive subsequent treatment. For example, Ackerman et al 
reported a retrospective analysis of 176 patients who discontinued BRAFi (+/- 
MEKi) therapy, where the median overall survival was 2.9 months. In the 34 
patients who received subsequent ipilimumab no objective responses were 
observed, and only half of patients were able to receive all 4 doses and median 
overall survival was 5 months.14 Additional retrospective data were reported by 
Ascierto et al.15 Of 93 patients with BRAFV600 mutation-positive advanced 
melanoma who received vemurafenib or dabrafenib before (n = 45) or after (n = 
48) treatment with ipilimumab 3 mg/kg, the median overall survival from the time 
of first treatment was 9.9 and 14.5 months, respectively. Among patients treated 
with a BRAF inhibitor first, median survival from the end of BRAF inhibitor 
treatment was 1.2 months for those who did not complete 4 doses of ipilimumab 
treatment. Both of these analyses are likely compromised by biases in the patient 
populations selected for initial treatment with molecular or immunomodulatory 
therapy. For example, reports of the phase I trial of the ipilimumab + nivolumab 
combination included at least one patient who had a dramatic antitumor response 
following disease progression on BRAF inhibitor therapy. Further, preliminary 
data from the BMS 037 trial showed that nivolumab administration to patients 
who had disease progression on both ipilimumab and a BRAFi produced tumor 
responses in 6 of 26 (23%) patients.³⁷ 
1.3 
Ipilimumab 
Ipilimumab was studied in a placebo-controlled phase III trial in which 676 
patients were randomly assigned in a 3:1:1 ratio to ipilimumab plus gp100 
peptide vaccine, ipilimumab alone or gp100 vaccine alone2. All patients were 
HLA-A*0201 positive and had unresectable metastatic melanoma. All patients 
had received prior systemic treatment for advanced disease with either cytotoxic 
chemotherapy or IL-2. 
Ipilimumab (3 mg/kg) and/or vaccine were given every three weeks for four 
doses. Patients with confirmed partial or complete response or stable disease for 
three months or more after completion of the 12-week induction period were 
allowed to receive reinduction with their original treatment if they subsequently 
had disease progression. The primary endpoint of the trial was overall survival. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
11 
Key results of this trial included the following: 
• 
Overall survival was significantly increased in the two groups that received 
ipilimumab (median 10.0 and 10.1 versus 6.4 months, in the ipilimumab plus 
gp100, ipilimumab alone, and gp100 groups, hazard ratios for death 0.68 and 
0.66 versus gp100 alone, respectively). Overall survival rates for the three 
groups were 44, 46, and 25 percent at 12 months and 22, 24, and 14 percent 
at 24 months, respectively. 
• 
Subset analyses found no evidence that the survival benefit was restricted to 
any particular patient subsets. Benefits were independent of sex, age  
(≤ 65 or >65 years), stage at presentation (M0, M1a, and M1b versus M1c), 
baseline LDH (normal versus elevated), or prior use of interleukin-2. 
• 
The objective response rate was significantly improved in both groups of 
patients treated with ipilimumab compared to gp100 alone (5.7 and 10.9 
versus 1.5 percent, respectively). When objective partial or complete 
responses were observed, these were maintained for at least two years in 4 
of 23 (17 percent) patients treated with ipilimumab plus gp100, 9 of 15 (60 
percent) with ipilimumab alone and 0 of 2 with gp100 vaccine only. 
Responses to ipilimumab, either alone or in combination with gp100, 
continued to improve more than 24 weeks after initiation of therapy; five 
patients with stable disease eventually achieved a partial response without 
additional therapy, and four patients with a partial response went on to 
achieve a complete response. 
• 
Among 31 patients who initially received ipilimumab either alone or with 
gp100 and then underwent reinduction therapy with ipilimumab, six (21 
percent) had an objective response to retreatment, and 15 (48 percent) had 
stable disease.  
Although this phase III trial limited enrollment to patients who were HLA-A*0201 
positive because of the use of the gp100 vaccine, retrospective analysis of 453 
patients previously treated with ipilimumab in four phase II trials compared 
patients who were HLA-A*0201 positive with those who were HLA-A*0201 
negative.16 In this analysis, ipilimumab had similar activity regardless of HLA 
type. Although patients in this trial did not have tumor profiling for BRAF 
mutations, limited recently published data suggests that the activity of ipilimumab 
is independent of BRAF mutational status. Recognizing this data and as a 
consequence of this study, ipilimumab was approved for the treatment of all 
patients with advanced melanoma. 
Although patients with untreated brain metastases were excluded from the phase 
III trial, other studies have observed antitumor activity with ipilimumab treatment 
in patients with brain metastases.5 Finally, data from phase II trials suggested 
that a number of patients (up to 10% of those treated) exhibited apparent disease 
progression after 12 weeks of ipilimumab (with either larger lesions or new 
lesions), followed by subsequent disease regression. The overall survival 
outcome of these patients was similar to those exhibiting a tumor response. This 
led to the establishment of Immune-related Response Criteria that endeavored to 
capture these patients in the subset of patients achieving treatment benefit.17 
A second phase III trial involved previously untreated patients.3 In this study, 502 
patients with metastatic melanoma were randomly assigned to ipilimumab plus 
dacarbazine or to placebo plus dacarbazine. Approximately one-fourth of patients 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
12 
had received prior adjuvant therapy, but those previously treated for metastatic 
disease were not eligible. Patients with brain metastases, ocular melanoma, 
mucosal melanoma, or autoimmune disease were excluded. 
All patients received dacarbazine (850 mg/m2 intravenously) every three weeks 
for eight cycles in the absence of disease progression or significant toxicity. 
Patients were randomly assigned to receive either ipilimumab at a dose of 10 
mg/kg or placebo on weeks 1, 4, 7, and 10. At week 24, patients with stable 
disease or an objective response were eligible for maintenance therapy with 
ipilimumab at 10 mg/kg or placebo given every twelve weeks. 
Major results of this trial include the following: 
• 
Overall survival, the primary endpoint of the trial, was significantly increased 
in patients assigned to ipilimumab plus dacarbazine compared with placebo 
plus dacarbazine (median 11.2 versus 9.1 months, 1, 2, and 3 year survival 
rates 47 versus 36, 29 versus 18, and 21 versus 12 percent, respectively). 
• 
The rate of disease control (objective response plus stable disease) did not 
differ significantly between the two groups (33 versus 30 percent), nor did the 
best overall response rate (15 versus 10 percent). 
• 
The overall incidence of grade 3 or 4 toxicity was significantly higher with 
ipilimumab plus dacarbazine compared with dacarbazine alone (56 versus 28 
percent). Overall, grade 3 or 4 immune-mediated adverse reactions were 
significantly more common with the ipilimumab combination (38 versus 4 
percent).  
• 
Hepatic toxicity was significantly more common with the combination than 
with dacarbazine alone (overall incidence of transaminase elevation 29 to 33 
versus 6 percent). Furthermore, the incidence of hepatic toxicity was much 
higher compared with that observed in the phase III trial when ipilimumab 
was given without dacarbazine or in prior phase II trials ipilimumab 
administered at this dose and schedule. The increase in hepatic toxicity may 
be due to its combination with dacarbazine, which is also known to be 
hepatotoxic. 
• 
The incidence of other immune related toxicities (colitis, rash, hypophysitis) 
was less than that seen in prior studies with ipilimumab alone, perhaps 
suggesting that DTIC may have blunted and/or the higher incidence of 
hepatotoxicity may have pre-empted or altered the immune toxicity profile.   
• 
Whether this blunting of immune toxicity by DTIC might have also blunted the 
antitumor effect of ipilimumab is a matter of speculation. However, the overall 
pattern of toxicity and efficacy on this trial do not support the addition of DTIC 
to ipilimumab nor the use of ipilimumab at the 10 mg/kg dose vs the already 
approved 3 mg/kg dose. 
A composite analysis of 12 clinical studies confirmed the potential long-term 
survival impact of ipilimumab. In this series, 1,257 patients were pretreated and 
604 were previously untreated for metastatic disease. The dose of ipilimumab 
was 3 mg/kg for 965 patients and 10 mg/kg for 706 patients. The median overall 
survival for the whole patient population was 11.4 months. Most importantly, the 
survival curve reached a plateau of 22% at 3 years, which extended to 10 years, 
and it was independent of the dose.4  

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
13 
1.4 
Nivolumab 
Nivolumab (BMS-936558) is a humanized monoclonal antibody that targets the 
PD-1 protein. This monoclonal antibody was evaluated in a phase I/II study in 
296 patients with a variety of heavily pretreated malignancies, including 107 
patients with melanoma.18 
Efficacy data from this study were updated with one year of additional follow-up 
for the cohort of 107 patients with advanced melanoma.19 The overall objective 
response rate was 31% for the entire melanoma patient cohort and an additional 
7% of patients had stable disease. There was no clear-cut dose response 
relationship, although the 3 mg/kg dose had the highest response rate (41%). 
The median duration of response was 24 months. Results were updated 14 
months after the last patient initiated therapy at the 2014 ASCO meeting. The 
median overall survival was 17 months, and the one, two and three years 
survival rates were 63, 48, and 41 percent, respectively.24 
Grade 3/4 treatment related adverse events were observed in 32 of the 296 
patients (14%) enrolled in the entire study.18 A variety of autoimmune side effects 
were observed including pneumonitis, vitiligo, hepatitis, hypophysitis and 
thyroiditis, although autoimmune toxicity was considerably less frequent than 
observed with ipilimumab. 
Three phase III trials have been conducted to evaluate the role of nivolumab in 
patients with advanced melanoma. In one, patients who have progressed 
following ipilimumab (and if indicated) BRAF inhibitor therapy were randomly 
assigned to nivolumab or chemotherapy with either dacarbazine or carboplatin 
plus paclitaxel. In the second trial, previously untreated patients known to have 
BRAF wild type tumors were randomly assigned to nivolumab or dacarbazine. 
Finally, in the third trial previously untreated patients were randomized to receive 
either ipilimumab, nivolumab or the combination of the two agents. Preliminary 
data from the first two of these trials have now been reported. 
Preliminary results from the first trial was reported at ESMO 2014. The trial 
accrued 405 patients and results in the preliminary report were based upon 167 
patients (120 patients treated with nivolumab, and 47 patients treated with 
chemotherapy), all of whom had a follow-up of ≥6 months: 
• 
Objective responses by independent review were significantly more common 
in patients treated with nivolumab compared with chemotherapy (32% vs 
10%). 
• 
Median duration of response was longer with nivolumab (median not 
reached, 36 of 38 still in remission, vs 3.5 months for chemotherapy treated 
patients). 
• 
Tumor responses were seen with nivolumab in patients with BRAF mutations 
who had progressed on a prior BRAF inhibitor (6/26= 23%) and appeared to 
be independent of benefit from prior ipilimumab treatment.   
• 
Grade 3-4 AEs were seen in 9% of patients on nivolumab and 31% of 
patients on chemotherapy. No nivlumab-related Grade 3-4 AE was reported 
in more than 2% of patients.  
• 
Based on this data nivolumab received FDA approval for the treatment 
patients with refractory melanoma on 12/22/2014. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
14 
A press release of results from the second trial reported that nivolumab was 
superior to dacarbazine in the treatment naïve population. 
1.5 
Nivolumab + Ipilimumab Combination 
The combined administration of anti-CTLA-4 immunotherapy with ipilimumab 
plus anti-PD-1 immunotherapy with nivolumab appears to have a higher level of 
anti-melanoma activity than either agent alone and a manageable toxicity profile.8 
In a phase I trial in which both drugs were given in successive dose escalation 
cohorts, 53 patients were treated with concurrent therapy administered every 3 
weeks for 4 doses followed by nivolumab alone every 3 weeks through week 24. 
Subsequent therapy with both drugs was continued once every 12 weeks for a 
maximum of 8 additional doses. In a separate sequential cohort, nivolumab was 
given on the same schedule to 33 patients who had received prior ipilimumab. 
Subsequently, another cohort of 41 patients was treated with the combination of 
ipilimumab plus nivolumab for four cycles, followed with nivolumab maintenance 
only given every 2 weeks for up to 84 weeks. 22 
In the 32 patients treated at the top dose levels of ipi 3/nivo 1 or ipi 1/nivo 3 53% 
of patients had tumor response with > 41% having tumor shrinkage of > 80% all 
of which was observed at the 12 week tumor evaluation. In the sequenced 
therapy group 6 of 30 patients had an objective response.   
Data was updated at the 2014 ASCO meeting. In the concurrent treatment 
cohort, the objective response rate was 42% (17% CR and 25% PRs). 
Responses appeared durable with 18 of 22 responses ongoing at the last follow-
up. Overall survival in the original concurrently treated cohort of 53 patients at 
one and 2 years was 94 and 88%, respectively. 
Among the patients treated with concurrent nivolumab + ipilimumab, treatment 
related AEs were observed in 93% of cases. The most common events were 
rash, pruritus, fatigue and diarrhea. Grade 3-4 AEs were reported in 49% of 
cases, including liver, GI and kidney toxicity (15, 9, and 6% of cases, 
respectively). Treatment was discontinued due to AEs in 11 cases (21%). 
Section 5.3.1 includes a summary of treatment related adverse events on the 
concurrent cohorts of the ipilimumab + nivolumab combination study. 
A randomized phase III registrational trial studying the combination of ipilimumab 
+ nivolumab administered at the above schedule compared with each single 
agent administered at its optimal schedule (NCT01844505) has completed 
accrual. Preliminary results from this trial showed that nivolumab alone and the 
combination of ipillimumab and nivolumab produced longer PFS, greater 
response rate and greater tumor shrinkage than ipilimumab alone. The 
combination also appeared to have superior efficacy than nivolumab alone 
although the trial was not powered to address this endpoint. Also of note, the 
combination or ipilimumab and nivolumab produced more treatment related side 
effects than either ipilimumab or nivolumab monotherapy, although there were no 
treatment related deaths in patients receiving the combination. Critical survival 
and response duration results are not anticipated until 2016. (Larkin J et N Engl J 
of Med 2015). 
Rev. 12/15 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
15 
1.6 
Dabrafenib Mesylate (GSK2118436B) 
Activating mutations in BRAF are present in approximately 40 to 60 percent of 
advanced melanomas. In 80 to 90 percent of cases, this activating mutation 
consists of the substitution of glutamic acid for valine at amino acid 600 (V600E 
mutation) with most the remainder consisting of an alternate substitution at the 
V600 locus (V to K).  
Dabrafenib is a potent inhibitor of the kinase domain in mutant BRAF. In the 
pivotal phase III trial, in which 250 patients with unresectable stage III or stage IV 
melanoma were randomly assigned in a 3:1 ratio to either dabrafenib (150 mg 
orally twice a day) or dacarbazine (1000 mg/m2 IV every three weeks).10 All 
patients had the V6000E mutation in BRAF. The primary endpoint of the trial was 
PFS as ascertained by the investigators; the PFS was independently reviewed as 
a secondary trial endpoint. Patients assigned to dacarbazine were allowed to 
cross over to dabrafenib upon development of progressive disease. The principal 
results were as follows: 
• 
Dabrafenib significantly increased PFS compared with dacarbazine (median 
5.1 versus 2.7 months, HR 0.33, 95% CI 0.20-0.54). Based upon 
independent review of the data, the PFS was similarly increased (6.7 versus 
2.9 months, HR 0.35, 95% CI 0.20-0.61). 
• 
Objective responses, as assessed by the independent review committee, 
were seen in 93 of 187 patients treated with dabrafenib (50 percent), 
including six cases (3 percent) with a complete response. Among those 
treated with dacarbazine there were four partial responses in 63 cases, for an 
overall response rate of 6 percent. 
• 
Overall survival was updated at the 2013 ASCO meeting.20 With a median 
follow-up of 15 and 13 months for the two groups, overall survival favored 
patients treated with dabrafenib (HR 0.76, 95% CI 0.48-1.21), but was not 
statistically significant. However, 26 of 63 patients (57%) originally treated 
with dacarbazine crossed over to dabrafenib, likely obscuring an overall 
survival benefit from the initial dabrafenib therapy.  
• 
Treatment with dabrafenib was generally well tolerated. The most frequent 
grade 2 or greater toxicities were dermatologic. Other grade 2 or greater 
toxicities observed in between 5 and 15 percent of cases included arthralgia, 
fatigue, headache, and fever.  
Dabrafenib was approved by the US Food and Drug administration in May 2013 
for use in patients whose tumors contain the V600 mutation in BRAF.  
The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many 
human cancers. This pathway can be constitutively activated by molecular 
alterations including BRAF activating mutations. Approximately 90% of all 
identified BRAF mutations in human cancer consist of a T1799 transversion 
mutation in exon 15, which results in a V600 E/D/K (T1799A) amino acid 
substitution. This mutation appears to mimic regulatory phosphorylation and 
increases BRAF activity approximately 10-fold compared to wild type (wt). RAF is 
a validated target in BRAF V600E-containing melanoma. In August 2011, the 
FDA approved vemurafenib (PLX4032, Zelboraf®), an ATP-competitive selective 
RAF inhibitor for the treatment of late-stage BRAFV600E melanoma. In the 
pivotal phase III trial of vemurafenib vs. dacabazine,31 vemurafenib demonstrated 
significant improvement in overall survival (OS) (6-month OS of 84% vs. 64%, 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
16 
hazard ratio [HR]=0.37; P< 0.001), progression-free survival (PFS) (estimated 
median PFS of 5.3 months vs. 1.6 months (HR=0.26; P< 0.001]), and overall 
response rate (ORR) (48% vs. 5%). However, in patients with colorectal cancer 
(CRC) bearing the BRAF V600E mutation, there was only one partial response 
(PR) among 20 patients treated (ORR 5%) and four minor responses.32 
Dabrafenib mesylate (GSK2118436B, Tafinlar®; referred to as dabrafenib 
hereafter), a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is an ATP-
competitive, selective inhibitor of RAF kinase currently in clinical development. 
On May 29, 2013, the U.S. FDA approved dabrafenib for the treatment of 
patients with unresectable or metastatic melanoma with BRAFV600E mutation as 
detected by an FDA-approved test (FDA, 2013). On January 10, 2014, the FDA 
granted accelerated approval to dabrafenib and MEK inhibitor trametinib for use 
in combination to treat patients with unresectable or metastatic melanoma with 
either BRAFV600E or BRAFV600K mutation as detected by an FDA-approved 
test.33 
1.6.1 
Mechanisms of Action and Preclinical Data with Dabrafenib 
Dabrafenib potently inhibits all RAF isoforms, with the strongest 
potency against the V600 mutant, as compared to its activity against 
wt BRAF and CRAF (see below). In a panel of more than 270 kinases 
tested outside RAF isoforms, only 10 kinases were inhibited at a 50% 
inhibitory concentration (IC50) < 100 nM: LIM domain kinase 1 
(LIMK1), activin receptor-like kinase 5 (ALK5)/ transforming growth 
factor (TGF)-beta receptor type-1 (TGFβ1R), Never In Mitosis Gene A 
(NIMA)-related kinase 11 (NEK11), salt-inducible kinase 1 (SIK1), 
salt-inducible kinase 2 (SIK2), polycystin-2 (PKD2), protein tyrosine 
kinase 6/breast tumor kinase (BRK), pancreatic eukaryotic initiation 
factor-2 alpha (eIF2α) kinase (PEK)/eIF2α kinase (PERK), 
endothelium-specific receptor tyrosine kinase 2 (TIE2) (R849W), and 
yeast casein kinase 1 (CK1) (IB, 2013a). 
Inhibitory activity of dabrafenib on RAF 
 
BRAFV600E 
BRAFV600K 
BRAFV600D 
wt BRAF 
CRAF 
IC50 
0.65 nM 
0.50 nM 
1.84 nM 
3.2 nM 
5.0 nM 
In a panel of > 110 human tumor cell lines with confirmed BRAF 
mutational status, dabrafenib potently inhibited proliferation of a 
majority (73%) of BRAFV600E mutant cell lines with growth IC50 
(gIC50) <100 nM (IB, 2013a). In contrast, there was poor or no activity 
in other BRAF mutants or wt BRAF cell lines. 
Dabrafenib given orally (PO) for 14 days at doses ranging from 0.1-
300 mg/kg administered once daily (QD), twice daily (BID), or three 
times daily (TID) inhibited tumor growth in mice bearing BRAFV600E 
A375P F11s or Colo205 tumor xenografts. The effect was generally 
dose dependent up to 10 mg/kg/day (A375P F11s) or 30 mg/kg/day 
(Colo205), yielding 90-120% tumor reduction relative to untreated 
animals. However, cessation of treatment was associated with 
regrowth of the tumors. In A375P F11s melanoma xenografts, 
inhibition of pERK by > 50% in the tumor was seen at doses of ≥3 
mg/kg. Based on the single-dose studies, ~100 nM (52 ng/mL) 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
17 
dabrafenib in blood at 6 h post-dosing was needed for effective 
pharmacodynamic biomarker inhibition in the tumor. At repeated 
dosing of 30 mg/kg/day, the tumor pERK levels were reduced by  
> 50% at 8 h after dosing (69% on Day 1 and 53% on Day 14). Levels 
of pERK returned to baseline 24 h post-dosing. Similar ↓pERK effects 
were seen in the ES-2 ovarian xenograft model, but pERK inhibition 
was weaker in the Colo205 xenograft model. Of note, concentrations 
of dabrafenib showing pharmacodynamic activity in xenografts did not 
cause a reduction in pERK/tERK levels in the normal intact brain. 
1.7 
Trametinib 
MEK is a direct target of phosphorylation by BRAF in the MAP kinase pathway 
and cells with BRAF mutation have an increased level of phosphorylated MEK 
and are exceptionally sensitive to MEK inhibition in vitro. Trametinib is a potent 
and highly selective inhibitor of MEK1 and MEK2. 
The efficacy of trametinib was demonstrated in the phase III METRIC trial, in 
which 322 patients with advanced melanoma were randomly assigned in a 2:1 
ratio to either trametinib (2 mg/day orally) or chemotherapy (dacarbazine or 
paclitaxel) 21. All patients had either the V600E or V600K mutation in their 
melanoma (87 and 13 percent, respectively). One third of patients had received 
prior chemotherapy and 30 percent had received prior immunotherapy, but prior 
BRAF inhibitor therapy was not allowed. Crossover to trametinib was permitted in 
patients who progressed on chemotherapy. 
Key results included the following: 
• 
Progression-free survival, the primary endpoint of the trial, was significantly 
increased with trametinib compared with chemotherapy (median 4.8 versus 
1.5 months, HR 0.47, 95% CI 0.34-0.65). 
• 
Overall survival was significantly improved with trametinib (6 month survival 
rate 81% vs 67%, HR for death 0.54, 95% CI 0.32-0.92), even though 47% of 
patients who progressed on chemotherapy received secondary treatment 
with trametinib. 
• 
The improvements in PFS and overall survival were present in all patient 
subsets, including those with brain metastases or other visceral metastases 
(M1c). 
Based on this data, trametinib received FDA approval for treatment of patients 
with BRAFV600 metastatic melanoma in May of 2013.  
The RAF-MEK-ERK pathway plays a critical role in multiple cellular functions. 
Activation of the pathway can result from activation/mutations of the upstream 
receptor tyrosine kinases (RTKs) and RAS, or upregulation/mutations in RAF and 
MEK. Upon activation, RAF acts as the MAPK kinase and activates MAPKK 
(MEK1/2), which in turn catalyze activation of the effectors ERK1/ERK2. Once 
activated, ERK1/2 translocate into the nucleus and phosphorylate a number of 
effector proteins and transcriptional factors that regulate cell proliferation, motility, 
differentiation, and survival. 
Trametinib is one of the several MEK inhibitors in clinical development. On May 
29, 2013, the U.S. Food and Drug Administration (FDA) approved trametinib for 
the treatment of patients with unresectable or metastatic melanoma with 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
18 
BRAFV600E or BRAFV600K mutations as detected by an FDA-approved test.³⁸ 
On January 10, 2014, the FDA granted accelerated approval to trametinib and 
dabrafenib for use in combination to treat patients with unresectable or 
metastatic melanoma with a BRAF V600E or V600K mutation as detected by an 
FDA-approved test.³³ 
Experience to date indicates that MEK is a valid target. In a phase 3 trial 
comparing trametinib with dacarbazine or paclitaxel in patients with BRAF V600E 
or V600K mutant metastatic melanoma, trametinib demonstrated a significantly 
better response rate, progression-free survival, and overall survival.¹³ However, 
single agent activities are limited. 
The most up-to-date preclinical and clinical study information for trametinib can 
be found in the GSK1120212 (trametinib) Investigator's Brochure (2013). 
1.7.1 
Mechanisms of Action and Preclinical Data with Trametinib 
Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 
1:1) with potent, allosteric and ATP non-competitive inhibition of 
MEK1/2 (IC50 of 0.7 and 0.9 nM against MEK1 and MEK2, 
respectively) (Gilmartin et al., 2011). Trametinib inhibited MEK1/2 
kinase activity and prevented RAF-dependent MEK phosphorylation 
(S217 for MEK1), producing prolonged pERK1/2 inhibition. Trametinib 
showed better potency against unphosphorylated MEK1/2 (u-MEK1/2) 
when compared with preactivated diphosphorylated MEK (pp-MEK), 
suggesting that u-MEK affords a higher affinity binding site for 
trametinib than does pp-MEK. 
The specificity of trametinib was confirmed against a panel of 183 
kinases, including MEK5 (the closet kinase homolog to MEK1/2), 
CRAF, BRAF, ERK1, and ERK2 (Yamaguchi et al., 2011). Trametinib 
demonstrated equal potency against activated MEK1- and MEK2-
mediated phosphorylation of ERK (sequence identity of 85% across 
the whole protein and 100% in the active site for humans). Trametinib 
demonstrated preferential inhibition of RAF-mediated MEK1 activation 
(IC50 = 0.60 nM) over pMEK1 kinase activity (IC50 = 13 nM) 
(Investigator’s Brochure, 2012a). 
BRAF-mutant Colo205, A375P F11s, and HT-29 human tumor 
xenograft mouse models showed the most significant mean tumor 
growth inhibition (TGI) (80% to 87%) at 3.0 mg/kg trametinib, with 
multiple complete and partial tumor regressions. In the Colo205 
model, tumor regression was observed even at a dose of 0.3 mg/kg 
(Yamaguchi et al., 2011). Two KRAS-mutant xenograft models, HCT-
116 and A549, also showed significant TGI (83% and 75%) but 
without significant tumor regressions (Gilmartin et al., 2011). As 
predicted by cell proliferation assays, tumor xenograft lines with wild-
type (wt) RAF/RAS (PC3, BxPC3, and BT474) were much less 
sensitive, showing only modest TGI (44-46%) with no tumor 
regressions. 
Pharmacodynamic studies were performed in mice treated with 
trametinib for 14 days (Gilmartin et al., 2011). In the A375P F11s 
xenograft model, the first dose of trametinib (3 mg/kg) significantly 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
19 
reduced pERK for more than 8 hours on Day 1. pERK inhibition was 
more sustained (over 24 hours) after the Day 7 dose, probably due to 
an increase in the steady-state levels of trametinib after repeated 
doses. The average Cmax in blood was 1,410 nM on Day 7, with an 
estimated half-life (t1/2) of 33 hours. In addition, 
immunohistochemistry (IHC) also confirmed inhibition of cell 
proliferation (reduced Ki67) and G1 cell cycle arrest (elevated 
p27Kip1/CDKN1B) following 4 days of treatment. 
1.8 
Dabrafenib and Trametinib Combination 
Trametinib has been combined with dabrafenib in an effort to delay the 
development of resistance to dabrafenib and potentially reduce toxicity 
associated with BRAF inhibitor induction of paradoxical activation of the MAP 
kinase pathway in cells lacking a BRAF mutation.  
A phase I/II study demonstrated the feasibility of combining full doses of 
dabrafenib (150 mg twice daily) and trametinib (2 mg daily). In the phase II 
component of the trial, 162 patients whose tumor contained a V600 mutation 
were randomly assigned to one of 3 regimens: dabrafenib (150 mg twice daily) 
as monotherapy, dabrafenib plus trametinib (150 mg twice daily and 1 mg once 
daily, respectively), or dabrafenib plus trametinib (150 mg twice daily and 2 mg 
once daily, respectively). In the analysis of this randomized component of the 
trial, treatment with the combination regimen using full doses of dabrafenib and 
trametinib (2 mg daily dose) significantly prolonged PFS compared to dabrafenib 
monotherapy (median 9.4 vs 5.8 months, HR 0.39, 95% CI 0.25-0.62) and 
significantly increased the proportion of patients alive and progression-free at 
one year (41% vs 9%).13 Recent updates for patients enrolled in the full dose 
dabrafenib + trametinib cohort showed a median overall survival of 25 months 
and a 2 year survival of 75% (56%-86%) for patients with a normal LDH 
compared with 18% (6%-36%) for patients with an elevated LDH.25 Dermatologic 
toxicity, manifested by squamous cell carcinoma (including keratoacanthoma) 
was decreased in both the combination arms relative to dabrafenib alone (5% vs 
19%), although the incidence of pyrexia was increased (71% vs 26%). 
Two phase III trials have been initiated in which patients with advanced 
melanoma containing either a V600E or K mutation are randomly assigned to the 
combination of dabrafenib and trametinib or to either dabrafenib plus placebo 
(Combi-d) or vemurafenib (Combi-v). These trials have completed accrual. The 
Combi-d enrolled 423 patients and reported preliminary results in a press release 
in January 2014. This trial confirmed the superior efficacy of dabrafenib and 
trametinib over dabrafenib alone. PFS for the combination was 9.3 months vs 8.8 
months for dabrafenib alone [HR 0.75; 95% CI (0.57-0.99)] and overall response 
rate 67% for the combination vs 51% for the single agent. These results 
supported to randomized Phase II which were the basis of FDA approval of 
combination dabrafenib + trametinib as standard therapy for patients with BRAF 
V600 mutant melanoma in early 2014. 
Results were formally presented at the 2014 American Society of Clinical 
Oncology (ASCO) meeting23 Additional information included: 
• 
Many more patients (18 vs 6) on the dabrafenib + placebo arm were 
censored early prior to formal imaging perhaps contributing to agreater than 
anticipated median PFS on the dabrafenib + placebo arm. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
20 
• 
Overall survival was potentially better with the combination (HR 0.63, 95% CI 
0.42-094). However, as these results were preliminary and did not cross the 
threshold for significance, additional follow-up for overall survival is required. 
• 
There were substantial differences in toxicity. Toxicities decreased with the 
combination of dabrafenib plus trametinib included the incidence of 
cutaneous squamous cell carcinoma and keratoacanthoma (2 versus 9 
percent), hyperkeratosis (3 versus 32 percent), skin papilloma (2 versus 21 
percent), hand-foot syndrome (5 versus 21 percent), and alopecia (7 versus 
26 percent). Toxicities more frequently associated with the combination 
included diarrhea (24 versus 14 percent) and hypertension (22 versus 14 
percent). 
• 
Dose interruptions were significantly more frequent with the combination. This 
was due to enhanced pyrexia and chills associated with the combination 
relative to dabrafenib alone.  
Table 2 includes a summary of frequently occurring treatment related adverse 
events on the dabrafenib + trametinib combination.23 
Table 2  
 
Dabrafenib + 
Trametinib* 
N=209   n (%) 
 
 
 
All Grades 
Grade 3 
Grade 4 
All Events 
199(95) 
66(32) 
7(3) 
Pyrexia 
107(51) 
12(6) 
0 
Fatigue 
74(35) 
4(2) 
0 
Headache 
63(30) 
1 (<1) 
0 
Nausea 
63 (30) 
0 
0 
Chills 
62(30) 
0 
0 
Arthralgia 
51(24) 
1 (<1) 
0 
Diarrhea 
51(24) 
2 (<1) 
0 
Rash 
48(23) 
0 
0 
Hypertension 
46(22) 
8(4) 
0 
Vomiting 
42(20) 
2(<1) 
0 
Alopecia 
15(7) 
0 
0 
Hyperkeratosis 
7(3) 
0 
0 
Skin papilloma 
3(1) 
0 
0 
*4 fatal SAEs, not treatment related: 3 intracranial hemorrhage, 1 pneumonia 
1.9 
Study rationale 
Given these new treatment approaches for patients with BRAFV600 mutant 
melanoma, patients and physicians now (and in the future) have to make a 
choice regarding initial treatment and the sequence of these modalities. There is 
currently little information to guide this choice. While BRAFi therapy appears to 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
21 
be equally active in patients whose disease has progressed following 
immunotherapy14 and those who are immunotherapy-naive there is no formal 
data on its activity following resistance to ipilimumab + nivolumab. Similarly, there 
is no formal prospective data on the activity of ipilimumab (or even the feasibility 
of stopping BRAFi therapy and administering ipilimumab) following disease 
progression on BRAF (+/- MEK) inhibitor therapy. While some anecdotal data 
suggests that response to either nivolumab or the ipilimumab + nivolumab 
combination can be seen in patients whose disease has become resistant to 
BRAFi, there is no formal data to assess the activity, tolerability or feasibility of 
this promising immunotherapy combination in that setting. It is conceivable that 
patients treated initially with immunotherapy may get the benefit of durable 
response in a subset of patients (up to 40%-50%) without compromising the 
benefit of subsequent BRAF inhibitor therapy for those patients who exhibit 
disease progression, while those started on BRAF/MEK inhibitor therapy may not 
be able to benefit as much from subsequent immunotherapy at time of 
progression as they would in the treatment naïve setting. It is also possible that 
the high response rate and prolonged PFS associated with dabrafenib + 
trametinib combination relative to ipilimumab + nivolumab may overwhelm any 
benefit that might be achieved with initial immunotherapy. Further, it is possible 
that subsets of patients, defined by clinical and/or tumor characteristics 
(Performance Status, disease stage, serum LDH level, PTEN loss, immune 
infiltration, PDL1 expression, germ line polymorphisms, etc.), might do better with 
one initial therapy or sequence than with the other. Finally, the sequence of 
treatments may be influenced by Quality of Life factors that are largely unknown 
for either treatment approach as described below. 
Patient-Reported Outcomes (PROs), which include patient-reported symptoms, 
physical, mental, social function, and toxicities, have become increasingly 
important in cancer clinical trials to provide information on the range and severity 
of treatment effects on a patient’s health and well-being. PROs are used to 
assess symptom relief from improved disease control, differences in treatment-
related toxicities, functional declines or improvement, and reasons for treatment 
non-adherence. Furthermore, PROs are an important complement to survival 
outcomes since PROs may provide crucial information for guiding treatment 
decision making when there are no (or minimal) survival difference between 
treatment arms. In addition, independent of survival outcomes, PROs can 
provide patients, their caregivers, and clinicians a more complete understanding 
of what to expect from treatment as part of managing expectations and planning 
for palliative care.  
Based on clinical experience and previous toxicity reports, the type and severity 
of treatment-related adverse events are different for ipilimumab-nivolumab vs. 
dabrafenib-trametinib. For ipilimumab-nivlumab the most common toxicities 
include severe rash, vomiting and diarrhea; while dabrafenib-trametinib toxicities 
are more commonly muscle pain, fatigue, and severe chills. Research examining 
PROs on these treatments are limited, mainly evaluating short-term effects. 
Individuals at 12-weeks on ipilimumab report moderate problems with fatigue, 
sleep disturbance, appetite loss and role-functioning.34 Dabrafenib and trametinib 
have reported minimal symptoms except diarrhea at 12-weeks.35, 36 To date, no 
research has examined the long-term functional treatment impact or differences 
due to therapy sequence, which could help inform treatment decisions. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
22 
Therefore, we propose to collect longitudinal information on PROs which we 
categorize under the following 3 sub-domains: patient toxicities, symptoms and, 
function. Our primary objective will be to compare quality-adjusted time without 
symptoms of disease progression or toxicity of treatment by initial treatment 
assignment over 2 years. Our secondary objectives will be to examine changes 
in function and symptoms during and after initial treatment, explore differences in 
function and symptoms due to treatment sequence, and describe differences in 
patient-reported treatment toxicities for each treatment. Our design will provide 
novel longitudinal information on PROs based on treatment sequence and 
crossover in patients with advanced melanoma. 
1.10 
Rationale for Tobacco Use Assessment 
NOTE: 
Please refer to Appendix XIII for EAQ16T references 
A significant proportion of cancer patients are current smokers at the time of 
cancer diagnosis,1–5 and there are known risks associated with continued 
smoking following cancer diagnosis. These include decreased survival time; 
increased complications from surgery, radiation, and chemotherapy; and 
increased risk of second primary tumors.6–11 As such, the National 
Comprehensive Cancer Network (NCCN), the American Association of Cancer 
Research (AACR) and the American Society of Clinical Oncology (ASCO) have 
identified persistent smoking as a modifiable risk factor and recommend 
cessation counseling for cancer patients who smoke. Although evidence-based 
guidelines for treating tobacco dependence exist,12 they have not yet been well-
integrated into cancer care settings. Moreover, knowledge regarding the scope 
and patterns of tobacco use among cancer patients is limited. 
Tobacco use following a cancer diagnosis compromises treatment outcomes but 
is not well understood. About 10% to 30% of cancer patients are smoking at the 
time of diagnosis,1–4,14,15 and the majority of cancer patients who smoke at 
diagnosis continue to smoke following diagnosis.3,16 Quitting smoking upon 
cancer diagnosis may improve cancer treatment effectiveness, reduce risk of 
recurrence and of developing new primary tumors,9–11,17–21 and improve chances 
of survival.1,22–24 Conversely, continuing to smoke may result in diminished 
QOL,1,25,26 treatment delays and increased treatment complications.2,6–8,22,27–34 
Tobacco use following a cancer diagnosis may compromise patient reported 
outcomes. It is hypothesized that smoking may be used as a means of reducing 
symptom burden among cancer patients, which may be a barrier to smoking 
cessation. Relatedly, research has shown that cancer patients who are smoking 
experience more difficulty with physical and psychological symptom control, 
compared to nonsmokers.35–38 Research is needed to examine how symptom 
levels differ, by tobacco use and exposure and how tobacco use changes may 
affect reported symptom burden. 
National initiatives emphasize the importance of identifying tobacco use in cancer 
care settings. Smoking status was designated as a core objective in the 2010 
federal government “Meaningful Use” electronic health record documentation.39,40 
In 2013, the American Association for Cancer Research (AACR) released 
guidelines emphasizing the provision of tobacco cessation services to cancer 
patients.41 The American Society of Clinical Oncology (ASCO) recommends 
cessation counseling to all smokers by their second oncology visit as a core 
Rev. 5/17, 
10/17 
Rev. Add10 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
23 
quality indicator.42 The National Comprehensive Cancer Network (NCCN) 
published Smoking Cessation guidelines to formalize these initiatives.43 
Integrated, evidence-based services are needed during cancer care. The USPHS 
Practice Guidelines recommend that evidence-based tobacco treatment be 
delivered to all smokers in health care settings, yet little progress has been made 
to integrate these guidelines into cancer care.44 This is unfortunate, as cessation 
closer to the time of diagnosis results in a higher likelihood for continued 
abstinence,1,45–48 effective interventions exist,1,45–48 and many cancer patients 
who smoke want to quit smoking.45,46,49,50 Little work has been done to explore 
the delivery and effectiveness of tobacco treatment among racial/ethnic minority 
cancer patients who are at elevated risk of continued smoking.51–53 
Tobacco use is often not being assessed or intervened upon during cancer care. 
Recent surveys of oncologists and of clinical practices at comprehensive cancer 
centers and community oncology settings demonstrate that assessment of 
tobacco dependence is lacking.54–57 During treatment, most cancer patients do 
not get assistance with smoking cessation support.58–60 Tobacco use 
assessments and cessation support have not been incorporated in most 
cooperative group clinical trials.61 No one has assessed cancer patients’ reports 
of their oncology providers’ assistance behaviors. 
The NCI-AACR Cancer Patient Tobacco Use Asssessment Task Force 
developed the Cancer Patient Tobacco Use 1–4,13,14 Questionnaire (C-TUQ). We 
propose that administering selected C-TUQ items to participants enrolling in 8 
Phase II and Phase III ECOG ACRIN (EA) therapeutic trials will add value to 
parent trial research questions by advancing the field. Specifically, among 
patients with varied cancers (tobacco-related and non tobacco-related) and 
cancer treatments, we will administer C-TUQ questions at EA trial enrollment and 
3 and 6 month follow-up. 
We have the following aims: 
1. Treatment toxicity: To determine the effects of tobacco, operationalized as 
combustible tobacco (1a), other forms of tobacco (1b), and environmental 
tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity 
(adverse events (both clinical and hematologic) and dose modifications). 
2. Symptom burden: To determine the effects of tobacco on patient-reported 
physical symptoms and psychological symptoms. 
3. Cessation patterns and treatment: To examine quitting behaviors and 
behavioral counseling/support and cessation medication utilization. 
4. Trial outcomes: To explore the effect of tobacco use and exposure on 
treatment duration and relative dose intensity, and on therapeutic benefit, of 8 
selected EA trials. 
The findings will advance the nascent field of tobacco use in the context of 
cancer care by: 1) longitudinal assessment of cigarette smoking, other forms of 
tobacco use and secondhand smoke exposure at trial enrollment and at 3 and 6 
month follow-up; 2) increase knowledge about the effects of tobacco use and 
exposure on treatment toxicity, physical and psychological symptoms and 3) 
oncology provider delivery, and 4) patient’s perceptions of stigma and utilization 
of behavioral and pharmacological treatment of tobacco dependence. Finally, the 
use of this assessment would provide a unique additional value to the hypothesis 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
24 
of this trial, by allowing investigation of previously unanswered questions about 
the effects of tobacco use and exposure on trial adherence and outcomes among 
patients with smoking-related and non-smoking related cancers. 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
25 
2. 
Objectives 
2.1 
Primary Objective 
To determine whether initial treatment with either combination ipilimumab + 
nivolumab (with subsequent dabrafenib in combination with trametinib) or 
dabrafenib in combination with trametinib (with subsequent ipilimumab + 
nivolumab) significantly improves 2 year overall survival (OS) in patients with 
unresectable stage III or stage IV BRAFV600 mutant melanoma. 
2.2 
Secondary Clinical Objectives 
2.2.1 
To evaluate the impact of initial treatment on median OS and Hazard 
Ratio for death. 
2.2.2 
To determine whether initial treatment choice significantly improves 3 
year OS. 
2.2.3 
To evaluate the anti-tumor activities (RECIST-defined response rate, 
median PFS) and safety profiles of ipilimumab + nivolumab and 
dabrafenib-trametinib in a Cooperative Group trial of patients with 
V600 mutant melanoma. 
2.2.4 
To evaluate the activity (RECIST-defined response rate, median PFS) 
and safety of dabrafenib + trametinib in patients who have had 
disease progression on ipilimumab + nivolumab and in comparison to 
its activity and safety in ipilimumab + nivolumab naïve patients. 
2.2.5 
To evaluate the activity of ipilimumab + nivolumab (RECIST-defined 
response rate, median PFS) and safety in patients who have had 
disease progression on dabrafenib + trametinib and in comparison to 
its activity and safety in dabrafenib + trametinib naïve patients. 
2.2.6 
To assess the feasibility of crossover to the alternative treatment 
strategy (percentage of patients who are able to cross-over from one 
arm to the other and complete at least an initial course (12 weeks) of 
treatment after crossover without intervening symptomatic disease 
progression or treatment limiting toxicity). 
2.3 
Secondary Laboratory Objectives 
2.3.1 
Association of inherited variation with immune mediated adverse 
events and response to ipilimumab + nivolumab 
2.3.1.1 
To determine the association of inherited genetic variation 
and immune-associated adverse events in patients with 
metastatic melanoma treated with ipilimumab containing 
regimens by completing candidate-based gene and 
pathway analyses of genes involved in lymphocyte 
activation, cytokines, cytokine receptors and within the 
MHC region and an agnostic genome-wide SNP-based 
approach. 
2.3.1.2 
To investigate the association between inherited genetics 
and survival in patients with metastatic melanoma treated 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
26 
with ipilimumab containing regimens by completing 
candidate-based gene and pathway analyses of genes 
involved in lymphocyte activation, cytokines profile, 
cytokine receptors and within the MHC region and an 
agnostic genome-wide SNP-based approach. 
2.3.1.3 
To replicate genomic markers identified in the above aims 
in an independent sample set of patients treated with 
ipilimumab containing regimens and preliminarily 
characterize their potential functional role by completing 
replication of variation as associated with irAEs and 
survival and bio-informatic assessment of genomic 
markers. 
2.3.2 
To determine the utility of circulating BRAF levels in determining the 
response and resistance to either BRAF/MEK directed and/or 
combination immunotherapy in patients with BRAF mutant melanoma. 
2.3.2.1 
To determine if changes in blood BRAF levels utilizing 
peripheral blood BRAFV600 mutational testing in patients 
with Stage IV BRAF mutant melanoma correlate with 
response and resistance to combination BRAF/MEK 
directed therapy.  
2.3.2.2 
To determine if changes in blood BRAF levels utilizing 
peripheral blood BRAFV600 mutational testing in patients 
with Stage IV BRAF mutant melanoma correlate with 
response and resistance to combination immunotherapy. 
2.3.2.3 
To compare the kinetics of peripheral blood BRAFV600 
levels during response and resistance in groups of patients 
receiving BRAF targeted therapy or combination 
immunotherapy as initial therapy. 
2.3.2.4 
To compare the kinetics of peripheral blood BRAFV600 
levels during response and resistance to combination 
BRAF targeted therapy or combination immunotherapy in 
individual patients (initial treatment vs crossover 
treatment). 
2.4 
Secondary Patient Reported Outcomes Objectives 
2.4.1 
To evaluate differences in overall health between initial treatment 
arms (dabrafenib + trametinib vs. ipilimumab + nivolumab 
immunotherapy) at 2 years, accounting for toxicities and overall 
survival. (Primary) 
2.4.2 
To assess differences in overall function over 2 years between initial 
treatment with dabrafenib + trametinib vs. ipilimumab + nivolumab. 
(Secondary) 
2.4.3 
To document the effects of treatment crossover and treatment 
administration sequence on symptom burden and overall function. 
(Secondary) 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
27 
2.4.3.1 
To compare differences in function and symptoms by 
treatment sequence for ipilimumab + nivolumab (arm A vs. 
D), and dabrafenib + trametinib, (arm B vs. C) at baseline, 
6 weeks, 12 weeks, and 6 months after the initiation of 
each treatment. 
2.4.3.2 
To describe the frequency and severity of treatment 
toxicities at baseline, 6 weeks, 12 weeks, and 6 months 
after initiation of each treatment. 
2.5 
Exploratory Tobacco Use Objectives 
2.5.1 
To determine the effects of tobacco, operationalized as combustible 
tobacco (1a), other forms of tobacco (1b), and environmental tobacco 
exposure (ETS) (1c) on provider-reported cancer-treatment toxicity 
(adverse events (both clinical and hematologic) and dose 
modifications). 
2.5.2 
To determine the effects of tobacco on patient-reported physical 
symptoms and psychological symptoms. 
2.5.3 
To examine quitting behaviors and behavioral counseling/support and 
cessation medication utilization. 
2.5.4 
To explore the effect of tobacco use and exposure on treatment 
duration, relative dose intensity, and therapeutic benefit. 
NOTE: 
Tobacco Use objectives described above are ancillary for the 
Tobacco Use Assessment project approved by NCI. A combined 
analysis of the data from the selected ECOG-ACRIN trials is planned. 
Data collected from the tobacco use assessment in each parent study 
will not be analyzed and reported in the clinical study report. 
2.6 
Exploratory Correlative Objective 
2.6.1 
To assess serum based biomarkers of efficacy and adverse events 
due to treatment with immune checkpoint inhibitors. 
2.6.2 
To monitor tumor response by comparing changes in circulating cell-
free mutant tumor DNA (ctDNA) as a readout of tumor burden (a) at 
week 12 relative to baseline before treatment in responders and non-
responders; (b) before and during immunosuppressive treatment to 
control irAEs. 
2.6.3 
To monitor organ-specific adverse events (irAEs) using circulating 
cell-free, tissue-specific methylated DNA (cmeDNA) as a readout of 
tissue-specific toxicity (a) at the time of grade 3-4 irAE relative to 
baseline and control patients without irAEs; (b) during 
immunosuppressive treatment for irAEs. 
 
Rev. 5/17 
Rev. Add10 
Rev. Add21 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
28 
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. 
3.1 
Eligibility Criteria Step 1: 
3.1.1 
Age ≥ 18 years. Because no dosing or adverse event data are 
currently available on the use of dabrafenib or dabrafenib + trametinib 
or nivolumab or nivolumab + ipilimumab therapy in patients < 18 years 
of age, children are excluded from this study, but will be eligible for 
future pediatric trials. 
3.1.2 
ECOG Performance status: 0 or 1 
3.1.3 
Women must not be pregnant or breast-feeding, as the effects of 
ipilimumab + nivolumab or dabrafenib + trametinib on the developing 
human fetus are unknown. 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. 
A female of childbearing potential is anyone, regardless of  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). 
Female of childbearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.4 
The effects of dabrafenib and trametinib or ipilimumab and nivolumab 
on the developing human fetus are unknown. Furthermore, dabrafenib 
has been reported to interfere with the effect of hormone based oral 
contraceptives. For this reason and because other therapeutic agents 
used in this trial are known to be teratogenic, women of child-bearing 
Rev. 11/16 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
29 
potential and sexually active males must agree to use at least two 
other accepted and effective methods of contraception and/or to 
abstain from sexual intercourse for the duration of their participation in 
the study, and for at least 4 weeks after treatment with dabrafenib or 
for 4 months after dabrafenib in combination with trametinib. Women 
of child-bearing potential must use at least two other accepted and 
effective methods of contraception and/or to abstain from sexual 
intercourse for at least 5 months after the last dose of nivolumab 
and/or ipilimumab. Should a woman become pregnant or suspect she 
is pregnant while she is participating in this study, she should inform 
her treating physician immediately. 
3.1.5 
Patients must have unresectable stage III or stage IV disease. 
3.1.6 
Patients must have measurable disease as defined in Section 6.1. All 
sites of disease must be evaluated within 4 weeks prior to 
randomization. 
3.1.7 
Patients must have histological or cytological confirmation of 
melanoma that is metastatic or unresectable and clearly progressive. 
NOTE: 
Any patient with BRAFV600 mutant melanoma (whether 
cutaneous, acral or mucosal primary) who meets the 
eligibility criteria is eligible for participation in this trial. 
Patients with uveal melanoma are not eligibile for this trial. 
3.1.8 
Patients must have BRAFV600 mutation, identified by an FDA-
approved test at a CLIA-certified lab. If test at CLIA-certified lab used 
a non-FDA approved method, information about the assay must be 
provided. (FDA approved tests for BRAF V600 mutations in 
melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF 
V600 Mutation Test, Foundation Medicine. Prompt information on 
tumor BRAF mutation status can also be obtained via Novartis 
“knowNow” Program. See link for details. 
https://www.knownowbraf.com/melanoma-testing). 
3.1.9 
Patients may have had prior systemic therapy in the adjuvant setting; 
however this adjuvant treatment must not have included a CTLA4 or 
PD1 pathway blocking antibody or a BRAF/MEK inhibitor. Also, 
patients may not have had any prior systemic treatment for advanced 
(measurable metastatic) disease. 
3.1.10 
Patients must have discontinued chemotherapy, immunotherapy or 
other investigational agents used in the adjuvant setting ≥ 4 weeks 
prior to entering the study and recovered from adverse events due to 
those agents. Mitomycin and nitrosoureas must have been 
discontinued at least 6 weeks prior to entering the study. Patients 
must have discontinued radiation therapy ≥ 1 week prior to entering 
the study and recovered from any adverse events associated with 
treatment. Prior surgery must be ≥ 2 weeks from registration and 
patients must be fully recovered from post surgical complications. 
3.1.11 
Patients must not receive any other investigational agents while on 
study or within four weeks prior to registration. 
Rev. 12/15 
Rev. 6/16 
Rev. 5/17 
Rev. 5/17 
Rev. Add13 
Rev. Add13 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
30 
3.1.12 
Patients are ineligible if they have any currently known active and 
definitive CNS metastases. Patients who have treated brain 
metastases (with either surgical resection or stereotactic radiosurgery 
(SRS)) could be eligible. Patients must not have taken any steroids ≤ 
10 days prior to randomization for the purpose of managing their brain 
metastases. Repeat imaging after SRS or surgical resection is not 
required so long as baseline MRI is within 4 weeks of registration. 
Patients with multiple brain metastases treated with SRS (w or w/o 
WBRT), are not an exclusion. Patients with definitive CNS metastases 
treated with only WBRT are ineligible. Patients with potential CNS 
metastases that are too small for treatment with either SRS or surgery 
(e.g. 1-2 mm) and/or are of uncertain etiology are potentially eligible, 
but need to be discussed with and approved by the Study PI. 
3.1.13 
Patients must not have other current malignancies, other than basal 
cell skin cancer, squamous cell skin cancer, in situ cervical cancer, 
ductal or lobular carcinoma in situ of the breast. Patients with other 
malignancies are eligible if they have been continuously disease-free 
for > 2 years prior to the time of registration. 
3.1.14 
Patients must have the following values for initial laboratory tests 
obtained within 4 weeks prior to randomization (ULN: institutional 
upper limit of normal): 
3.1.14.1 
White Blood Count ≥ 3,000/uL 
3.1.14.2 
ANC ≥ 1,500/uL 
3.1.14.3 
Platelet Count ≥ 100,000/uL 
3.1.14.4 
Hemoglobin > 8 g/dL 
3.1.14.5 
Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or 
serum creatinine clearance (CrCl) ≥ 40ml/min. (CrCl= Wt 
(kg) x (140-age)*/72 x Cr. level, *female x 0.85) 
3.1.14.6 
AST and ALT ≤ 3 x ULN (≤ 5 x ULN for patients with 
documented liver metastases) 
3.1.14.7 
Alkaline Phosphatase ≤ 2 x ULN (≤ 5x ULN for patients 
with known liver involvement and ≤ 7x ULN for patients 
with known bone involvement) 
3.1.14.8 
Total Bilirubin ≤ 1.5 x ULN except subjects with normal 
direct bilirubin or those with known Gilbert’s syndrome 
3.1.15 
Patients must not have any serious or unstable pre-existing medical 
conditions (aside from malignancy exceptions specified above), 
including but not limited to, ongoing or active infection requiring 
parenteral antibiotics on day 1, or psychiatric illness/social situations 
that would limit compliance with study requirements, interfere with 
subject’s safety, or obtaining informed consent. Therapeutic level 
dosing of warfarin can be used with close monitoring of PT/INR by the 
site. Exposure may be decreased due to enzyme induction when on 
treatment, thus warfarin dosing may need to be adjusted based upon 
PT/INR. Consequently, when discontinuing dabrafenib, warfarin 
Rev. 10/17 
Rev. Add13 
Rev. Add13 
Rev. Add13 
Rev. Add13 
Rev. Add16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
31 
exposure may be increased and thus close monitoring via PT/INR and 
warfarin dose adjustments must be made as clinically appropriate. 
Prophylactic low dose warfarin may be given to maintain central 
catheter patency. 
3.1.16 
Patients must not have a history of or evidence of cardiovascular risks 
including any of the following:  
• 
QT interval corrected for heart rate using the Bazett’s formula 
QTcB ≥ 480 msec.at baseline.  
• 
History of acute coronary syndromes (including myocardial 
infarction or unstable angina), coronary angioplasty, or stenting 
within the past 24 weeks prior to registration. 
• 
History prior to registration or evidence of current ≥ Class II 
congestive heart failure as defined by the New York Heart 
Association (NYHA) functional classification system. (See 
Appendix IX) 
• 
LVEF ≤ 45% on cardiac echo or MUGA. 
• 
Intra-cardiac defibrillator. 
3.1.17 
Individuals who are known to be HIV infected are ineligible (Note: HIV 
testing is not required for entry into the study). 
3.1.18 
Patients with active autoimmune disease or history of autoimmune 
disease that might recur, which may affect vital organ function or 
require immune suppressive treatment including systemic 
corticosteroids, should be excluded. These include but are not limited 
to patients with a history of immune related neurologic disease, 
multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-
Barre syndrome, myasthenia gravis; systemic autoimmune disease 
such as SLE, connective tissue diseases, scleroderma, inflammatory 
bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients 
with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson 
syndrome, or phospholipid syndrome should be excluded because of 
the risk of recurrence or exacerbation of disease. Patients with vitiligo, 
endocrine deficiencies including thyroiditis managed with replacement 
hormones including physiologic corticosteroids are eligible. Patients 
with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome 
and psoriasis controlled with topical medication and patients with 
positive serology, such as antinuclear antibodies (ANA), should be 
evaluated for the presence of target organ involvement and potential 
need for systemic treatment. If no systemic immune suppression is 
deemed necessary they can be eligible. 
3.1.19 
The following medications or non-drug thrapies are also prohibited 
while on treatment in this study: 
• 
Other anti-cancer therapies 
• 
Other investigational drugs 
Patients taking any medications or substances that are strong 
inhibitors or inducers of CYP3A or CYP2C8 are ineligible (see 
Appendix XI). 
Rev. 6/16 
Rev. 11/16 
Rev. Add13 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
32 
3.1.20 
Patients must not have history of retinal vein occlusion (RVO).   
3.1.21 
Patients must not have evidence of interstitial lung disease or 
pneumonitis. 
3.1.22 
Patients must not have malabsorption, swallowing difficulty, or other 
conditions that would interfere with the ingestion or absorption of 
dabrafenib or trametinib. 
3.2 
Eligibility Criteria Step 2 (Crossover arms): 
3.2.1 
The patient must have met all eligibility criteria in Section 3.1 (except 
as detailed below) at the time of crossover. 
3.2.1.1 
(3.1.6) – RECIST defined measurable disease is not 
required (see 0). 
3.2.1.2 
(3.1.9) - Only prior systemic therapy as part of Step 1 is 
allowed. Patients who received allowed systemic therapy 
in the adjuvant setting prior to Step 1 (see Section 3.1.9) 
and were eligible for Step 1 are not excluded from 
proceeding to Step 2 if they meet other eligibility criteria. 
3.2.1.3 
(3.1.22 and 3.1.21) malabsorption, swallowing difficulty, or 
other conditions that would interfere with the ingestion or 
absorption of dabrafenib or trametinib, or history of retinal 
vein occlusion are acceptable for patients crossing over to 
Arm D (ipilimumab + nivolumab) treatment. 
3.2.1.4 
(3.1.19, 3.1.22) history of autoimmune disease, excluding 
interstitial lung disease or pneumonitis, is allowed in 
patients crossing over to Arm C (dabrafenib/trametinib) 
therapy (see 3.2.4). 
3.2.1.5 
(3.1.10, 3.1.12) Patients crossing over from Arm A 
(nivolumab/ipilimumab) to Arm C (dabrafenib/trametinib) 
who underwent surgery or SRS to CNS metastases need 
not be off of steroids to start treatment (see 3.2.6). 
3.2.1.6 
(3.1.14) There is no restriction on serum LDH at crossover.  
3.2.1.7 
(3.1.16) Patients with a history of cardiovascular risks that 
developed during Step 1 of therapy should be discussed 
with study PI at time of crossover. 
3.2.2 
Patients randomized to Arm A on Step 1 must have melanoma that is 
metastatic and clearly progressive on Step 1 therapy prior to crossing 
over to Arm C. 
NOTE: 
Patients should (if possible) be at least 1 week from 
documented PD on Step 1 of current study. All sites of 
disease must be evaluated within 4 weeks prior to 
registration. 
3.2.3 
Patients randomized to Arm B on Step 1 may cross over to Arm D at 
or prior to disease progression 
Rev. 6/16 
Rev. 10/17 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
33 
NOTE:  
If possible, patients should wait to cross over until after the 
cycle with the next protocol-required imaging assessment 
is completed. All sites of disease must be evaluated within 
4 weeks prior to Step 2 registration.  
NOTE: 
Patients should start Arm D treatment at least 1 week after 
stopping dabrafenib and trametinib, unless otherwise 
clinically indicated. 
NOTE: 
Baseline labs and QOL assessments should be completed, 
and patients should follow the Arm D schedule as 
described in Section 5.1.4. 
3.2.4 
Patients must have recovered from adverse events (toxicities resolved 
to grade 1 or less) of prior therapy. Patients with immune related 
toxicities from ipilimumab + nivolumab may continue onto Step 2 even 
if still on steroids to control side effects, so long as toxicity has 
resolved to grade 1 or less. 
3.2.5 
Patients must have discontinued radiation therapy prior to registering 
to Step 2 of the study and recovered from any adverse events 
associated with treatment. Prior surgery must be ≥ 2 weeks from 
registration to Step 2 and patients must be fully recovered from post-
surgical complications. 
3.2.6 
Patients are ineligible if they have any currently active and definitive 
CNS metastases. Patients who have treated brain metastases (with 
either surgical resection or stereotactic radiosurgery (SRS)) could be 
eligible to proceed. Patients crossing over from Arm B 
(dabrafenib/trametinib) to Arm D (nivo/ipi) must not have taken any 
steroids ≤ 10 days prior to Step 2 registration for the purpose of 
managing their brain metastases. Patients with only Whole Brain 
irradiation for treatment of CNS metastases are ineligible. Patients 
with definitive CNS metastases treated with only WBRT are ineligible. 
Patients with potential CNS metastases that are too small for 
treatment with either SRS or surgery (e.g. 1-2 mm) and/or are of 
uncertain etiology are potentially eligible, but need to be discussed 
with and approved by the Study PI. 
3.2.7 
Patients must not have other current malignancies. 
3.2.8 
Women must not be pregnant or breast-feeding, as the effects of 
ipilimumab + nivolumab or dabrafenib + trametinib on the developing 
human fetus are unknown. All females of childbearing potential must 
have a blood test or urine study within 2 weeks prior to registration to 
Step 2 crossover to rule out pregnancy. 
A female of childbearing potential is anyone , regardless of  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. 
Female of child bearing potential? ______ (Yes or No) 
Rev. Add10 
Rev. Add10 
Rev. Add13 
Rev. Add13 
Rev. Add16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
34 
Date of blood test or urine study___________ 
3.2.9 
The effects of dabrafenib and trametinib or ipilimumab and nivolumab 
on the developing human fetus are unknown. Furthermore, dabrafenib 
has been reported to interfere with the effect of hormone based oral 
contraceptives. For this reason and because other therapeutic agents 
used in this trial are known to be teratogenic, women of child-bearing 
potential and sexually active males must agree to continue to use the 
same contraception requirements as on Step 1 of this study (ie: use at 
least two other accepted and effective methods of contraception 
and/or to abstain from sexual intercourse for the duration of their 
participation in the study, and for at least 4 weeks after treatment with 
dabrafenib or for 4 months after dabrafenib in combination with 
trametinib. Women of child-bearing potential must use at least two 
other accepted and effective methods of contraception and/or to 
abstain from sexual intercourse for at least 5 months after the last 
dose of nivolumab and/or ipilimumab.Should a woman become 
pregnant or suspect she is pregnant while she is participating in this 
study, she should inform her treating physician immediately. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
35 
4. 
Registration and Randomization Procedures 
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).  
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
 
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>. 
Rev. 11/16 
Rev. 5/17 
Rev. Add10 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
36 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by emailing the email address above or calling 1-888-651-
CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the EA6134 protocol page located on 
the CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment 
housed in the CTSU RSS. 
Rev. 6/16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
37 
• 
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 EA6134 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Requirements for EA6134 (DREAMseq) Trial Site Registration: 
• 
EA Ipilimumab Investigator Training (please see Section 4.3.5) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 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 
Rev. 6/16 
Rev. 10/17 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
38 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website 
• 
Log on to the CTSU members’ website; 
• 
Click on the Regulatory tab at the top of your screen; 
• 
Click on the Site Registration tab; 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status shown only reflects institutional compliance with site registration 
requirements as outlined above. 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 Step 1 randomization. 
Treatment should start within seven working days after Step 1 randomization.  
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.  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; and 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
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. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. 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. 
Rev. 10/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
39 
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 
Randomization (Step 1) 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.1.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient demographics 
• 
Sex 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
ZIP code 
• 
Method of payment 
• 
Country of residence 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.1.5 
Stratification Factors 
• 
ECOG PS: 0 or 1 
• 
Serum LDH: Normal or elevated, defined as above ULN for 
institution. 
4.2 
Randomization (Step 2) 
Patients on Arm A or Arm B will re-register and crossover to Step 2. Arm A 
patients will re-register and crossover to Arm C in Step 2. Arm B patients 
will re-register and crossover to Arm D in Step 2. 
NOTE: 
Before crossover to Arm C, Arm A patients must have melanoma that 
is metastatic and clearly progressive on Step 1 therapy. Confirmation 
of PD with second imaging scan after 4 weeks is not needed in 
patients with symptoms or laboratory data (rising LDH) supporting 
disease progression.  
NOTE: 
In response to the Data and Safety Monitoring Committee (DSMC) 
recommendations, Arm B patients may cross over to Arm D either 
prior to or at disease progression. 
Treatment must start within 7 working days of registration to Step 2. 
Rev. 12/15 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
40 
4.2.1 
Protocol Number 
Investigator Identification 
• 
Institution and affiliate name 
• 
Investigator’s name 
4.2.2 
Patient Identification 
• 
Patient’s initials (first and last) 
• 
Patient demographics 
• 
Sex 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
ZIP code 
• 
Method of payment 
• 
Country of residence 
4.2.3 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3.2. 
4.3 
Additional Requirements  
4.3.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.3.2 
Pathological samples are required to be submitted for central 
diagnostic review (mandatory) and for defined laboratory research 
studies (per patient consent) as indicated in Section 10. 
4.3.3 
Biological samples are to be submitted for defined laboratory research 
studies per patient consent as outlined in Section 10. 
 Medidata Rave is a clinical data management system being used for 
data collection for this trial/study. Access to the trial in Rave is 
controlled through the CTEP-IAM system and role assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site 
of: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave 
SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum 
of an Associate Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
Rev. 5/17 
Rev. Add10 
Rev. Add13 
Rev. Add21 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
41 
• 
Rave Read Only role must have at a minimum an Associates (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be listed in the upper right pane of the iMedidata screen. 
If an eLearning is required and has not yet been taken, the link to the 
eLearning will appear under the study name in iMedidata instead of 
the Rave EDC link; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a 
Rave EDC link will display under the study name. 
Users that have not previously activated their iMedidata/Rave 
accounts at the time of initial site registration approval for the study in 
RSS will also receive a separate invitation from iMedidata to activate 
their account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.3.4 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff 
to manage unanswered queries and form delinquencies, monitor data 
quality and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing 
summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, 
delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and 
have access to the CTSU website. Staff that have Rave study access 
can access the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon 
displayed on the Rave Home, DQP Queries, and DQP Delinquent 
Forms modules. 
Rev. Add21 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
42 
NOTE: 
Some Rave protocols may not have delinquent form details 
or reports specified on the DQP. A protocol must have the 
Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details 
and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
4.3.5 
Additional Registration Training Requirement 
Mandatory Investigator Training Course: 
ECOG-ACRIN has developed a training course to provide additional 
information to enrolling investigators on the toxicity profile of the 
ipilimumab and nivolumab combination. Each investigator is required 
to take the training course entitled: ECOG-ACRIN EA6134 Protocol 
Training, prior to their first patient enrollment.  
Investigators and site staff are able to self-enroll in the course by 
accessing the training URL: 
http://coccg.mindflash.com/PublicCoursePage.aspx?c=1232832108. 
Patient enrollments will be blocked via the OPEN system if the 
enrolling investigator has not completed the required training. All 
site research staff participating in EA6134 are also encouraged to 
take the training course. 
Upon completion of the training course, continue through to the end of 
the module until you are directed to the electronic copy of your 
completion certificate. You will also receive an email notification at the 
email address registered with Mindflash that the training has been 
completed. Download and save the certificate, as you will need to 
upload this to the CTSU Regulatory Submission Portal, following the 
process listed below. Please note that only investigators need to 
submit the training completion certificate to the CTSU. Once 
submitted, the training record will be stored in the regulatory database 
as a person attribute and the corresponding site regulatory 
requirement will be updated. 
If you have questions regarding training, please contact the CTSU 
Regulatory Office at 1-866-651-2878 or the ECOG-ACRIN Clinical 
Education and Awareness Team at EAClinEd@ecog-acrin.org. 
Additional information can be accessed on the CTSU: Search EA6143 
→ Supplemental Documents → 12Dec2019 post date 
Training Requirement Approval Process: 
1. Complete the required protocol training, using the link provided in 
the protocol 
2. Save a copy of the training completion certificate 
3. Submit certificate to the CTSU Regulatory Office: 
3.1. Regulatory Submission Portal: https://www.ctsu.org  
Rev. 12/15 
Rev. Add21 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
43 
3.2. Log in to the Members’ area using your CTEP-IAM 
username and password  
3.3. Select the Regulatory Tab → Regulatory Submission → Add 
New Submission 
3.4. Under the “Documents being submitted are for:” drop-down 
menu, select “Specific Person(s) Only”  
3.5. In the “Pick Person(s)” field either select the applicable 
name(s) using the drop-down menu, or type the applicable 
name(s) into the search field to narrow down the choices in 
the drop-down menu 
3.6. Select “Add to Cart” 
3.7. Select “Next” 
3.8. Upload and submit a copy of your training certificate 
4.3.6 
ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO) System: 
When patients consent to participate, they will be asked to provide a 
contact email address and that address along with their registration 
information will be sent directly from the parent trial’s registration 
system to EASEE-PRO, and the patient will be automatically 
registered into EASEE-PRO for participation. To activate their account 
for self-directed web entry of surveys, the system will send an 
activation message to the contact email address that will explain how 
to activate their account for self-directed web entry of surveys. After 
their account is activated, the patient will be able to complete 
questionnaires using a secure browser interface from any web 
enabled computer, tablet, or mobile device. 
4.4 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave and EASEE-PRO according to the schedule in the EA6134 Forms 
Completion Guidelines. 
 
Rev. 5/17 
Rev. 5/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
44 
5. 
Treatment Plan 
5.1 
Administration Schedule  
In Step 1, patients will be randomized to either Arm A (Induction Immunotherapy 
with Nivolumab 1mg/kg IV infusion + Ipilimumab 3mg/kg followed by 
Immunotherapy Maintenance with Nivolumab 3mg/kg alone) or Arm B 
(Dabrafenib 150 mg + Trametinib 2 mg). 
Treatment must be started within 7 working days of randomization to Step 1. 
Patients progressing on either Arm A or Arm B will re-register and crossover to 
Step 2. Arm A patients will re-register and crossover to Arm C in Step 2. Arm B 
patients will re-register and crossover to Arm D in Step 2. 
NOTE: 
In response to the Data and Safety Monitoring Committee (DSMC) 
recommendations, patients on Arm B may crossover to Arm D prior to 
progression. 
Treatment must start within 7 working days of registration to Step 2. 
Doses are based on actual body weight. Recalculate dosing at each cycle only if 
there is a 10% change in weight (See Section 8.1.5 for dosing specifics for 
Ipilimumab. See Section 8.2.8 for dosing specifics for Nivolumab.) 
For all arms, 1 cycle is 42 days (6 weeks) long. 
5.1.1 
ARM A 
5.1.1.1 
Initial Treatment 
Immunotherapy Induction: 1 cycle is 42 days (6 weeks) 
long. 
Investigators can choose between two induction 
regimens (Regimen 1 or Regimen 2 below) of nivo/ipi 
which appear to have equivalent efficacy. (Lebbe C et 
al ESMO 2018) 
Regimen 1: Nivolumab 1 mg/kg IV infusion Day 1 and 
22 of Cycles 1 and 2. 
Nivolumab is to be administered as a 30-60-minute IV 
infusion, using a volumetric pump with a 0.2 to 1.2 micron 
low-protein binding in-line filter at the protocol-specified 
dose. The drug can be diluted with 0.9% normal saline for 
delivery but the total drug concentration of the solution 
cannot be below 1 mg/mL. It is not to be administered as 
an IV push or bolus injection. At the end of the infusion, 
flush the line with a sufficient quantity of normal saline. 
Ipilimumab 3 mg/kg IV infusion Day 1 and 22 of Cycles 
1 and 2. 
Ipilimumab is to be administered as a 30-90-minute IV 
infusion (dependent on institutional standard/policy), using 
a volumetric pump with a 0.2 to 1.2 micron low-protein 
Rev. 6/16 
Rev. Add14 
Rev. Add16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
45 
binding in-line filter. Ipilimumab is given undiluted or further 
diluted in 0.9% NaCl Injection, USP or 5% Dextrose 
Injection, USP in concentrations between 1 mg/mL and 2 
mg/mL. 
Regimen 2: Nivolumab 3 mg/kg IV infusion Day 1 and 
22 of Cycles 1 and 2.  
Nivolumab is to be administered as a 30-60 minute IV 
infusion, using a volumetric pump with a 0.2 to 1.2 micron 
low-protein binding in-line filter at the protocol-specified 
dose. The drug can be diluted with 0.9% normal saline for 
delivery but the total drug concentration of the solution 
cannot be below 1 mg/mL. It is not to be administered as 
an IV push or bolus injection. At the end of the infusion, 
flush the line with a sufficient quantity of normal saline. 
Ipilimumab 1 mg/kg IV infusion Day 1 and 22 of Cycles 
1 and 2. 
Ipilimumab is to be administered as a 30-90-minute IV 
infusion, using a volumetric pump with a 0.2 to 1.2 micron 
low-protein binding in-line filter. Ipilimumab is given 
undiluted or further diluted in 0.9% NaCl Injection, USP or 
5% Dextrose Injection, USP in concentrations between 1 
mg/mL and 2 mg/mL. 
When infusions of ipilimumab and nivolumab are given on 
the same day, the preferred treatment is to give nivolumab 
followed by ipilimumab. Separate infusion bags and filters 
must be used for each infusion. The nivolumab infusion 
must be promptly followed by a saline flush to clear the line 
of nivolumab before starting the ipilimumab infusion. 
Toxicity management for the combined agents follows the 
same template guidelines and algorithms for single agent 
nivolumab. 
5.1.1.2 
Immunotherapy Maintenance: 1 cycle is 42 days (6 
weeks) long. 
Nivolumab 3 mg/kg IV infusion Day 1, 15 and 29 of cycles 
3-14 (max until 84 weeks or 72 weeks of maintenance). 
At disease progression, crossover to Arm C. 
5.1.2 
ARM C 
Dabrafenib 150 mg po twice daily days 1-42 of each 6 week cycle 
Trametinib 2 mg po daily days 1-42 of each 6 week cycle 
Treatment will continue for as long as patient is responding and 
tolerating therapy. 
Rev. Add14 
Rev. Add14 
Rev. Add16 
Rev. Add16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
46 
5.1.3 
ARM B 
Initial Treatment 
Dabrafenib 150 mg po twice daily days 1-42 of each 6 week cycle 
Trametinib 2 mg po daily days 1-42 of each 6 week cycle 
Treatment will continue for as long as patient is responding and 
tolerating therapy. 
At (or prior to) disease progression, crossover to Arm D. 
5.1.4 
ARM D 
Immunotherapy Induction (See Section 5.1.1.1 for treatment 
administration details). 
Investigators can choose between two induction regimens 
(Regimen 1 or Regimen 2 below) of nivo/ipi which appear to have 
equivalent efficacy. (Lebbe C et al ESMO 2018) 
Regimen 1: Nivolumab 1 mg/kg IV infusion Day 1 and 22 of 
Cycles 1 and 2 (Should be administered ahead of ipilimumab on 
days when both to be administered) 
Nivolumab is to be administered as a 30-60-minute IV infusion, using 
a volumetric pump with a 0.2 to 1.2 micron low-protein binding in-line 
filter at the protocol-specified dose. The drug can be diluted with 0.9% 
normal saline for delivery but the total drug concentration of the 
solution cannot be below 1 mg/mL. It is not to be administered as an 
IV push or bolus injection. At the end of the infusion, flush the line with 
a sufficient quantity of normal saline. 
Ipilimumab 3 mg/kg IV infusion Day 1 and 22 of Cycles 1 and 2 
Ipilimumab is to be administered as a 30-90-minute IV infusion, using 
a volumetric pump with a 0.2 to 1.2 micron low-protein binding in-line 
filter. Ipilimumab is given undiluted or further diluted in 0.9% NaCl 
Injection, USP or 5% Dextrose Injection, USP in concentrations 
between 1 mg/mL and 2 mg/mL. 
OR 
Regimen 2: Nivolumab 3 mg/kg IV infusion Day 1 and 22 of 
Cycles 1 and 2 (Should be administered ahead of ipilimumab on 
days when both to be administered) 
Nivolumab is to be administered as a 30-60 minute IV infusion, using 
a volumetric pump with a 0.2 to 1.2 micron low-protein binding in-line 
filter at the protocol-specified dose. The drug can be diluted with 0.9% 
normal saline for delivery but the total drug concentration of the 
solution cannot be below 1 mg/mL. It is not to be administered as an 
IV push or bolus injection. At the end of the infusion, flush the line with 
a sufficient quantity of normal saline. 
Rev. Add14 
Rev. Add14 
Rev. Add16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
47 
Ipilimumab 1 mg/kg IV infusion Day 1 and 22 of Cycles 1 and 2. 
Ipilimumab is to be administered as a 30-90-minute IV infusion 
(dependent on institutional standard/policy), using a volumetric pump 
with a 0.2 to 1.2 micron low-protein binding in-line filter. Ipilimumab is 
given undiluted or further diluted in 0.9% NaCl Injection, USP or 5% 
Dextrose Injection, USP in concentrations between 1 mg/mL and 2 
mg/mL. 
Immunotherapy Maintenance 
Nivolumab 3 mg/kg IV infusion Day 1,15 and 29 of cycles 3-14 (max 
84 or 72 weeks of maintenance) 
5.1.5 
Progressive disease will be determined by RECIST criteria for all 
arms. Crossover should occur at a minimum of 1 week after defined 
PD on either arm. Patients on either arm with “equivocal” progression, 
defined as PD by RECIST in the absence of disease related 
symptoms and in the setting of evidence of potential ongoing 
treatment benefit (e.g. falling LDH, shrinkage of the majority of 
lesions) can delay cessation of initial treatment and crossover until PD 
is confirmed with a repeat scan performed 4 weeks (+/- 1 week) after 
the initial scan. If RECIST PD is confirmed then treatment 
discontinuation must happen at that time. The initial PD scan will be 
designated the time of PD. For patients on Step 1, a washout period 
of 1 week is still required from either the last dose of 
dabrafenib/trametinib or the first missed dose of nivo +/- ipi due to 
documentation of PD prior to crossover. Potential exceptions to this 1 
week washout must be discussed with study PI and approved. 
Crossover should happen within 12 weeks of initial date of RECIST 
defined PD. Exceptions to this timeframe must be discussed with the 
study PI. If PD is not confirmed, (e.g. new lesions no longer present or 
are getting smaller, or overall disease is smaller and no longer meets 
criteria for RECIST defined PD) patient may continue on therapy with 
scans performed at the time dictated by the protocol e.g. subsequent 
scans should continue at the 12 week interval defined from the time of 
treatment initiation for that step of therapy. The same rules will apply 
to discontinuation of study treatment after crossover to the alternative 
treatment regimen. 
Patients taken off treatment for any reason other than progression per 
RECIST criteria will undergo tumor imaging at protocol defined times 
and cannot proceed to Step 2 until RECIST defined disease 
progression is documented (more frequent scanning is allowed in this 
situation). Patients taken off treatment on Arm B can proceed to Arm 
D without the need for documented progression. 
Patients must meet Step 2 eligibility criteria at the time of crossover 
registration with improvement of treatment related toxicity to grade 1 
or less. Some notable exceptions are below. Please see Section 3.2 
for more details. 
1. Patients on Arm A may be on a stable (for at least 1 week) or 
tapering dose of steroids at time of crossover to dabrafenib and 
Rev. 6/16 
Rev. Add16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
48 
trametinib. Patients on Arm B must be off of steroids for at least 2 
weeks at time of crossover. 
2. There is no LDH cutoff at time of crossover.  
Patients may undergo local therapy (e.g. RT or surgery) for treatment 
of local disease progression, but still must meet eligibility criteria 
regarding treatment interval before initiating crossover therapy.  
Patients who are more than 4 weeks from previous staging CT scan 
at time of crossover should have a repeat staging prior to initiating 
crossover therapy.   
5.2 
Adverse Event Reporting Requirements 
Effective April 1, 2018 expedited adverse event reporting done via CTEP-
AERS will use CTCAE version 5.0 terminology and grading.  Routine 
adverse event reporting and dose modifications guidelines will continue to 
be based on CTCAE version 4.0 terminology and grading. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0 and 5.0. A copy of both versions of the CTCAE can be 
downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.ht
m). 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done so investigators and regulatory 
agencies can detect and analyze adverse events and risk situations to 
ensure the safety of the patients enrolled, as well as those who will 
enroll in future studies using similar agents. 
5.2.2 
Routine Reporting of Adverse Events (Medidata Rave) 
Adverse events are reported in a routine manner at scheduled times 
during a trial using the Medidata Rave clinical data management 
system. Please refer to Section 4 of the protocol for more information 
on how to access the Medidata Rave system and the E1912 forms 
packet for instructions on where, when and what adverse events are 
to be reported routinely on this protocol. 
5.2.3 
Expedited Reporting of Adverse Events (CTEP-AERS) 
In addition to routine reporting, certain adverse events must be also 
reported in an expedited manner for timelier monitoring of patient 
safety and care using the Cancer Therapy Evaluation Program 
Adverse Event Reporting System (CTEP-AERS). Sections 5.2.5-
5.2.10 outline the procedure for expedited reporting of adverse events 
on this protocol. 
5.2.4 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent in humans, whether or not 
considered agent related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
Rev. 12/15 
Rev Add 15 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
49 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. For patients developing AEs attributable to protocol 
treatment following crossover, attribution should be designated to 
the appropriate treatment regimen (e.g. Ipilimumab+Nivolumab or 
Dabrafenib+Trametinib) to the extent possible. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to protocol 
treatment. 
Unlikely 
The AE is doubtfully related to protocol 
treatment. 
Possible 
The AE may be related to protocol treatment. 
Probable 
The AE is likely related to protocol treatment. 
Definite 
The AE is clearly related to protocol treatment. 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List): An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND. Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Hospitalization (or prolongation of hospitalization): For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event: Any AE that places the patient 
at immediate risk of death from the AE as it occurred.   
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious when, based upon medical judgment, 
they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in 
this definition. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
50 
• 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting): A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting. If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported in CTEP-AERS if the grade being reported exceeds the 
grade listed in the parentheses next to the event.  Since this 
protocol uses multiple investigational agents, if an AE is listed on 
multiple SPEERS, use the lower of the grades to determine if 
expedited reporting is required. 
5.2.5 
Expedited Adverse Event Reporting Procedure 
Adverse events requiring expedited reporting will 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 via the CTEP-
AERS Web-based application located at 
https://ctepcore.nci.nih.gov/ctepaers. Use the protocol number and 
the protocol-specific patient ID assigned during registration on the 
CTEP-AERS reports and all supporting or follow up data. 
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 (857-504-2900) 
• 
the NCI (301-897-7497)  
Once Internet connectivity is restored, the 24-hour notification that 
was phoned in must be entered immediately into CTEP-AERS by the 
original reporter. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 230-7404) and in the 
same timeframe. All supporting and follow up documentation must 
include the protocol number, patient ID number, and CTEP-AERS 
ticket number on each page. 
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. 
Many factors determine the requirements for expedited reporting of 
adverse events on each individual protocol. The instructions and 
tables in the following sections have been customized for protocol 
EA6134 and outline the specific expedited adverse event reporting 
requirements for study EA6134. 
Rev. Add13 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
51 
5.2.6 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arms A, B, C, and D 
5.2.6.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the investigational agent(s). 
 
 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the table 
below in Section 5.2.7. 
Yes 
No 
Identify the type and grade 
of the event using the 
CTCAE. 
Refer to Section 5.2.8 to determine if the 
event meets the criteria as a protocol 
specific exception to reporting on this 
study. 
Refer to Section 5.2.8 to 
determine if the event meets the 
protocol specific reporting 
requirements on this study. If 
so, report the event within 24 
hours of learning of the event in 
CTEP-AERS. 
Report the event in 
Medidata Rave only. 
No CTEP-AERS 
report is required. 
The event is NOT 
an exception 
The event IS an 
exception 
Immediately report the event within 24 hours of learning of the 
event in CTEP-AERS. 
Complete the full CTEP-AERS report within the timeframes 
outlined in the table in Section 5.2.7. 
Complete the full CTEP-AERS 
report within the timeframes 
outlined in the table in Section 
5.2.7. 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
52 
5.2.6.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.7 OR the 
protocol specific requirements in Section Error! Reference 
source not found., AND has an attribution of possible, 
probably or definite, the following events require reporting 
as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4-5 SAEs 
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported within 24 hours of learning of the 
events in CTEP-AERS even if the patient is off 
study. 
Expedited 24-hour notification followed by complete 
report within 10 calendar days for: 
• 
All Grade 1-3 SAEs 
5.2.7 
Expedited Reporting Requirements for Arm A, B, C, and D on protocol 
EA6134 
Investigational Agents: Ipilimumab, Nivolumab, Dabrafenib, 
Trametinib 
Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent(s).1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
of investigational agent(s). 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
54 
5.2.8 
Additional instructions, requirements and exceptions for protocol 
EA6134 
Additional Instructions 
• 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events , please contact the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
• 
Reporting a death on study: A death occurring while on study 
treatment or within 30 days of the last dose of study treatment 
requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be 
provided. 
NOTE: 
A death due to progressive disease should be 
reported as a Grade 5 “Disease progression” under 
the System Organ Class (SOC) “General disorder and 
administration site conditions”. Evidence that the 
death was a manifestation of underlying disease (e.g. 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
EA6134 specific expedited reporting requirements: 
• 
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless of 
age or disease state) occurring while the  patient is onprotocol 
treatment, or within 90 days of the patient’s last dose of protocol 
treatment are considered immediately reportable events . The 
pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test must be reported immediately (within 24 hours of 
learning of the event) in  CTEP-AERS.Complete the full CTEP-
AERS report within 5 calendar days.  . Please refer to Appendix 
VI for detailed instructions and timeframes on how to report the 
occurrence of a pregnancy as well as the outcome of all 
pregnancies. 
• 
Immune Related Adverse Events (IRAEs): Any grade 3 or 
higher immune related adverse events (see Section 5.4.3 for 
definitions) must be reported immediately (within 24 hours of 
learning of the event) in CTEP-AERS. Complete the full CTEP-
AERS report within the timeframes outlined in the SAE table in 
Section 5.2.7. If available, please submit any supporting data as 
well (e.g.: autoimmune serology tests or biopsy reports). Any 
questions regarding if an event qualifies as an IRAE can be 
directed to the study chair. Of note, delayed IRAEs may still 
occur in patients on Arm C as a consequence of delayed toxicity 
from prior ipilimumab/nivolumab with or without potential 
exacerbation by dabrafenib/trametinib. Examples include but are 
Rev. 12/15 
Rev. Add10 
Rev. Add13 
Rev. Add14 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
55 
not limited to interstitial nephritis and renal failure, severe 
potentially immune related hepatitis or skin rash. 
NOTE:  
In order for ECOG-ACRIN to appropriately report 
these events to regulatory agencies, please be sure to 
state that the event being reported is an IRAE in the 
‘Description of Event’ section of the CTEP-AERS 
report. 
For Arms B and C only: 
• 
LVEF Changes: If any of the following circumstances occur, the 
event(s) must be reported immediately (within 24 hours of 
learning of the event) in CTEP-AERS. Complete the full CTEP-
AERS report within the timeframes outlined in the AE table in 
Section 5.2.7. 
• 
Asymptomatic: Absolute decrease of >10% in LVEF 
compared to baseline and ejection fraction below the 
institution’s LLN and LVEF does not recover within 4 weeks 
• 
Symptomatic: Grade 3-4 LVEF 
Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for LVEF Decrease 
• 
Visual Changes: If RPED (retinal pigment epithelial 
detachments) or RVO (retinal vein occlusion) are diagnosed, the 
event(s) must be reported immedieately (within 24 hours of 
learning of the event) in CTEP-AERS. Complete the full CTEP-
AERS report within the outlined in the SAE table in Section 5.2.7. 
Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for Visual Changes. 
• 
Liver Chemistry Changes: If any of the following circumstances 
occur, the event(s) must be reported immediately (within 24 
hours of learning of the event) in CTEP-AERS Complete the full 
CTEP-AERS report within the outlined in the SAE table in 
Section 5.2.7. 
• 
ALT ≥ 3xULN and bilirubin ≥ 2x ULN or > 35% direct bilirubin 
• 
ALT ≥ 3xULN and INR >1.5, if INR measured (INR threshold 
does not apply if subject is on anticoagulant) 
Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for Liver Chemistry Changes 
For Arms A and D only: 
• 
Infusion Reactions: Any grade 3 or higher Nivolumab related 
infusion reaction that meets the definition of SAE in Section 5.2.7 
must be reported immediately (within 24 hours of learning of the 
event) in CTEP-AERS. Complete the full CTEP-AERS report 
within the timeframes outlined in the SAE table in Section 5.2.7. 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
56 
EA6134 specific expedited reporting exceptions: 
For study arms A, B, C and D the adverse events listed below do 
not require expedited reporting in CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and it 
is listed on the SPEER, it should ONLY be reported via CTEP-
AERS if the grade being reported exceeds the grade listed in the 
parentheses next to the event. Since this protocol uses multiple 
investigational agents, if an AE is listed on multiple SPEERs, use 
the lower of the grades to determine if expedited reporting is 
required. 
NOTE: 
Any reporting requirement outlined in the EA6134 specific 
expedited reporting requirements section above 
supercedes any exception listed in the SPEER. 
5.2.9 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Supporting and follow up data must be forwarded to ECOG-ACRIN, 
and the NCI as outlined in Section 5.2.5. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.10 
Second Primary Cancer Reporting Requirements 
All cases of second (second malignancy is a cancer that is unrelated 
to any prior anti-cancer treatment, including the treatment on this 
protocol) and secondary malignancies (secondary malignancy is a 
cancer caused by any prior anti-cancer treatment, including the 
treatment on this protocol), including acute myeloid leukemia (AML), 
myelodysplastic syndrome (MDS), and RAS-mutation positive 
malignancies, regardless of attribution, that occur following treatment 
on NCI-sponsored trials must be reported as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis in the CTEP-AERS application, regardless of 
attribution, at https://ctepcore.nci.nih.gov/ctepaers 
Report under a.) leukemia secondary to oncology chemotherapy, 
b.) myelodysplastic syndrome, or c.) treatment related secondary 
malignancy, d.) Neoplasms Other, malignant (grade 3 or 4) 
3. Upload a copy of the pathology report to ECOG-ACRIN in 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
Rev. 12/15 
Rev. Add13 
Rev. Add14 
Rev Add 15 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
57 
4. If the patient has been diagnosed with AML/MDS, upload a copy 
of the cytogenetics report (if available) to ECOG-ACRIN in 
Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
All new malignant tumors must be reported through 
CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment. All new 
malignancies should be reported including solid tumors 
(including non-melanoma skin malignancies), hematologic 
malignancies, Myelodysplastic Syndrome (MDS)/Acute 
Myelogenous Leukemia (AML), and in situ tumors. 
Whenever possible, the CTEP-AERS report should include the 
following: 
• 
tumor pathology 
• 
history of prior tumors 
• 
prior treatment/current treatment including duration 
• 
any associated risk factors or evidence regarding how long the 
tumor may have been present 
• 
when and how the tumor was detected 
• 
molecular characterization or cytogenetics, including RAS-
mutation status, of the original tumor (if available) and of any new 
tumor 
• 
tumor treatment and outcome (if available).   
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 
Rev. 12/15 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
62 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment 
changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; Gastrointestinal 
disorders - Other (gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
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 - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase 
increased; Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
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; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; 
Dyspnea; Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Skin 
hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal 
arteritis) 
NOTE: 
Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) 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. 
5.3.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
BMS-936558 (Nivolumab, MDX-1106, NSC 748726) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/do
cs/aeguidelines.pdf for further clarification. Frequency is provided 
based on 2069 patients. Below is the CAEPR for Nivolumab. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
67 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; 
Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis) 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Vomiting   
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Malaise; 
Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune 
thrombotic microangiopathy); Immune system disorders - Other (complications of allogeneic 
HSCT); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper 
respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Lymphocyte 
count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal 
and connective tissue disorder - Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (histiocytic 
necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other 
(tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; 
Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and 
subcutaneous tissue disorders - Other (rosacea) 
VASCULAR DISORDERS - Hypertension; Hypotension; Vasculitis 
NOTE: 
Nivolumab 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. 
5.3.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol 
Rev. 1/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
71 
that trametinib dimethyl sulfoxide (GSK1120212B) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular 
coagulation; Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial infarction; 
Restrictive cardiomyopathy; Sinus tachycardia 
EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing lights; Floaters; 
Glaucoma; Photophobia 
GASTROINTESTINAL DISORDERS - Ascites; Duodenal ulcer; Esophageal necrosis; 
Esophageal ulcer; Esophagitis; Gastric hemorrhage7; Gastric ulcer; Gastritis; 
Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal disorders - 
Other (pneumatosis intestinalis); Gastrointestinal fistula; Gingival pain; Hemorrhoidal 
hemorrhage7; Ileus; Obstruction gastric; Pancreatitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like 
symptoms; General disorders and administration site conditions - Other (axillary pain); 
Localized edema; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic pain; 
Hepatobiliary disorders - Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter related infection; 
Device related infection; Endocarditis infective; Enterocolitis infectious; Hepatitis viral; 
Infections and infestations - Other (abscess limb); Infections and infestations - Other 
(necrotizing fasciitis); Infections and infestations - Other (oral infection); Pharyngitis; 
Sepsis; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood bilirubin increased; Blood lactate dehydrogenase increased; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; 
Lipase increased; Lymphocyte count decreased; Platelet count decreased; Serum 
amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other 
(compression fracture); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor hemorrhage7; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial 
hemorrhage7; Lethargy; Nervous system disorders - Other (diplopia); Seizure; 
Somnolence; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; 
Insomnia; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria; 
Hematuria; Proteinuria; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal 
hemorrhage7 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage7; Hypoxia; Laryngeal edema; Oropharyngeal pain; Pleural effusion; 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
75 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent 
should be included in the e-mail. 
2 The incidence of anemia is increased when dabrafenib (GSK2118436B) is used in combination with 
trametinib dimethyl sulfoxide (GSK1120212B). 
3 The frequencies of these events are based upon laboratory findings rather than being due to 
patient-reported outcomes. 
4 The incidence of left ventricular systolic dysfunction is increased when dabrafenib 
(GSK2118436B) is used in combination with trametinib dimethyl sulfoxide (GSK1120212B). 
5 Dabrafenib (GSK2118436B) has been associated with ocular toxicities including chorioretinitis, 
retinitis, iridocyclitis, iritis, and uveitis. 
6 Edema limbs (peripheral edema) is a risk associated when dabrafenib (GSK2118436B) is used in 
combination with trametinib dimethyl sulfoxide (GSK1120212B) compared to dabrafenib 
(GSK2118436B) alone. 
7 Fever (pyrexia) can be associated with hypotension and/or (in rare cases) syncope. The 
frequency of fever and serious febrile events is increased when dabrafenib (GSK2118436B) is 
used in combination with trametinib dimethyl sulfoxide (GSK1120212B). 
8 Manifestations of allergic reactions (hypersensitivity) to dabrafenib (GSK2118436B) may include 
bullous rash (bullous dermatitis). 
9 The incidence of hemophagocytic lymphohistiocytosis (HLH)) is increased when dabrafenib 
(GSK2118436B) is used in combination with trametinib dimethyl sulfoxide (GSK1120212B). 
10 Squamous cell carcinoma (SCC), including SCC of the skin, SCC in situ (Bowen’s disease), and 
keratoacanthoma have been observed. 
11 New non-SCC malignancies have been reported including primary melanoma, basal cell 
carcinoma, and non-cutaneous malignancies. 
12 Rash includes the terms: rash, rash acneiform, rash papular, rash maculo-papular, and erythema. 
13 Recurrent neutrophilic panniculitis has been observed in at least one patient treated with 
dabrafenib (GSK2118436B) in combination with the MEK inhibitor trametinib dimethyl sulfoxide 
(GSK1120212B). 
14 Venous thromboembolic events (including deep vein thrombosis and pulmonary embolism) is a 
risk associated when dabrafenib (GSK2118436B) is used in combination with trametinib dimethyl 
sulfoxide (GSK1120212B). 
15 Treatment with dabrafenib (GSK2118436B) in combination with trametinib dimethyl sulfoxide  
(GSK1120212B) resulted in an increased incidence and severity of hemorrhagic events 
compared to patients treated with dabrafenib (GSK2118436B) as a single agent. Sites of 
hemorrhage may include, but are not limited to, intracranial, reproductive tract, respiratory tract, 
and gastrointestinal hemorrhage. 
Adverse events reported on Dabrafenib (GSK2118436B) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Dabrafenib 
(GSK2118436B) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (agranulocytosis); Blood and lymphatic system disorders - Other (pancytopenia); 
Disseminated intravascular coagulation; Febrile neutropenia; Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Heart failure; 
Mitral valve disease; Myocardial infarction; Pericardial effusion; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Eye disorders - Other (amaurosis fugax); Eye disorders - 
Other (vitreous detachment); Floaters; Photophobia; Retinal detachment; Retinopathy 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
76 
GASTROINTESTINAL DISORDERS - Dry mouth; Dyspepsia; Gastritis; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS - Death NOS; Disease 
progression; Gait disturbance; Localized edema; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic pain 
INFECTIONS AND INFESTATIONS - Bacteremia; Bronchial infection; Catheter related 
infection; Device related infection; Gallbladder infection; Infections and infestations - Other 
(bacterial peritonitis); Infections and infestations - Other (blood culture positive); Infections and 
infestations - Other (croup infectious); Infections and infestations - Other (Epstein-Barr virus 
infection); Infections and infestations - Other (respiratory tract infection); Lung infection; Otitis 
media; Pharyngitis; Rash pustular; Rhinitis infective; Sepsis; Skin infection; Urinary tract 
infection; Viremia 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Injury, poisoning 
and procedural complications - Other (complication associated with device); Injury, poisoning 
and procedural complications - Other (device occlusion); Injury, poisoning and procedural 
complications - Other (radiation injury, stroke-like migraine attacks after radiation therapy); 
Seroma 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; CD4 lymphocytes decreased; 
Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Lipase increased; Lymphocyte count decreased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypernatremia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Generalized 
muscle weakness; Muscle cramp; Muscle weakness lower limb; Muscle weakness upper limb; 
Neck pain 
NEOPLASMS, BENINGN, MALIGNANT AND UNSPECIFIED (INCL CYST AND POLYPS) - 
Leukemia secondary to oncology chemotherapy; Myelodysplastic syndrome; Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (acrochordon); Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (bile duct adenocarcinoma); 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (mycosis 
fungoides) 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysgeusia; Dysphasia; Hydrocephalus; Lethargy; Nervous system disorders - 
Other (expressive aphasia); Nervous system disorders - Other (intracranial pressure increased); 
Paresthesia; Seizure; Somnolence; Stroke 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Hallucinations; 
Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria; Renal calculi; Urinary frequency; Urinary 
retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Menorrhagia; Prostatic obstruction; 
Reproductive system and breast disorders - Other (hematospermia) 
RESPIRATORY, THORACIC AND MEDAISTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Dyspnea; Hypoxia; Nasal congestion; Oropharyngeal pain; Pleuritic 
pain; Productive cough; Pulmonary edema; Respiratory failure; Rhinorrhea; Sore throat; Stridor; 
Voice alteration 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
77 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS- Bullous dermatitis8; Eczema; 
Erythroderma; Photosensitivity; Purpura; Skin and subcutaneous tissue disorders - Other 
(palmoplantar keratoderma); Skin and subcutaneous tissue disorders - Other (sunburn); Skin 
hyperpigmentation 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension 
NOTE: 
Dabrafenib 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. 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
78 
5.4 
Dose Modifications  
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
When a patient’s adverse reactions are under effective management, dose re-
escalation following the same dosing steps as de-escalation may be considered. 
The dabrafenib dose should not exceed 150 mg twice daily. Missed doses should 
not be made up. 
The dose modifications may involve one or both agents, and should be based on 
the nature, severity and attributions of the AEs. General guidelines are provided 
in Tables below, with details stipulated in subsequent sections. The Study Chair 
should be consulted if there are questions about the attribution of AEs and how 
the doses should be modified. 
NOTE: 
Patients who develop toxicity requiring drug discontinuation in 
step 1 can still cross over to step 2 at the time of disease 
progression if RECIST defined progressive disease is 
documented and eligibility criteria for step 2 are met (see Section 
3.2). Patients off treatment on Arm B due to toxicity do not need 
to exhibit progressive disease before crossing over to Arm D. 
5.4.1 
Dose Modifications for Dabrafenib/Trametinib 
For patients on Arm A who have crossed over to dabrafenib/trametinib 
and who experience toxicity that is clearly attributable to 
ipilimumab/nivolumab (e.g. colitis, hypophysitis) or potentially 
attributable to prior ipilimumab/nivolumab (e.g. interstitial nephritis, 
transaminitis, inflammatory skin rash/vasculitis) dabrafenib and 
trametinib should be held until toxicity returns to grade 1 and then 
dabrafenib and trametinib could be resumed at the previous dose. 
Steroids may be administered to treat the potential IRAE and 
dabrafeinib/trametinib treatment could be resumed while steroid 
treatment and taper is ongoing.  
A dose reduction below 50 mg BID for dabrafenib is not allowed. For 
dabrafenib + trametinib combination, dose below 1 mg once daily for 
trametinib is not allowed. 
If dabrafenib will be permanently discontinued for dabrafenib-related 
toxicities, patients will be allowed to continue trametinib. Conversely, if 
trametinib is permanently discontinued for trametinib-related toxicities, 
patients will be allowed to continue dabrafenib. 
The Study Chair's approval is required to restart study treatment after 
≥ 28 days of dose interruption/delay. 
Rev. 12/15 
Rev. 12/15 
Rev. 11/16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
84 
• 
These should be surgically removed according to institutional 
practices. Dose modification or interruption of study treatment 
is not required for cuSCC or KA, however cuSCC should be 
reported as an SAE through CTEP-AERS (refer to Section 
5.2). In addition, a biopsy of the lesion should be taken, where 
possible, and a summary of the results submitted to CTEP 
through the SAE reporting. 
• 
Patients should be instructed to immediately inform their 
physician if new lesions develop.  
• 
New Primary Melanoma 
• 
New primary melanomas have been reported in patients 
treated with dabrafenib. These were identified primarily within 
the first 5 months of therapy and did not require treatment 
modification other than excision. New primary melanoma 
should be reported as SAE through CTEP-AERS according to 
the instructions in Section 5.2. 
• 
Non-Cutaneous Malignancies 
• 
In vitro experiments have demonstrated paradoxical activation 
of MAP-kinase signalling in BRAF wild type cells with RAS 
mutations when exposed to BRAF inhibitors, which may lead 
to increased risk of non-cutaneous malignancies in patients 
treated with dabrafenib. Cases of RAS-driven malignancies 
have been seen with BRAF inhibitors. Patients should be 
monitored as clinically appropriate. 
• 
Consider the benefits and risks before continuing treatment 
with dabrafenib in patients who develop RAS mutation-positive 
non-cutaneous malignancies. If used in combination with 
trametinib, trametinib may continue. 
• 
Following discontinuation of dabrafenib, monitoring for non-
cutaneous secondary/recurrent malignancies should continue 
for up to 6 months or until initiation of another anti-neoplastic 
therapy. 
• 
New non-cutaneous malignancies should be reported as a 
SAE through CTEP-AERS according to the instructions in 
Section 5.2. A biopsy of the new malignancy should be taken, 
where possible, and submitted for further analyses with the 
results provided to CTEP via SAE reporting. Testing of these 
biopsies should include RAS mutation analysis and may 
include analysis of genomic alterations, which include but not 
limited to DNA, RNA and protein analysis of these biopsy 
specimens, and would analyze the biological pathways known 
to be associated with, and relevant to, BRAF-mutant tumor 
activation. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
85 
Dabrafenib-Trametinib Dose Modification for Hemorrhage 
Table 4: 
Dabrafenib-Trametinib Treatment Modifications for Hemorrhage 
Grade 3 
• Hold dabrafenib or dabrafenib-trametinib for up to 3 weeks 
• If improved, resume the drugs at one dose reduction 
• If no improvement, permanently discontinue dabrafenib or dabrafenib-trametinib 
Grade 4 
• Permanently discontinue dabrafenib or dabrafenib-trametinib 
Dabrafenib-Trametinib Dose Modification for Pancreatitis 
In the event of abdominal pain or suspected pancreatitis, amylase and 
lipase laboratory samples should be collected for confirmation of the 
diagnosis. Dabrafenib and trametinib should be held until toxicity 
returns to grade 1. Treatment should be resumed with dabrafenib 
dose reduced by 1 dose level. Patients should be closely monitored 
when re-starting dabrafenib after an episode of pancreatitis. 
Dabrafenib or Dabrafenib-Trametinib Dose Modification for 
Hyperglycemia 
Hyperglycemia requiring an increase in the dose of, or initiation of 
insulin or oral therapy can occur with dabrafenib. Monitor serum 
glucose levels as clinically appropriate during treatment with 
dabrafenib in subjects with pre-existing diabetes or hyperglycemia. 
Advise patients to report symptoms of severe hyperglycemia such as 
excessive thirst or any increase in the volume or frequency of 
urination. 
Dabrafenib-Trametinib Dose Modification for Renal Insufficiency 
Cases of renal insufficiency have occurred in patients receiving the 
combination of dabrafenib and trametinib. Prior to start of study 
treatment, concomitant medications should be reviewed for the 
potential risk of inducing nephrotoxicity and modified if clinically 
possible. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
96 
guidelines. These algorithims should be followed unless there are 
specific clinical circumstances which the treating physician indicates 
variations or alternative treatment is needed. 
In several places there are differences regarding protocol directed 
drug modification rules identified with (^). In these cases please follow 
the protocol specific guidelines in this section. 
Generally we strongly encourage early evaluation, withholding drug, 
and appropriate treatment as indicated in the management tables and 
following event specific guidelines. 
NOTE: 
In the text that if a patient experiences several adverse 
events and there are conflicting recommendations, the 
investigator should use the recommended dose 
adjustment that reduces the dose to the lowest level. 
NOTE: 
In the event that the dosing management outlined in 
Section 5.4.2 conflicts with Appendix X Management 
Algorithms, the EA6134 reccomendation is to follow the 
Section 5.4.2 management guidelines. 
ALL OTHER EVENTS* 
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 OR baseline. Resume at same dose 
level. For lab abnormalities, no change in therapy or dose. 
Grade 3 
Hold* until ≤ Grade 1 continue at investigator discretion 
Grade 4 
Off protocol therapy. For lab abnormalities, may restart at 
investigator discretion. 
* non-immunologically mediated 
Recommended management: As clinically indicated 
ALL OTHER EVENTS** 
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 OR baseline. When resolved to ≤ 
Grade 1 and off of steroids for at least 1 week, resume at 
same dose level. 
Grade 3 
Off protocol induction therapy. May resume nivolumab 
monotherapy if resolved to Grade 1 or less (off of > than 
physiologic replacement doses of corticosteroids) by end of 
week 16. (exceptions noted in 5.4.2) If occurs with 
nivolumab monotherapy, then off protocol therapy. 
Grade 4 
Off protocol therapy 
** immunologically mediated 
Recommended management: As clinically indicated  
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
97 
Skin Rash and 
Oral Lesions 
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
No change in dose * 
Grade 2 
Hold/ omit therapy* until ≤ Grade 1 or resolved^. Consider oral steroid 
treatment if > 7 days. Resume at same dose level at time of an 
originally scheduled dose administration once toxicity returned to 
grade 1 and patient is off steroids. 
Grade 3 
Hold* until ≤ Grade 1. Resume at same level at investigator discretion  
Grade 4 
Off protocol therapy 
* Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-
Johnson syndrome, TEN, and autoimmune bullous disease including oral lesions of 
bullous pemphigus/pemphagoid. Pruritus may occur with or without skin rash and 
should be treated symptomatically if there is no associated liver or GI toxicity. Note skin 
rash typically occurs early and may be followed by additional events particularly during 
steroids tapering.   
Recommended management: AE management guidelines 
 
Liver Function AST  
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
Continue protocol therapy. 
Grade 2 
Hold/ omit therapy until WNL or baseline. Consider oral steroid 
treatment if > 7 days. Resume at same dose level at time of an 
originally scheduled dose administration once toxicity return to 
grade 1 and patient off steroids. 
Grade 3 
Discontinue protocol induction therapy. Initiate IV or PO steroids. 
May begin nivolumab monotherapy if returns to grade 1 off 
steroids or other immunosuppressive treatment by week 16 (no 
earlier than week 13); if not returned to grade 1 after week 16, 
discontinue nivolumab monotherapy. Hold maintenance therapy. 
Initiate IV or PO steroids. If not returned to grade 1 off steroids 
by 6 weeks from missed dose, then off protocol therapy. 
Grade 4 
Off protocol therapy. Initiate IV steroids. 
Continued treatment of patients with active immune mediated hepatitis may exacerbates 
ongoing inflammation. Holding drug to evaluate LFT changes and early treatment are 
recommended.  
LFT changes may occur during steroid tapers from other events and may occur together 
with other GI events including cholecystitis/pancreatitis. 
Recommended management: see Hepatic AE management algorithm 
 
Diarrhea/ Colitis  
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
Hold until Grade 0 (if Grade 1) or baseline^. No change in dose 
Grade 2 
Hold/ omit until Grade 0 or baseline. Oral steroid treatment if > 7 
days and hold further induction therapy. May begin nivo 
monotherapy at time of a previously scheduled dose if resolved to 
grade 0 (or baseline) off of steroids by week 16. 
Rev. Add14 
Rev. Add14 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
98 
Diarrhea/ Colitis  
Management/Next Dose for Nivolumab + Ipilimumab 
Grade 3 
Off protocol therapy; may begin nivo monotherapy if resolved to 
grade 0 (or baseline) by week 16. If occurs during nivo 
monotherapy then patient is off protocol therapy. 
Grade 4 
Off protocol therapy 
See GI AE Algorithm for management of symptomatic colitis (Appendix X). 
Patients with ≤ Grade 2 toxicity resolving to Grade 0 or baseline within 7 days in the 
absence of oral steroids during induction may resume with omitted dose and have 
treatment scheduled postponed 1 week. Scans should still be done at week 12 and first 
maintenance dose of nivo should be omitted. If during maintenance, dose should just be 
omitted and treatment resumed with next dose. 
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated 
after resolution.  
Patients who require steroids should be taken off study induction treatment.  
Please evaluate pituitary function prior to starting steroids if possible without 
compromising acute care.   
Evaluation for all patients for additional causes includes C. diff, acute and self-limited 
infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD.  
Recommended management: see GI AE management Algorithm; Patients with grade 2 
toxicity requiring steroid therapy should not resume induction therapy. 
 
Pancreatitis 
Amylase/Lipase  
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
Continue protocol therapy if asymptomatic 
Grade 2 
Continue protocol therapy if asymptomatic 
Grade 3 
Continue protocol therapy if asymptomatic at investigator 
discretion 
Grade 4 
If asymptomatic, hold protocol therapy until < grade 2, then 
resume at same dose level. 
Patients with symptomatic or radiologic evidence of pancreatitis as well as DM and DKA 
should be off protocol therapy. Lipase elevation may occur during the period of steroid 
withdrawal and with other immune mediated events or associated with colitis, hepatitis, 
and patients who have asymptomatic lipase elevation typically have self-limited course 
and may be retreated. 
For treatment management of symptomatic pancreatitis please follow the Hepatic 
Adverse Event Management Algorithm  
 
Pneumonitis 
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
Hold/ omit dose pending evaluation and resolution to ≤ Grade 0 or 
baseline including baseline pO2. Resume no change in dose after 
pulmonary and/or ID consultation  
Grade 2 
Hold/ omit dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation if lymphocytic pneumonitis is 
excluded. Off protocol therapy if steroids are required. ^  
Grade 3 
Hold/ omit dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation only if lymphocytic pneumonitis is 
excluded. Otherwise, off protocol therapy  
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
99 
Pneumonitis 
Management/Next Dose for Nivolumab + Ipilimumab 
Grade 4 
Off protocol therapy 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients 
who do not respond to antibiotics and have no causal organism identified including 
influenza. Most patients with respiratory failure or hypoxia will be treated with steroids. 
Bronchoscopy may be required and analysis of lavage fluid for lymphocytic 
predominance may be helpful. Patients with new lung nodules should be evaluated for 
sarcoid like granuloma. If seasonal influenza vaccine is considered, killed vaccines 
should be recommended. 
Recommended management: See Pulmonary Adverse Event Management Algorithm  
 
Other GI N-V  
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
No change in dose.  
Grade 2 
Hold/ omit pending evaluation for gastritis duodenitis and other 
immune adverse events or other causes. Resume at same 
dose level after resolution to ≤ Grade 1.   
Grade 3 
Hold/ omit pending evaluation until ≤ Grade 1. Resume at 
same dose level. If symptoms do not resolve within 7 days with 
symptomatic treatment patients should go off protocol 
induction therapy. May resume nivo monotherapy if resolved to 
grade ≤ 1 (off of > replacement steroids for 2 wks by wk 16 
Grade 4 
Off protocol therapy 
Patients with grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events. 
 
Fatigue  
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose 
Grade 3 
Hold/ omit until ≤ Grade 2. Resume at same dose level 
Grade 4 
Off protocol therapy 
Fatigue is the most common adverse event associated with immune checkpoint therapy. 
Grade 2 or greater fatigue should be evaluated for associated or underlying organ 
involvement including pituitary, thyroid, and hepatic, or muscle (CPK) inflammation  
 
Neurologic events  
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
Hold dose pending evaluation and observation.^ If symptoms 
don’t progress and processing below excluded may resume with 
no change in dose.* 
Grade 2 
Hold dose pending evaluation and observation.^ Hold until ≤ 
Grade 1. *Off protocol therapy if treatment with steroids is 
required.^ Resume at same dose level for peripheral isolated n. 
VII (Bell’s palsy)^ 
Grade 3 
Off protocol therapy  
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
100 
Neurologic events  
Management/Next Dose for Nivolumab + Ipilimumab 
Grade 4 
Off protocol therapy  
* Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy 
(other than peripheral n. VII), GB syndrome, myasthenia gravis, should be permanently 
off IO treatment, but can remain on study. If the patient has disease progression and 
the toxicity from the IO has resolved, they should be able to cross over to targeted 
therapy. 
Recommended management: See Neurologic Adverse Event Management Algorithm  
 
Endocrine Hypophysitis 
Adrenal Insufficiency  
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
Asymptomatic TSH elevation. Add hormone replacement 
as clinically indicated. Continue therapy. 
Grade 2 
Hold/ omit until patients are on a stable replacement 
hormone regimen. Resume at same dose level. 
Grade 3 
Hold/ omit until patients are on a stable replacement 
hormone regimen. Resume at same dose level. If 
diagnosed with hypophysitis should hold induction therapy, 
but may begin nivo monotherapy when returned to grade 1 
(must be no earlier than week 13 and by end of week 16) 
Grade 4 
Off protocol therapy 
Note all patients with symptomatic pituitary enlargement, exclusive of hormone 
deficiency, but including severe headache or enlarged pituitary on MRI should be 
considered grade 3 events. Isolated thyroid or testosterone deficiency may be treated as 
grade 2 if there are no other associated deficiencies and adrenal function is monitored.  
Please evaluate pituitary function before beginning steroid therapy or replacement 
therapy of any kind.  
• 
Note patients with thyroiditis may be retreated on replacement therapy. Patients 
must be evaluated to rule out pituitary disease prior to initiating thyroid replacement. 
• 
Patients with symptomatic hyperthyroidism can be given a short course of a beta 
blocker (e.g propranolol). Hyperthyroidism usually converts to hypothyroid within 4 
weeks. 
Recommended management: See Endocrine Management Algorithm  
 
Fever  
Management/Next Dose for Nivolumab + Ipilimumab 
≤ Grade 1 
Continue protocol therapy. 
Grade 2 
Hold/ omit until ≤ Grade 1. Resume at same dose level. 
Grade 3 
Hold/ omit until ≤ Grade 1. Resume at same dose level. 
Grade 4 
Off treatment 
Patients with fever should be evaluated as clinically appropriate. Patients may 
experience isolated fever during infusion reactions or up to several days after infusion. 
Evaluation over the course of 1-2 weeks should be done for other autoimmune events 
that may present as fever  

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
101 
Fever  
Management/Next Dose for Nivolumab + Ipilimumab 
See Section 5. infusion reactions   
 
Cardiac* 
Management/Next Dose for BMS-936558 (Nivolumab) + 
Ipilimumab Cardiac Toxicities 
≤ Grade 1 
Hold dose pending evaluation and observation.** Evaluate for signs 
and symptoms of CHF, ischemia, arrhythmia or myositis. Obtain 
history EKG, CK (for concomitant myositis), CK-MB. Repeat 
troponin, CK and EKG 2-3 days. If troponin and labs normalize may 
resume therapy. If labs worsen or symptoms develop then treat as 
below. Hold pending evaluation 
Grade ≥ 2 with 
suspected 
myocarditis 
Hold dose.** Admit to hospital. Cardiology consult. Rule out MI and 
other causes of cardiac disease. Cardiac Monitoring. Cardiac Echo. 
Consider cardiac MRI and cardiac biopsy. Initiate high dose 
methylprednisolone. If no improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Resume therapy at a time of next 
scheduled dose if there is a return to baseline and myocarditis is 
excluded or considered unlikely. 
Grade ≥ 2 with 
confirmed 
myocarditis 
Off protocol therapy. Admit to CCU (Consider transfer to nearest 
Cardiac Transplant Unit). Treat as above. Consider high dose 
methylprednisolone; Add ATG or tacrolimus if no improvement. Off 
treatment. 
* Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
** Patients with evidence of myositis without myocarditis may be treated according as 
“other event”   
NOTE: The optimal treatment regimen for immune mediated myocarditis has not been 
established. Since this toxicity has caused patient deaths, an aggressive 
approach is recommended.  
• Drug will be held for grade 2 cardiac dysfunction pending evaluation 
• Drug will be permanently discontinued for grade 3 or 4 cardiac dysfunction and grade 
2 events that do not recover to baseline or that reoccur 
• Treatment with steroids as clinically indicated 
Patients requiring a delay of > 6 weeks, or > 8 weeks for patients on 
high dose steroids with required 4 weeks minimum taper and 2 week 
observation, should go off protocol therapy, except as specified in 
Section 5.4.2 (Dose Modifications for Ipilimumab/Nivolumab). 
Patients requiring > two dose delays/ dose omissions for the same 
event should go off protocol therapy. 
Prior to starting corticosteroids or hormone replacement for any 
reason, appropriate endocrine testing including cortisol, ACTH, TSH 
and T4 must be obtained to document baseline.  
Patients may be dose-delayed for evaluation and restarted depending 
on results.  
Any patient started on corticosteroids initially who is determined to not 
require steroids treatment for an autoimmune adverse event may 
resume therapy after a 2 week observation period without further 
symptoms at the discretion of the PI or investigator. Therapy should 
Rev. Add14 
Rev. Add14 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
102 
be resumed at the time of a next scheduled dose and held doses 
should be omitted or skipped. 
5.4.3 
Immune-Related Adverse Events (IRAE’s) 
5.4.3.1 
Definition of Immune-Related Adverse Events (IRAE’s) 
Blocking CTLA 4 or PD1 function may permit the 
emergence of auto-reactive T cells and resultant clinical 
autoimmunity. Rash/vitiligo, diarrhea/colitis, 
uveitis/episcleritis, hepatitis, and hypopituitarism were 
noted in previous ipilimumab studies. These drug-related 
events are presumptive autoimmune events, now termed 
IRAEs. 
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 case report form 
and as an SAE via CTEP-AERS (see Section 5.2). 
5.4.3.2 
Monitoring and Treatment of Immune-Related Adverse 
Events (IRAE’s) 
Patients should be informed of and carefully monitored for 
evidence of clinically significant systemic IRAE (e.g., 
systemic lupus erythematosus-like diseases) or organ 
specific IRAE (e.g., rash, colitis, uveitis, hepatitis or thyroid 
disease). If an IRAE is noted, appropriate work-up 
(including biopsy if possible) should be performed, and 
steroid therapy may be considered if clinically necessary.  
It is unknown if systemic corticosteroid therapy has an 
attenuating effect on ipilimumab activity. However, clinical 
anti-tumor responses have been maintained in patients 
treated with corticosteroids and discontinued from 
ipilimumab. If utilized, corticosteroid therapy should be 
individualized for each patient. Prior experience suggests 
that colitis manifested as ≥ Grade 3 diarrhea, as well as 
other grade 3 IRAEs (skin rash, hepatitis, etc), requires 
corticosteroid treatment.   
5.5 
Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, 
bronchospasm, or other allergic-like reactions. All grade 3 and 4 infusion 
reactions that meet the definition of SAE in Section 5.2 must be reported via 
Rev. 12/15 
Rev. 11/16 
Rev. Add13 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
103 
CTEP-AERS according to the timeframes outlined in the AE table in Section 
5.2.7.  
Treatment recommendations are provided below and may be modified based on 
local treatment standards and guidelines, as appropriate: 
• 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; 
intervention not indicated): 
• 
Study staff (e.g, RN, NP, PA or MD) should remain at bedside and 
monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 
50 mg IV or PO (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg at least 30 minutes before additional nivolumab administrations. 
• 
For Grade 2 symptoms: (moderate reaction required therapy or infusion 
interruption but responds promptly to symptomatic treatment (e.g., 
antihistamines, non-steroidal anti-inflammatory drugs, narcotics, 
corticosteroids, bronchodilators, IV fluids); prophylactic medications 
indicated for  24 hours): 
• 
Stop the nivolumab infusion, begin an IV infusion of normal saline, 
and treat the subject with diphenhydramine 50 mg IV or PO (or 
equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg; 
remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart 
the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion rate. Monitor 
subject closely. If symptoms recur, then no further nivolumab will be 
administered at that visit. 
• 
For future infusions, the following prophylactic premedications are 
recommended: diphenhydramine 50 mg IV or PO (or equivalent) 
and/or acetaminophen/paracetamol 325 to 1000 mg should be 
administered at least 30 minutes before nivolumab infusions. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or 
equivalent) may be used. 
• 
For patients experiencing infusion reactions to nivolumab 
administered over 30 or 60 minutes, subsequent infusions could be 
administered over 90 minutes. 
• 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not 
rapidly responsive to symptomatic medication and/or brief interruption of 
infusion]; recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates). Grade 4: Life-threatening; pressor or 
ventilatory support indicated): 
• 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of 
normal saline and treat the subject as follows: Recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg 
Rev. Add14 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
104 
IV or PO with methylprednisolone 100 mg IV (or equivalent), as 
needed. Subject should be monitored until the Investigator is 
comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at 
bedside and monitor subject until recovery of the symptoms. 
• 
In case of late-occurring hypersensitivity symptoms (e.g., appearance 
of a localized or generalized pruritus within 1 week after treatment), 
infusion reactions reported via CTEP-AERS should be graded 
according to NCI-CTCAE (Version 5.0) guidelines. 
5.6 
Treatment of Ipilimumab Related Infusion Reactions 
Since ipilimumab contains only human protein sequences, it is less likely that any 
allergic reaction will be seen in patients. However, it is possible that infusion of 
ipilimumab will induce a cytokine release syndrome that could be evidenced by 
fever, chills, rigors, rash, pruritus, hypotension, hypertension, bronchospasm, or 
other symptoms. No prophylactic pre-medication will be given unless indicated by 
previous experience in an individual patient. Reactions should be treated based 
upon the following recommendations. 
• 
For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, 
flushing, rash): 
• 
Decrease the rate of infusion until recovery from symptoms, remain at 
bedside and monitor patient. 
• 
Complete the ipilimumab infusion at the initial planned rate. 
• 
Diphenhydramine 50 mg IV or PO may be administered at the discretion 
of the treating physician and patients may receive additional doses with 
close monitoring. 
• 
Premedication with diphenhydramine may be given at the discretion of 
the investigator for subsequent doses of ipilimumab. 
• 
For moderate symptoms (any symptom not listed above [mild symptoms] or 
below [severe symptoms] such as generalized pruritus, flushing, rash, 
dyspnea, hypotension with systolic BP > 80 mmHg): 
• 
Interrupt ipilimumab. 
• 
Administer diphenhydramine 50 mg IV or PO. 
• 
Monitor patient closely until resolution of symptoms. 
• 
Corticosteroids may abrogate any beneficial immunologic effect, but may 
be administered at the discretion of the treating physician. 
• 
Resume ipilimumab infusion after recovery of symptoms. 
• 
At the discretion of the treating physician, ipilimumab infusion may be 
resumed at one half the initial infusion rate, then increased incrementally 
to the initial infusion rate. 
• 
If symptoms develop after resumption of the infusion, the infusion should 
be discontinued and no additional ipilimumab should be administered that 
day. 
• 
The next dose of ipilimumab will be administered at its next scheduled 
time and may be given with pre-medication (diphenhydramine and 
Rev. 11/16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
105 
acetaminophen) and careful monitoring, following the same treatment 
guidelines outlined above. 
• 
At the discretion of the treating physician additional oral or IV 
antihistamine may be administered prior to dosing with ipilimumab. 
• 
For severe symptoms (e.g., any reaction such as bronchospasm, generalized 
urticaria, systolic blood pressure  80 mm Hg, or angioedema): 
• 
Immediately discontinue infusion of ipilimumab, and disconnect infusion 
tubing from the subject. 
• 
Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or 
diphenhydramine 50 mg IV or PO, with solumedrol 100 mg IV, as needed. 
• 
Patients should be monitored until the investigator is comfortable that the 
symptoms will not recur. 
• 
No further ipilimumab will be administered. 
• 
In case of late-occurring hypersensitivity symptoms (e.g., appearance within 
one week after treatment of a localized or generalized pruritus), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids). 
5.7 
Prohibited and Restricted Therapies During the Study 
Concomitant systemic or local anti-cancer medications or treatments are 
prohibited in this study while receiving ipilimumab/nivolumab and/or 
dabrafenib/trametinib 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 
• 
Immunosuppressive agents (for Arms A and D). 
• 
Physiologic replacement doses of corticosteroids are permitted if required 
• 
Any non-oncology live vaccine therapies used for the prevention of infectious 
diseases (for up to 30 days prior to or after any dose of study drug) 
NOTE: 
Patients are permitted to receive the seasonal influenza vaccine. If 
seasonal influenza vaccine is considered, killed vaccines should 
be recommended. 
• 
Strong inhibitors or inducers of CYP3A4 or CYP2C8 (see Appendix XI) 
5.8 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
5.9 
Quality of Life Studies 
5.9.1 
Patient Reported Outcome Measures: PRO-CTCAE, PROMIS, EQ-5D 
Treatment-Related Symptoms & Toxicities: Due to a need for brief 
symptom-based PRO measures to assess unique side effects from 
ipilimumab + nivolumab and dabrafenib + trametinib with minimal 
participant burden, we propose administering items from the patient-
reported outcomes version of the common terminology criteria for 
adverse events. (PRO-CTCAE) 
Rev. 6/16 
Rev. 6/16 
Rev. 11/16 
Rev. 11/16 
Rev. 5/17 
Rev. Add10 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
106 
Based on provider feedback, 12 PRO-CTCAE toxicities have been 
selected to reflect the full range of toxicities experienced by patients 
undergoing these two treatments. The items selected are: rash, 
headache, joint pain, decreased appetite, nausea, diarrhea, fatigue, 
cough, itching, abdominal pain, shortness of breath, swelling. PRO-
CTCAE is not designed for comparisons and will be descriptive. We 
will report the number, frequency, and severity of toxicities if 
applicable. 
Functional Domains: Functional areas that may show long-term 
deficits due to treatment will be assessed using the PROMIS® Profile-
29. This standardized IRT-calibrated instrument contains the following 
measures: physical function, fatigue, pain interference, pain intensity, 
depression, anxiety, sleep disturbance, and social function. PROMIS 
item banks used to develop this profile have been extensively 
developed and tested.40, 41 PROMIS measures have exhibited strong 
construct validity when compared to existing PRO questionnaires in 
the domains of fatigue (FACT-Fatigue), pain (Brief Pain Inventory), 
sleep (Epworth Sleepiness Scale), and depression (CES-D).42 
Health Utility: The EQ-5D (5L) questionnaire will be used to elicit utility 
values from a societal perspective necessary for a quality adjusted 
time without symptoms of disease progression and toxicities of 
treatment (Q-TWiST) analysis. The EQ-5D (5L) brief preference-
based health status measure, which contains 5 health attributes: 
mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each attribute is measured by a question that has 
5 possible responses: no problem, slight problem, moderate problem, 
severe problem, or unable/extreme problem. The combination of 
responses results in 125 (55) possible health states. Prior research 
has developed a method for assigning a score between 0 and 1 to 
each across health states that represents an average US population 
preference for one state versus another.43 
Assessment schedule 
Initial Treatment (Arms A, B) 
• 
Baseline (at randomization or prior to the start of protocol 
treatment including Day 1 of cycle 1): PROMIS Profile-29, PRO-
CTCAE, EQ-5D (5L) 
• 
End of each treatment cycle (starting with cycle 1): PRO-CTCAE, 
EQ-5D (5L),  
• 
End of first treatment cycle (6 weeks, can be measured on Day 1 
of cycle 2): PRO-CTCAE, EQ-5D (5L), PROMIS Profile-29  
• 
End of second treatment cycle (3 months, can be measured on 
Day 1 of cycle 3): PRO-CTCAE, EQ-5D (5L), PROMIS Profile-29 
• 
Disease Stability (6 months; can be measured on Day 1 of cycle 
5): PRO-CTCAE, EQ-5D (5L), PROMIS Profile-29 
Long-Term Follow-up (for patients starting at least one dose of 
protocol treatment and not receiving any non-protocol therapy) 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
107 
regardless of still receiving any protocol treatment (All study arms, 
indexed to study entry) 
• 
EQ-5D (5L): every 3 months from study entry up to 2 years 
• 
PROMIS Profile-29: at 6 weeks, 3 months and 6 months from 
study entry, then every 6 months up to 2 years 
Ad-Hoc Assessments (End of Treatment in Each Step, Dose 
Modification) 
• 
End of Step 1 Treatment (before crossover, for any reason 
including Section 5.9.2.2): PROMIS Profile-29, PRO-CTCAE, EQ-
5D (5L) 
• 
End of Step 2 Treatment (after crossover, for any reason including 
Section 5.9.2.2): PROMIS Profile-29, PRO-CTCAE, EQ-5D (5L) 
• 
Dose Modification (Section 5.4): PRO-CTCAE, EQ-5D (5L) 
Second Treatment (Crossover, Arms C, D, indexed to second 
treatment)  
• 
Baseline (at randomization or prior to the start of protocol 
treatment including Day 1 of cycle 1): PROMIS Profile-29, PRO-
CTCAE, EQ-5D (5L) 
• 
End of each treatment cycle (starting with cycle 1): PRO-CTCAE, 
EQ-5D (5L) 
• 
End of first treatment cycle (6 weeks, can be measured on Day 1 
of cycle 2): PRO-CTCAE, EQ-5D (5L), PROMIS Profile-29  
• 
End of second treatment cycle (3 months, can be measured on 
Day 1 of cycle 3): PRO-CTCAE, EQ-5D (5L), PROMIS Profile-29 
• 
Disease Stability (6 months; can be measured on Day 1 of cycle 
5): PRO-CTCAE, EQ-5D (5L), PROMIS Profile-29 
Assessments 
We will conduct PRO assessments in regular, clinically informative 
intervals to evaluate short-term and long-term toxicities and functional 
impact for each treatment. We will assess all PROs at study 
randomization to provide the overall baseline scores to evaluate 
change across initial treatment, and long-term follow-up. We will 
evaluate treatment sequence by using the overall baseline 
assessment at randomization for treatment 1 and the initiation of 
treatment 2 (after progression and washout period) for baseline 
assessments. 
During initial and secondary treatment periods, we will measure 
patient-reported toxicities (PRO-CTCAE) and overall health (EQ-5D 
(5L)) at each clinical visit where adverse events (CTCAE) are 
evaluated. Broader measures of physical and mental function 
(PROMIS Profile-29) will be collected at important clinical points: at 
six weeks (end of cycle 1), three months (end of second cycle), and 6 
months (disease stability).  
We will conduct all long term follow-up assessments (regardless of 
still on study treatment given no non-protocol treatment has been 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
108 
administered) indexed to study entry every 3 months up to 2 years. 
EQ-5D (5L) assessments will be collected more frequently to coincide 
with the adverse events assessment (by CTCAE, every 3 months) 
until year 2. These additional assessments will be used to provide 
toxicity severity informing our primary 2-year PRO endpoint. 
Throughout the study period we will conduct additional ad-hoc 
assessments for the following situations that may occur: end of 
treatment in each step (before crossover and after crossover). We will 
administer PRO-CTCAE and EQ-5D (5L) at the start of all dose 
modifications (Section 5.3).  
End of step 1 treatment and subsequent enrollment into step 2 
treatment will trigger two assessments. One at the point end of step 1 
treatment is documented, and a separate assessment at the initiation 
of secondary treatment after washout (treatment 2 baseline). 
Assessments will also be administered at the point end of step 2 
treatment (after crossover) occurring within our follow-up window.  
We acknowledge that post-crossover assessments must be 
interpreted cautiously given that participants will crossover at different 
times and may have residual symptoms from the first treatment, 
despite washout. However, these assessments will allow us to identify 
an optimal sequence of the 2 therapies from the patient’s perspective. 
Following crossover, PROMIS Profile-29, PRO-CTCAE, EQ-5D (5L) 
will be administered following the same procedure as the initial 
treatment to month-6 allowing comparisons by treatment sequence. 
5.9.2 
Patient Reported Outcome Measures: Tobacco Use Assessment 
5.9.2.1 
Assessments 
Assessments will be captured directly from the participants 
using the EASEE-PRO portal. When patients consent to 
participate, they will be asked to provide a contact email 
address and that address along with their registration 
information will be sent directly from the parent trial’s 
registration system to EASEE-PRO, and the patient will be 
automatically registered into EASEE-PRO for participation. 
To activate their account for self-directed web entry of 
surveys, the system will send an activation message to the 
contact email address that will explain how to activate their 
account for self-directed web entry of surveys. After their 
account is activated, the patient will be able to complete 
questionnaires using a secure browser interface from any 
web enabled computer, tablet, or mobile device. 
The Core and Extension C-TUQ items will be assessed, 
together with patient-reported physical and psychological 
symptoms (See Table 2). Specifically, these items will be 
administered using the EASEE-PRO system described in 
the companion EA NCORP application. The advantage of 
our virtual electronic data capture system is that our 
proposed assessments will not be limited to, or dependent 
Rev. 5/17 
Rev. 5/17, 
10/17 
Rev. Add10 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
109 
upon, patient trial visits. Confidential and potentially 
stigmatizing information can be provided without requiring 
direct contact with the care team. 
The selected Core and Extension C-TUQ items (from 
categories of Basic Tobacco Use Information, Tobacco 
Use in Relation to Cancer Diagnosis and Treatment, 
Smoking Cessation/Cessation Products/Assistance 
Methods, Use of Other Products, and Second-Hand 
Smoke Exposure) will be assessed. The 4-item Short Form 
PROMIS® for anxiety and depression, the Lung Cancer 
Stigma Scale, and six symptom items (general pain, 
fatigue, nausea, cough, sleep difficulties, shortness of 
breath) from FACIT (Functional Assessment of Chronic 
Illness Therapy) together with modifications of these same 
six questions to address the degree of bother associated 
with each symptom will be administered as well. 
Additionally, we will ask participants’ perceptions of how 
smoking improves or worsens each of the six symptom 
experience. All these items will be compiled into Survey of 
Tobacco Use (STU). Detailed information on various 
measures is outlined in Appendix XIII. 
Contents and Corresponding Questions in Survey of 
Tobacco Use (STU) 
Dimension 
Source of Measures 
Baseline STU 
Follow-up 
STU 
Basic Tobacco Use Information 
C-TUQ 
Q1 – Q5 
Q1-Q2 
Tobacco Use in Relation to Cancer 
Diagnosis and Treatment 
C-TUQ 
Q6 – Q7 
Q3 
Smoking Cessation, Cessation 
Products, and Assistance Methods 
C-TUQ 
Q8 – Q13 
Q4-Q9 
Use of Other Products  
C-TUQ 
Q14 
Q10 
Second-Hand Smoke Exposure 
C-TUQ 
Q15-Q16 
Q11-Q12 
Psychological Symptoms 
PROMIS  
Lung Cancer Stigma Scale 
Q17-Q18 
Q13-Q14 
Physical Symptoms 
FACIT 
Q19 
Q15 
Sociodemographics 
 
Q20-21 
 
NOTE: 
In order to minimize ambiguity and assure that 
patients are oriented to answer appropriately, 
the specific phrasing of items may vary 
depending specific cancer type and treatment. 
5.9.2.2 
Assessment Schedule 
Survey of Tobacco Use will be administered at the 
following time points: 
• 
at baseline (trial enrollment) 
Rev. 5/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
110 
• 
at 3 month follow-up from study registration 
• 
at 6 month follow-up from study registration 
5.10 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
EA6134 Forms Packet.  
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered.  
• 
Patient progressed through both step 1 and step 2 study therapies 
5.11 
Duration of Follow-up  
Patients will be followed for disease status until documented disease 
progression, and for survival for 5 years after registration or until death, 
whichever occurs first. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
111 
6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors-RECIST  
For the purposes of this study, patients should be re-evaluated for response 
every 12 weeks. Confirmatory scans for tumor response should also be obtained 
6 weeks following initial documentation of objective response. In addition, 
patients with equivocal disease progression (e.g. a new lesion in the setting of 
major disease regression and the absence of or improvement in disease related 
symptoms and serum LDH) should have a scan confirming disease progression 
4-6 weeks following the initial scan showing RECIST defined PD. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the 
definitions stated below. 
NOTE: 
Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable. 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment. The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
112 
6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area might or might not be considered measurable. If the 
investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered 
must be defined in the protocol. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
113 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected.   
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
114 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
115 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
FDG-PET 
While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning 
to complement CT scanning in assessment of progression 
(particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following 
algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD. If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be 
the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a 
manner similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical 
literature for the indication. However, it must be acknowledged 
that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/sensitivity. 
NOTE: 
A ‘positive’ FDG-PET scan lesion means one which is 
FDG avid with an uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image. 
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. To be assigned a status of 
complete response, changes in tumor measurements must 
be confirmed by a repeat assessment performed no less 
than six weeks after the criteria for response is met. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
116 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. To be assigned a status of partial response, 
changes in tumor measurements must be confirmed by a 
repeat assessment performed no less than six weeks after 
the criteria for response is met. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered progression, See Section 
6.1.4.2. 
Patients with equivocal disease progression (e.g. a new 
lesion in the setting of major disease regression and the 
absence of or improvement in disease related symptoms 
and serum LDH) should have a scan confirming disease 
progression 4-6 weeks following the initial scan showing 
RECIST defined PD. Patients may continue on protocol 
therapy until repeat scan confirms PD. If repeat scan does 
not confirm PD, patients should proceed with treatment 
and evaluation as directed by the protocol with the 
confirmatory scan (if between 4 and 6 weeks from last 
scan) being counted as the 6 week interval scan. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 24_ weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
117 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or  
b) there is new pathological confirmation that it is disease 
(regardless of size). 
New effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
118 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the 
achievement of both measurement and confirmation 
criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
**** 
CR 
Non-CR/Non-PD*** 
No 
PR 
**** 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 24 wks from study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation.  
**** To be assigned a status of partial or complete response, changes in tumor measurements must be 
confirmed by a repeat assessment performed no less than six weeks after the criteria for response 
is met. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
6.1.4.5 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
119 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 24 weeks. 
6.1.4.6 
Additional Criteria to Continue Treatment after Progression 
Patients may continue on protocol therapy until repeat 
scan confirms PD. If repeat scan does not confirm PD, 
patients should proceed with treatment and evaluation as 
directed by the protocol with the confirmatory scan (if 
between 4 and 6 weeks from last scan) being counted as 
the 6 week interval scan. 
6.1.4.7 
Survival 
Survival will be measured from the date of randomization 
to death from any cause. 
6.1.4.8 
Time to Progression 
This interval will be measured from the date of 
randomization to the study to the appearance of new 
metastatic lesions or objective tumor progression. 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
120 
7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans must be performed within 4 weeks prior to randomization. 
2. Prestudy CBC (with differential and platelet count) should be done ≤ 4 weeks before randomization.  
3. All required prestudy chemistries, as outlined in Section 3, should be done ≤ 4 weeks before randomization – 
unless specifically required on Day 1 as per protocol.  
4. Day 1 tests (such as EKG, labs) may be done within (+/-) 72 hours of day 1 and restaging imaging within 7 days. 
5. It is recommended that patients on Arm A and D be contacted weekly during Cycles 1 and 2 and have weekly labs 
+/- exams if they report symptoms at any time during these Cycles or abnormal labs are noted at the reqularly 
scheduled visits (C1 Day 22, C2 D1 or D22). Weekly troponins will be obtained first 4 weeks on Arm A and D (see 
Footnote 16) 
7.1.1 
Schedule of events 
 
Step 1 
 
Step 2 
 
Baseline; all 
arms 
Arm A9, 2 
Arm B 
Crossover 
Arm C 
Arm D9, 2 
End of 
Treatment9 
Follow-
Up8 
 
Within 4 weeks 
prior to 
Randomization 
Induction, 
Cycles 1 
and 2: Day 
1 & 22 
Maintenance
, Cycles 3-
14: Day 1 
Day 1 of 
each  
Cycle 9 
Within 4 
weeks of 
Registration to 
Step 2 
Day 1 of 
each  
Cycle 9 
Induction, 
Cycles  
1 & 2: Day 1 
& 22 
Maintenance
, Cycle 3-14: 
Day 1 
 
 
BRAFV600 mutation7 
 
 
 
 
 
 
 
 
 
 
Medical History1 
X 
 
 
 
X 
 
 
 
 
 
Physical Exam/ ECOG PS1 
X 
X 
  X15 
X 
X 
X 
X 
  X15 
X 
X 
Serum or urine Pregnancy Test2 
X 
 
 
 
X 
 
 
 
 
 
Weight/Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology Labs4 
X 
X 
X15 
X 
X 
X 
 X 
  X15 
X 
X 
Chemistry Labs5, 14 
X 
X 
  X14 
X 
X 
X 
 X 
X14 
X 
X 
Troponin Screening16 
X16 
  X16 
 
 
X16 
 
X16 
 
 
 
Imaging Studies6 
 X6 
 
 X6 
 X6 
 
 X6 
 
 X6 
 
X6 
Skin assessment10 
X 
 
  X15 
  X10 
X 
  X10 
 
X15 
X 
 
Ophthalmologic examination11 
 
 
 
 
 
 
 
 
 
 
EKG18 
X 
 
 
X 
X 
X 
 
 
 
 
Rev. 12/15, 6/16 
Rev. 12/15, 6/16 
Rev. 11/16 
Rev. 11/16, 
2/17, 5/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
121 
 
Step 1 
 
Step 2 
 
Baseline; all 
arms 
Arm A9, 2 
Arm B 
Crossover 
Arm C 
Arm D9, 2 
End of 
Treatment9 
Follow-
Up8 
 
Within 4 weeks 
prior to 
Randomization 
Induction, 
Cycles 1 
and 2: Day 
1 & 22 
Maintenance
, Cycles 3-
14: Day 1 
Day 1 of 
each  
Cycle 9 
Within 4 
weeks of 
Registration to 
Step 2 
Day 1 of 
each  
Cycle 9 
Induction, 
Cycles  
1 & 2: Day 1 
& 22 
Maintenance
, Cycle 3-14: 
Day 1 
 
 
Cardiac Echo or MUGA to assess 
LVEF18 
X 
 
 
X17 
X 
X17 
 
 
X 
 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Pill Calendar12 
 
 
 
X 
 
X 
 
 
 
 
Biological Sample Submissions 
See Section 7.2 
PRO assessment13 
See Section 5.9 
1. Medical history documented during screening should include previous toxicities from prior therapies. If the screening physical is conducted 
within 24 hours of dosing on Day 1, then a single examination may count as both the Screening and pre-dose evaluation. There is a (+/-) 3 
day window for clinic visits and treatment. 
2. Women of child-bearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to randomization and again at 
crossover to Step 2 for screening purposes.  
3. Vital signs will be obtained during day 1 visit of each cycle, in the beginning of infusion and immediately after completion of infusion of 
ipilimumab and/or nivolumab. Vitals required are temperature, pulse, respiratory rate, blood pressure, and oxygen saturation. 
4. Hematology Labs should include CBC with differential (hemoglobin, hematocrit, white blood cells, platelets, neutrophils, lymphocytes, 
eosinophils and monocytes). Additional draws must be incorporated when monitoring recovery from any hematologic AE. 
5. Chemistry Labs should include albumin, amylase, lipase, BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, direct and total 
bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3, calcium, uric acid and CPK. Labs should also include TSH and free T4 if 
TSH is elevated.TSH is only required for Arms A and D. 
6. Non-CNS Imaging should include a chest, abdomen and pelvis CT. Imaging of other sites should be obtained when clinically indicated. (CNS 
Imaging at the time of PD is generally considered clinically indicated and therefore is encouraged at time of PD on all arms of the study). If 
follow up scans indicate partial or complete response, a repeat confirmatory scan should be obtained within 12 weeks (but no sooner than 6 
weeks). Following crossover, imaging and calendar will be reset at Cycle 1. Baseline imaging will be done within 4 weeks prior to registration, 
then every 12 weeks (+/- 1 week) from start of treatment (every 2 cycles) if patient is < 2 years from study entry (or < 2 years from crossover), 
then every 6 months (+/- 4 weeks) until 5 years from study entry. 
7. BRAF mutation status should be verified by CLIA approved assay prior to registration. Test must be done on primary or metastatic lesion from 
this particular melanoma. Patients with a history of multiple primary melanomas must have test performed on a metastatic lesion (lymph node 
or distant). 
Rev. Add10 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
122 
8. Every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry. Patients who develop 
melanoma progression will be followed for survival. Patients who stop treatment for reasons other than disease progression after 2.5 years 
from study entry will be followed every 3 months for a year (or until disease progression), then every six months until 5 years from study entry. 
9. 1 Cycle= 42 days (6 weeks) for all arms. Treatment and follow-up schedule is the same for either ipilimumab/nivolumab or 
dabrafenib/trametinib when administered as either initial treatment or at crossover. Patients receiving ipilimumab/nivolumab (either Arm A or 
Arm D) will receive treatment at most through cycle 14 (week 84). They will then have treatment stopped and be followed as described in 
footnote 8 until disease progression or study closure. An End of Treatment visit should occur 30 days (+/- 7 days) from last dose for all 
patients. For patients experiencing toxicities, End of Treatment visits should occur every 2 weeks (+/-3 days) until toxicities resolve. 
10. Skin assessments to examine for cutaneous SCCs. Suspicious lesions detected at baseline should be treated. Patients on 
dabrafenib/trametinib treatment should have a skin assessment follow-up every 6 weeks after initiating treatment. Skin assessments can be 
done by investigator with Dermatology backup if new lesions are noted. 
11. Ophthalmologic examination - Patients with visual complaints (eye irritation, blurred vision, etc) on either treatment approach should see an 
ophthalmologist to rule/out uveitis (ipilimumab/nivolumab) or evidence of retinal pathology that is considered a risk factor for neurosensory 
retinal detachment, RVO or neovascular macular degeneration (dabrafenib/trametinib). Ophthalmologic examination must be performed by a 
qualified eye specialist. Patients diagnosed with these problems should be managed as per criteria in Section 5.4. 
12. Pill calendars will only be used for patients receiving dabrafenib/trametinib. 
13. PRO Assessments will be administered according to the Assessment Schedule (Section 5.9.). 
14. Additional chemistry labs to include BUN, creatinine, ALT, AST, serum alkaline phosphatase, direct and total bilirubin and TSH every 2 weeks 
prior to nivolumab in patients on nivolumab monotherapy (C3-14 Arms A and D). Labs should also include free T4 if TSH is elevated. 
15. Day 1 of cycle 3-14 only. 
16. Obtain Troponin at baseline (only for patients on Arm A), at crossover (only for patients on Arm D), Cycle 1 Week 2, Cycle 1 Week 3, and 
Cycle 1 Week 4. 
17. Cardiac Echo or MUGA to be performed every 12 weeks (C3, D1, C5D1 etc) while on Arm B or Arm C. 
18. EKG and echocardiograms are required at baseline. They should be conducted as clinically indicated for any patients with a history of CHF or 
at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs for patients on Arm A and D. For patients with evidence 
of congestive heart failure (CHF), myocardial infarction (MI), cardiomyopathy, or myositis, further cardiac evaluation, lab tests and cardiology 
consultations, including EKG, CPK and troponin should be conducted as clinically indicated. 
 
Rev. Add10 
Rev. Add10 
Rev. Add14 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
123 
7.2 
Biological Sample Submissions 
Specimens are to be submitted as outlined in Section 10. 
All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). 
Biological Materials 
Prior to Start of 
Treatment 
Every Week for 
Patients with 
Grade 3-4 irAEs5 
Every Six (6) 
Weeks [initial 
and crossover] 
Time of 
Crossover 
Time of 
Progression 
Submit to: 
 
MANDATORY for Central Diagnostic Review 
Primary and Metastatic 
Tumor Tissue Biopsies 
(pretrial diagnostic 
material)1,2 
X 
 
 
CBPF 
From patients who answer “Yes” to “I agree to have my samples collected and I agree that my samples and related 
information may be used for the laboratory studies.”  
Peripheral Blood (five 
10cc green top heparin 
tubes)3,4 
X 
 
X 
X 
X 
IMCPL 
Peripheral Blood 
(two10cc red top tubes)3,4 
X 
X 
X 
X 
X 
Peripheral Blood (one 
10cc yellow top ACD 
tube)3,4 
X 
 
 
 
 
1. Representative primary and metastatic tumor tissue (blocks preferred) and related pathology reports must be submitted for 
central diagnostic review within one (1) month following registration as outlined in Section 10. Failure to submit the required 
materials may render the case unevaluable. 
2. Tumor tissue will also be used for defined laboratory research studies from patients who answer “Yes” to “I agree to have my 
samples collected and I agree that my samples and related information may be used for the laboratory studies.”   
3. Kits are being provided for the collection and shipment of the blood samples. See Section 10.3.1.1 for instructions. 
4. Please completely fill all blood tubes as full as possible. Blood samples should be shipped the day they are drawn. If you have 
any questions concerning sample collection and shipment, please contact the ECOG-ACRIN Study Coordinator at (412) 624-
0078 at the IMCPL. Note: Blood should NOT be collected and shipped on Fridays. 
5. Collect weekly for patients with grade 3-4 irAEs until the irAE resolves to grade 1 and then at the patients’ regularly scheduled 
visits until they are tapered off of immunosuppressive agents. 
Rev. 6/16 
Rev. 5/17 
Rev. Add10 
Rev. 12/15 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
124 
8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
Drug Ordering: GlaxoSmithKline is supplying dabrafenib and trametinib through the 
Division of Cancer Treatment and Diagnosis, NCI, for this protocol. Bristol-Myers Squibb 
is supplying nivolumab and ipilimumab through the Division of Cancer Treatment and 
Diagnosis, NCI, for this protocol. Maintenance of NCI drug accountability records is 
required. Agents 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). Active CTEP-registered 
investigators and investigator-designated shipping designees and ordering designees 
can submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status 
and a “current” password. 
NCI Supplied Agent(s) – General Information 
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 or email PMBAfterHours@mail.nih.gov 
anytime. 
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. A separate NCI Investigational Agent Accountability Record must be 
maintained for each agent on this protocol. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password. Questions about IB 
access may be directed to the PMB IB coordinator at IBCoordinator@mail.nih.gov 
8.1 
Ipilimumab 
In this study, ipilimumab is considered investigational. 
Rev. 5/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
125 
8.1.1 
Other Names  
Anti-CTLA-4 monoclonal antibody, MDX-010 (MDX-CTLA4, 
Transfectoma-derived), Yervoy® 
8.1.2 
Classification  
Human monoclonal antibody, IgG1 subclass 
M.W.: 147, 991 Daltons 
8.1.3 
Mode of Action  
Ipilimumab is specific for the CTLA4 antigen expressed on a subset of 
activated T-cells. CTLA4 interaction with the B7 molecule, one of its 
ligands expressed on professional antigen presenting cells, can down-
regulate T-cell response. Ipilimumab is, thought to act by blocking the 
interaction of CTLA4 with the B7 ligand, resulting in a blockade of the 
inhibitory effect of T-cell activation. The CTLA4/B7 creates the 
interaction. 
8.1.4 
Storage and Stability  
Ipilimumab must be stored in a secure area according to local 
regulations. The investigator must ensure that it is stored at a 
temperature between 2C to 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 2 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. Do not freeze. 
Shelf-life surveillance of the intact vials is ongoing. 
CAUTION: 
Ipilimumab does not contain antibacterial preservatives. 
Vials are for single use only. 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. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
126 
 
Process C 
Component 
200 mg/ viala 
Ipilimumab 
213 mg 
Sodium Chloride, USP  
249 mg 
TRIS-hydrochloride 
134.3 mg 
Diethylenetriamine pentacetic acid 
1.67 mg 
Mannitol, USP 
426 mg 
Polysorbate 80 (plant-derived) 
4.69 mg 
Sodium Hydroxide 
QS to pH 7 
Hydrochloric acid 
QS to pH 7 
Water for Injection 
QS: 42.6 mL 
Nitrogenb 
Processing agent 
a Includes 2.6 mL overfill.  
b Nitrogen is used to transfer the bulk solution through the pre-filled and 
sterilizing filters into the aseptic area. 
In 2023, PMB will transition to a 50 mg/10 mL (5 mg/mL) vial, which 
will replace the 200 mg vial. The 50 mg vial is packaged in a 10-cc 
Type I flint tubing glass vial, stoppered with a 20-mm gray butyl rubber 
stopper, and sealed with a 20-mm aluminum flip-off seal. Each vial 
includes a 0.7-mL overfill for vial, needle, and syringe (VNS) holdup. 
8.1.5 
Dose Specifics  
Calculate Total Dose as follows: 
Patient body weight in kg x 3 mg/kg (Regimen 1) or 1 mg/kg 
(Regimen 2) = total dose in mg 
Ipilimumab should be diluted with 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP to prepare a diluted solution with 
a final concentration ranging from 1 mg/mL to 2 mg/mL.  
The dosing calculations should be based on the actual body weight. If 
the patient’s weight on the day of dosing differs by > 10% from the 
weight used to calculate the original dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram. 
There will be no dose modifications allowed. 
8.1.6 
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 3 
mg/kg dose (Regimen 1) or 1 mg/kg dose (Regimen 2), to complete 
the infusion in 30-60 minutes, with a 3-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. 
Rev. 6/16 
Rev. Add14 
Rev. Add14 
Rev. Add25 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
127 
• 
Aseptically withdraw the required volume of ipilimumab solution 
into a syringe. Insert the needle at an angle into the ipilimumab 
vial by placing the needle – bevel side down – against the glass, 
with the tip touching the neck of the vial. The initial solution 
concentration is 5 mg/mL. [Note: A sufficient excess of ipilimumab 
is incorporated into each vial to account for withdrawal losses]. 
• 
Ensure that the ipilimumab solution is clear colorless, essentially 
free from particulate matter on visual inspection. If multiple vials 
are needed for a subject, it is important to use a separate sterile 
syringe and needle for each vial to prevent problems such as 
dulling of needle tip, stopper coring, repeated friction of plunger 
against syringe barrel wall, etc. 
• 
Inject ipilimumab solution withdrawn into an appropriate size 
evacuated infusion bag to produce a final infusion volume that has 
been calculated from the weight of the patient. For example, if 
preparing a 3mg/kg treatment for a 114 kg patient you will use 2 
vials of the 200 mg size (or 7 vials of the 50 mg vial size) for a 
dose of 342 mg. 
• 
Place the total dose in 106 – 277 mL of NS or D5W for a final 
concentration between 1 mg/mL and 2 mg/mL. 
• 
Mix by GENTLY inverting several times. DO NOT shake. 
• 
Visually inspect the final solution. If the initial diluted solution or 
final dilution for infusion is not clear or contents appear to contain 
precipitate, the solution should be discarded. 
• 
Do not draw into each vial more than once. Any partial vials 
should be safely discarded and should not be stored for reuse. 
8.1.7 
Route of Administration  
Ipilimumab is administered as an IV infusion only. Infusions should be 
given over 30- 90 minutes, dependent on institutional standard/policy, 
(not bolus or IV push). Ipilimumab should be administered under the 
supervision of a physician experienced in the use of intravenous (IV) 
agents. 
8.1.8 
Incompatibilities  
No compatibility information is available. 
8.1.9 
Availability  
Ipilimumab is available in 5 mg/mL single-use vials (40 mL). The 
sterile solution in the vial is clear and colorless. 
8.1.10 
Side Effects  
See the Comprehensive Adverse Events and Potential Risks List 
(CAEPR) in Section 5.3.1 for list of side effects 
8.1.11 
Nursing/Patient Implications  
Monitor patients for immune-related adverse events, e.g., rash/vitiligo, 
diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism. If you 
Rev. Add14 
Rev. Add16 
Rev. Add25 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
128 
suspect toxicity, refer to the protocol guidelines for ruling out other 
causes. 
Ipilimumab may be excreted in milk or cross the placenta; therefore, 
nursing women and women with known or suspected pregnancy 
should not take ipilimumab. 
Closely monitor patients who are on narcotics during the treatment 
with ipilimumab. 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. 
8.1.12 
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. 
8.1.13 
Ipilimumab Destruction 
Partial vials can be destroyed on site per institution policy. Intact vials 
of the expired drug, recalled, or when protocol is closed to treatment 
cannot be destroyed on site without the PMB/NCI approval. If 
ipilimumab is to be destroyed on site, it is the investigator’s 
responsibility to ensure that arrangements have been made for 
disposal and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and 
institutional procedures. Appropriate records of the disposal must be 
maintained. 
8.2 
Nivolumab (NSC748726) 
In this study, nivolumab is considered investigational. 
8.2.1 
Amino Acid Sequence: 4 polypeptide chains, which include 2 identical 
heavy chains with 440 amino acids and 2 identical light chains. 
8.2.2 
Other Names  
BMS-936558; MDX1106; ONO-4538; anti-PD-1 
8.2.3 
Classification  
Fully humanized monoclonal antibody 
8.2.4 
Mode of Action 
Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) 
antibody (HuMAb) that targets the programmed death – 1 (PD-1) cell 
surface membrane receptor. PD-1 is a negative regulatory molecule 
expressed by activated T and B lymphocytes. Binding of PD-1 to its 
Rev. Add16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
129 
predominant ligand, PD-L1, results in the down regulation of 
lymphocyte activation. Loss of effective immune response to antigens 
expressed by tumors may be a significant factor in tumor progression. 
PD-L1 expression has been found on a number of tumors & may also 
be a mechanism by which tumors can directly engage PD-1 to evade 
an  effective anti-tumor immune response. Inhibition of PD-1 
interaction with PD-L1 promotes immune responses and antigen 
specific T cell responses to both foreign antigens as well as self-
antigens. BMS-936558 was shown to promote the proliferation of 
human T-cells in a variety of assays, which is an anticipated 
pharmacologic result of PD-1 inhibition. 
8.2.5 
Description 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow 
liquid; light (few) particulates may be present. The drug product is a 
sterile, nonpyrogenic, single-use, isotonic aqueous solution 
formulated in sodium citrate dihydrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 
(Tween® 80), and water for injection. Dilute solutions of hydrochloric 
acid and/or sodium hydroxide may be used for pH adjustment (pH 
5.5-6.5). 
8.2.6 
How Supplied 
Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg 
vials (10 mg/mL) with a 0.7mL overfill. It is supplied in 10 mL type I 
flint glass vials, with fluoropolymer film-laminated rubber stoppers and 
aluminum seals. 
8.2.7 
Storage and Stability  
Vials of Nivolumab must be stored at 2-8°C (36-46°F); Protect from 
light, protect from freezing; Infusion – room temp: 8 hours max 
including infusion and up to 24 hours if refrigerated for the first 16 
hours. The unopened vials can be stored at room temperature (up to 
25°C, 77°F) and room light for up to 48 hours. 
If a storage temperature excursion is identified, promptly return 
Nivolumab to 2°C-8°C and quarantine the supplies. Provide a detailed 
report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Shelf-life surveillance of the intact vials is ongoing. 
The administration of undiluted and diluted solutions of Nivolumab 
must be completed within 24 hours of preparation. If not used 
immediately, the infusion solution may be stored up to 24 hours in a 
refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the 
total 24 hours can be at room temperature (up to 25°C, 77°F) and 
room light. The maximum 8-hour period under room temperature and 
room light conditions includes the product administration period. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
130 
CAUTION: The single-use dosage form contains no antibacterial 
preservative or bacteriostatic agent. Therefore, it is advised that the 
product be discarded 8 hours after initial entry. 
8.2.8 
Dose Specifics  
The dosing calculations should be based on the actual body weight. If 
the patient’s weight on the day of dosing differs by > 10% from the 
weight used to calculate the original dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram. 
There will be no dose modifications allowed. 
8.2.9 
Preparation  
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted 
with 0.9% Sodium Chloride Injection, USP or 5% Dextrose. When the 
dose is based on patient weight (i.e., mg/kg), nivolumab injection can 
be infused undiluted or diluted to protein concentrations as low as 
0.35 mg/mL. For patients weighing less than 40 kilograms (kg), the 
total volume of infusion must not exceed 4 mL per kg of patient 
weight. During drug product preparation and handling, vigorous 
mixing or shaking is to be avoided. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or 
polyolefin containers and infusion sets, and glass bottles. 
8.2.10 
Route of Administration  
Intravenous infusion over 30minutes using a volumetric pump with 0.2 
to 1.2 micron pre size, low-protein binding in-line filter. Should be 
administered ahead of ipilimumab on days when both to be 
administered. 
8.2.11 
Incompatibilities  
No incompatibilities between Nivolumab injection and polyolefin bags 
have been observed.  
8.2.12 
Side Effects  
See the Comprehensive Adverse Events and Potential Risks List 
(CAEPR) in Section 5.3.2 for list of side effects. 
8.2.13 
Nursing/Patient Implications  
Infuse over 30 minutes in a minimum of 60 ml infusion volume through 
a 0.2 to 1.2 micron in-line filter. 
Women of childbearing potential (WOCBP) receiving nivolumab must 
continue contraception for a period of 5 months after the last dose of 
nivolumab. 
Monitor carefully for infusion reactions and treat accordingly. 
8.2.14 
Handling and Disposal 
Use appropriate precaution for handling and disposal. 
8.2.15 
References  
LexiComp (2014), AHFS (2014) 
Rev. 6/16 
Rev. 6/16 
Rev. Add14 
Rev. Add14 
Rev. Add17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
131 
8.3 
Dabrafenib  
In this study, dabrafenib is considered investigational. 
8.3.1 
Other Names  
Tafinlar®, GSK2118436, GSK2118436A (free base) 
8.3.2 
Classification  
Antineoplastic Agent, BRAF Kinase Inhibitor 
8.3.3 
Mode of Action 
Dabrafenib mesylate (GSK2118436B) is a potent and selective BRAF 
kinase inhibitor. This inhibition suppresses downstream activity of 
pERK, a biomarker, and has anti proliferative activity against BRAF 
mutant tumors. The mode of action is consistent with ATP-competitive 
inhibition. The combination of dabrafenib and trametinib allows for 
greater inhibition of the MAPK pathway, resulting in BRAF V600 
melanoma cell death. 
Dabrafenib is metabolized by CYP 3A4 and 2C. It is a moderate 
inducer of CYP3A4 and possible inducer of other CYP isoenzymes 
(e.g., 2B6, 2C8, 2C9, 2C19). Dabrafenib is also a substrate of P-
glycoprotein (P-gp) and breast cancer resistance protein (BCRP). It is 
a moderate inhibitor of BCRP in vitro. Dabrafenib also inhibits organic 
anion-transporting polypeptides (OATP) 1B1 and 1B3 and organic 
anion transporters (OAT) 1 and 3 in vitro. It may induce uridine 
diphosphate glucuronosyltransferase (UGT). 
8.3.4 
How Supplied 
Dabrafenib mesylate (GSK2118436B) capsules are supplied by 
Novartis and distributed by the DCTD, NCI as 50 mg and 75 mg 
capsules (equivalent to the free-base) for oral administration. 
Each commercially-labeled bottle contains 120 capsules and a silica 
gel desiccant. 
• 
50 mg capsule is dark red and imprinted with ‘GS TEW’ and ‘50 
mg.’  
• 
75 mg capsule is dark pink and imprinted with ‘GS LHF’ and ‘75 
mg.’  
Capsule excipients include microcrystalline cellulose, magnesium 
stearate (vegetable source), and colloidal silicon dioxide. Capsule 
shells contain hypromellose, red iron oxide (E172), and titanium 
dioxide (E171). 
8.3.5 
Storage and Stability  
Store at 25°C (excursions between 15°C to 30°C are permitted). 
8.3.6 
Dose Specifics  
Patients randomized to receive dabrafenib 150mg PO BID 
continuously and trametinib 2mg PO once daily continuously before or 
after ipilimumab with nivolumab. 
Rev. 6/16 
Rev. 5/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
132 
8.3.7 
Route of Administration  
Dabrafenib is taken orally at least 1 hour before or 2 hours after a 
meal; doses should be approximately 12 hours apart. The capsules 
should not be opened, crushed, or broken. A food effect study showed 
that food may decrease the dabrafenib Cmax and AUC(0-∞) by 60% 
and 33%, respectively.   
When dabrafenib and trametinib are administered in combination, 
take the once-daily dose of trametinib at approximately the same time 
each day with either the morning dose or the evening dose of 
dabrafenib. The second dose of dabrafenib should be administered 
approximately 12 hours after the morning dose. Study medication 
should be taken orally with approximately 200 mL of water under 
fasting conditions, either 1 hour before or 2 hours after a meal.   
If a subject vomits after taking study medication, the subject should be 
instructed not to retake the dose and should take the next dose as 
originally scheduled.   
If administration of trametinib is interrupted or permanently 
discontinued, administration of dabrafenib may be continued. If 
administration of dabrafenib is interrupted or permanently 
discontinued, administration of trametinib may continue.  
If a subject misses a dose of dabrafenib, the subject may take the 
dose immediately if the next dose is scheduled for at least 6 hours 
later. If the next scheduled dose of dabrafenib is due in less than 6 
hours, the subject should skip the dose and resume dabrafenib dosing 
at the next scheduled dose. If a subject misses a dose of trametinib, 
the subject may take the dose immediately if the next dose is 
scheduled for at least 12 hours later. 
8.3.8 
Incompatibilities  
Potent inhibitors of CYP 3A4 or 2C8 have increased dabrafenib 
concentrations. Alternative therapy to potent inhibitors of CYP 3A4 or 
2C8 is recommended. If concomitant use is unavoidable, monitor 
patients closely for dabrafenib-associated adverse reactions. Potent 
inducers of CYP 3A4 or 2C8 have decreased dabrafenib 
concentrations. Alternative therapy to potent inducers of CYP 3A4 or 
2C8 is recommended. If concomitant use is unavoidable, monitor 
patients closely for reduced dabrafenib efficacy. 
Dabrafenib has the potential to decrease concentrations of CYP 3A4, 
2B6, 2C8, 2C9, 2C19 substrate drugs. Alternative therapy to the 
substrate drug is recommended. If concomitant use is unavoidable, 
monitor for reduced efficacy of the substrate drug. Also, dabrafenib 
has the potential to decrease the concentrations of UGT substrate 
drugs. Consider alternative therapy to the substrate drug. If 
concomitant use is unavoidable, monitor for reduced efficacy of 
substrate drug. 
Subjects should receive full supportive care during the study, 
including transfusions of blood and blood products, and treatment with 
Rev. 11/16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
133 
antibiotics, anti-emetics, anti-diarrheals, and analgesics, and other 
care as deemed appropriate, and in accordance with their institutional 
guidelines. Use of anticoagulants such as warfarin is permitted 
however, caution should be exercised and additional International 
Normalized Ratio (INR) monitoring is recommended when dabrafenib 
is used concomitantly with warfarin. 
The investigator must be informed as soon as possible about any 
medication taken from the time of screening until 30 days after the last 
dose of study treatment. Because there is a potential for interaction of 
dabrafenib with other concomitantly administered drugs through the 
cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies. The minimum requirement is that drug name, 
dose, and the dates of administration are to be recorded. Additionally, 
a complete list of all prior surgical procedures will be recorded in the 
eCRF. The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes.   
Specific Drug Interactions 
Antacid: Possible decreased dabrafenib concentrations; effect on 
dabrafenib efficacy is unknown 
Anticonvulsants (carbamazepine, phenobarbital, phenytoin: 
Possible decreased dabrafenib concentrations. Monitor closely for 
reduced dabrafenib efficacy. 
Clarithromycin: Possible increased dabrafenib concentrations. 
Monitor closely for dabrafenib-associated adverse effects 
Dexamethasone: Possible decreased dexamethasone 
concentrations and reduced efficacy. Alternative therapy to 
dexamethasone is recommended; if concomitant use is unavoidable, 
monitor closely for reduced dexamethasone efficacy. 
Gemfibrozil: Possible increased dabrafenib concentrations. Use 
alternative to gemfibrozil; if concomitant use is unavoidable, monitor 
closely for dabrafenib-associated adverse effects 
Histamine H2-receptor antagonists: Possible decreased dabrafenib 
concentrations; effect on dabrafenib efficacy is unknown. 
Hormonal contraceptives: Possible decreased estrogen/progestin 
concentrations and reduced efficacy. Advise females of childbearing 
potential to use alternative nonhormonal contraception during and for 
4 weeks after discontinuing dabrafenib therapy. If concomitant use is 
unavoidable, monitor closely for reduced hormonal  
Ketoconazole: Possible increased dabrafenib concentrations. Use 
alternative to ketoconazole; if concomitant use is unavoidable, monitor 
closely for dabrafenib-associated adverse effects. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
134 
Midazolam: Decreased midazolam concentrations. Use alternative to 
midazolam; if concomitant use is unavoidable, monitor closely for 
reduced midazolam efficacy. 
Nefazodone: Possible increased dabrafenib concentrations. Use 
alternative to nefazodone; if concomitant use is unavoidable, monitor 
closely for dabrafenib-associated adverse effects. 
Proton-pump inhibitors: Possible decreased dabrafenib 
concentrations; effect on dabrafenib efficacy is unknown 
Rifampin: Possible decreased dabrafenib concentrations. Use 
alternative to rifampin; if concomitant use is unavoidable, monitor 
closely for reduced dabrafenib efficacy. 
St. John’s wort: Possible decreased dabrafenib concentration. Use 
alternative to St. John's wort; if concomitant use is unavoidable, 
monitor closely for reduced dabrafenib efficacy. 
Warfarin: Possible decreased warfarin concentrations. Use 
alternative to warfarin; if concomitant use is unavoidable, monitor 
closely for reduced warfarin efficacy. 
Radiation skin injury has been reported with concurrent use of 
dabrafenib and radiation. If radiation therapy is administered, it is 
recommended that dabrafenib be held at least 24 hours before XRT is 
administered. 
8.3.9 
Side Effects  
See the Comprehensive Adverse Events and Potential Risks List 
(CAEPR) in Section 5.3.4 for list of side effects. 
8.3.10 
Nursing/Patient Implications  
Discuss specific use of drug and side effects with patient as it relates 
to treatment.  
Patient may experience alopecia, pachyderma, headache, arthralgia, 
myalgia, back pain, or constipation. Have patient report immediately 
to prescriber severe dizziness, syncope, urinary retention, 
hyperhidrosis, dehydration, wound healing impairment, skin changes, 
sudden vision changes, ophthalmalgia, eye irritation, or signs of 
hyperglycemia. 
Educate patient about signs of a significant reaction (e.g., wheezing; 
chest tightness; fever; itching; bad cough; blue skin color; seizures; or 
swelling of face, lips, tongue, or throat). 
In the case of overdose, patients should be treated symptomatically 
since there is no specific antidote. Hemodialysis is likely to be 
ineffective since dabrafenib mesylate is highly bound to plasma 
proteins. 
Patient should consult prescriber for additional questions. 
8.3.11 
Handling and Disposal 
Use appropriate precaution for handling and disposal. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
135 
8.3.12 
References  
LexiComp (2014), AHFS (2014) 
8.4 
Trametinib (NSC 763093) 
In this study, trametinib is considered investigational. 
8.4.1 
Other Names 
Trametinib, GSK1120212B, TMT212-NXA, JTP-74057, JTP-78296, 
JTP-75303, Mekinist® 
8.4.2 
Chemical Name  
Equimolecular combination of N-(3-{3-cyclopropyl-5-[(2-fluoro-4-
iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-
tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide with 
(methylsulfinyl)methane 
8.4.3 
Classification 
MEK inhibitor. 
8.4.4 
Molecular Formula  
C26H23FIN5O4  •  C2H6OS M.W.: 693.53 (dimethyl sulfoxide solvate), 
615.41 (anhydrous parent) 
8.4.5 
Approximate Solubility 
Trametinib dimethyl sulfoxide is almost insoluble in aqueous media at 
pH range of 2-8. 
8.4.6 
Mode of Action 
Trametinib dimethyl sulfoxide is a reversible, highly selective, 
allosteric inhibitor of mitogen-activated extracellular signal regulated 
kinase 1 (MEK1) and MEK2. Tumor cells commonly have 
hyperactivated extracellular signal-related kinase (ERK) pathways in 
which MEK is a critical component. Trametinib dimethyl sulfoxide 
inhibits activation of MEK by RAF kinases and MEK kinases. 
8.4.7 
Description 
Trametinib dimethyl sulfoxide is a white to almost white powder. 
8.4.8 
How Supplied 
Novartis supplies and CTEP, NCI, DCTD distributes trametinib as 0.5 
mg and 2 mg (as free base) tablets. Tablets may be provided in 
investigationally-labeled bottles or commercially-labeled bottles.  
The tablet core contains mannitol, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, magnesium stearate 
(vegetable source), colloidal silicon dioxide and sodium lauryl sulfate. 
The aqueous film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, iron oxide yellow (0.5 mg tablet), iron oxide red (2 
mg tablet) and polysorbate 80 (2 mg tablet). 
Rev. 6/16 
Rev. 5/17 
Rev. Add20 
Rev. Add20 
Rev. Add20 
Rev. Add20 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
136 
Each investigationally-labeled bottle contains 32 tablets with a 
desiccant: 
• 
0.5 mg tablets are yellow, modified oval, biconvex and film-coated.  
• 
2 mg tablets are pink, round, biconvex and film-coated. 
Each commercially-labeled bottle contains 30 tablets with a desiccant: 
• 
0.5 mg tablets are yellow, modified oval, biconvex, film-coated 
tablets with ‘GS’ debossed on one face and ‘TFC’ on the 
opposing face.  
• 
2 mg tablets are pink, round, biconvex, film-coated tablets with 
‘GS’ debossed on one face and ‘HMJ’ on the opposing face. 
8.4.9 
Storage and Stability 
Store tablets at 2°C -8°C (36° F to 46° F) in the original bottle and 
dispense unopened bottles. Do not repackage tablets or remove 
desiccant. Bottles should be protected from light and moisture.  
If a storage temperature excursion is identified, promptly return 
trametinib to 2°C -8°C and quarantine the supplies. Provide a detailed 
report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability studies are ongoing. Tablets are only stable for 32 days once 
bottle has been opened. If multiple bottles are dispensed to a patient 
in the same visit, please advise the patient to open only one bottle at 
a time. 
8.4.10 
Dose Specifics 
Patients randomized to receive trametinib 2mg PO once daily 
continuously and dabrafenib 150mg PO BID continuously before or 
after ipilimumab with nivolumab. 
8.4.11 
Route of Administration 
Oral. Take by mouth on an empty stomach, either 1 hour before or 2 
hours after a meal. If a dose of trametinib is missed, the dose can be 
taken if it is more than 12 hours until the next scheduled dose. 
See Section 8.3.7 for instructions when Dabrafenib + Trametinib are 
administered in combination. 
8.4.12 
Potential Drug Interactions 
In vitro studies suggest that trametinib is not a substrate of CYP 
enzymes or of human BCRP, MRP2, OATP1B1, OATP1B3, 
OATP2B1, OCT1 or MATE1 transporters. Trametinib elimination by 
deacetylation to metabolite M5 is dependent on carboxylesterases 
(CES1b, CES1c and CES2). Trametinib is a substrate for P-gp and 
BSEP, but this is not expected to be clinically relevant due to 
trametinib’s high permeability. 
Trametinib is an in vitro inhibitor of CYP 2C8 and is anticipated to 
have overall low potential for drug interactions as a perpetrator. It is 
Rev. 11/16 
Rev. Add20 
Rev. Add20 
Rev. Add20 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
137 
also a weak CYP 2B6 and 3A4 inducer and expected to have little 
clinical effect on sensitive substrates. Trametinib is not an inhibitor of 
CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4 and not an inhibitor of 
MRP2 or BSEP, but an in vitro inhibitor of P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, OCT2 and MATE1 at systemic 
concentrations that are not clinically relevant. No clinically relevant 
inhibition by trametinib is predicted in the liver or kidney and a low risk 
of intestinal drug-drug interaction is possible with BCRP.  
Trametinib is highly bound to plasma proteins (97.3%) and has the 
potential to interfere with other highly protein-bound drugs. Use 
caution in patients taking concomitant drugs that are highly protein-
bound and have narrow therapeutic ranges. 
Table 3: Trametinib drug interactions 
Interacting Drugs 
Description 
ARIPiprazole 
CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. 
Management: Double the oral aripiprazole dose and closely monitor clinical 
response. Reduce the oral aripiprazole dose to 10-15 mg/day if the inducer is 
discontinued. Avoid use of CYP3A4 inducers for more than 14 days with 
extended-release injectable aripiprazole. Consider therapy modification. 
Axitinib 
CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum 
concentration of Axitinib. Avoid combination. 
Dabrafenib 
Trametinib may enhance the adverse/toxic effect of Dabrafenib. Monitor therapy. 
Ibrutinib 
CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum 
concentration of Ibrutinib. Consider therapy modification. 
Saxagliptin 
CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Monitor 
therapy. 
Simeprevir 
CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum 
concentration of Simeprevir. Avoid combination. 
8.4.13 
Side Effects 
See the Comprehensive Adverse Events and Potential Risks List 
(CAEPR) in Section 5.3.3 for list of side effects. 
8.4.14 
Nursing/Patient Care Implications  
Trametinib should be taken on an empty stomach, at least 1 hour 
before or 2 hours after a meal/snack. Do not take a missed dose 
within 12 hours of the next dose. 
Advise women study participants of reproductive potential to use 
effective contraception while receiving study treatment and for 4 
months after the last dose of trametinib. Advise women not to 
breastfeed while receiving study treatment and for 4 months after the 
last dose of trametinib. Advise men study participants to use barrier 
contraception and not to father a child while taking study treatment 
and for 4 months after the last dose of trametinib. 
Rev. Add20 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
138 
9. 
Statistical Considerations 
9.1 
Study Design and Objectives 
In this randomized phase III study, patients with unresectable stage III or stage 
IV BRAFV600 mutant melanoma will be equally randomized to A: ipilimumab-
nivolumab (with subsequent dabrafenib in combination with trametinib) or B: 
dabrafenib in combination with trametinib (with subsequent ipilimumab-
nivolumab) using the stratification factors (ECOG PS, Serum LDH). The stratified 
randomization will be based on the permuted block method.   
The primary objective is to evaluate whether initial treatment with either 
combination ipilimumab-nivolumab (with subsequent dabrafenib in combination 
with trametinib) or dabrafenib in combination with trametinib (with subsequent 
ipilimumab-nivolumab) significantly improves 2 year overall survival. 
9.2 
Study Endpoints 
Overall Survival (OS) is defined as the time from randomization to death from 
any cause. Patients who have not died will be censored at the date of last known 
alive. 2-year OS rate will be defines as a proportion of patients who are alive 
after two years of follow-up time among all cases who have died within 2 years or 
alive after 2-year follow-up time.  
Progression-Free Survival (PFS) is defined as the time from randomization to 
disease progression or death (whichever occurs first). Cases without an event to 
date will be censored at the date of last disease assessment documenting the 
patient was free of progression. Progression will be evaluated based on 
international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) as described in Section 6.1. 
Response will be defined by the RECIST guidelines (version 1.1) as described in 
Section 6. 
Toxicity will be defined using the CTCAE version 4.0 criteria.  
9.3 
Sample Size Considerations and Monitoring Plan 
The primary comparison will be overall survival (OS) in arms A: ipilimumab-
nivolumab (with subsequent dabrafenib in combination with trametinib) vs. B: 
dabrafenib in combination with trametinib (with subsequent ipilimumab-
nivolumab). The primary endpoint for this study is the 2-year overall survival (OS) 
rate. Since the proportional hazard assumption is not appropriate for the 
proposed treatment arms, the most meaningful endpoint is the 2-year OS rate. 
The sample size calculation was conducted using the 2-year OS as a binary 
data. The primary analysis will be an ITT analysis based on the 2-year OS rate, 
using the Mantel-Haenszel test. The number of cases censored before two years 
is expected to be minimal in this study. 
The sample size for 2-year OS rate of 70 % in arm A vs. 50% in arm will be 270 
for 90% power. This is based on the two-sided type I error rate of 0.05 and allows 
for three interim analyses. An additional 10% (30 patients) have been added to 
cover for potential ineligibility or patient loss at the crossover time point. 
Assuming accrual rate of 16 (based on E2603/E1608 40/month and a 40% 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
139 
BRAFV600 mutation rate seen in E2603) accrual is estimated to take a maximum 
of 19 months. In addition, the follow-up time will be 2 years to assess the 2-year 
OS rate endpoint. Note that a clinically meaningful difference in 2-year OS rate is 
70% vs. 50%. This assumption was used for the above power calculation of 90%. 
However if there is slightly smaller difference, i.e. 67.5% vs. 50%, the proposed 
design still provides 80% power.  
Formal interim analysis based on the difference of 2-year OS rate between the 
two arms will be conducted, starting at 33% information time (that is when first 
100 patients enrolled are followed for 2 years). We expect this will be around 30 
months (2.52 years) after the study activates. After that, interim analysis will be 
repeated every 6 months. It is expected to be at 65% and 100% information time. 
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. Table 1 below summarizes 
operating characteristics of the proposed monitoring plan.  
This study will also be monitored for early stopping in favor of the null hypothesis 
based on the Jennison-Turnbull repeated confidence interval (RCI) approach. At 
each interim analysis, the difference in 2-year OS rates in arms A and B and 
variance will be estimated. The RCI on the difference in 2-year OS rates will be 
computed using the critical value from the error spending rate function and 
estimated variance. Strata will be taken into account for the RCI monitoring. If 
this RCI does not include the target alternative difference, then the study may be 
stopped early for lack of benefit.  
Table 1. Operating Characteristics of Interim Analyses 
Repeated 
Analyses 
Real Time 
(years) 
Total No. Of 
cases 2-yr OS 
assessed 
Information 
Time 
Upper 
Boundary 
Nominal 
Significance 
1 
2.52 
100 
.33 
3.7307 
0.954874E-
04 
2 
3.02 
196 
.65 
2.5498 
0.538891E-
02 
3 
3.56 
300 
1 
1.9903 
0.232812E-
01 
Starting from 1 year after activation and every 6 months subsequently, the 
following issues will also be discussed at the ECOG-ACRIN DSMC meeting. It is 
assumed that the hazard rates for OS will vary over the course of study. For the 
safety of patients, hazard ratios (HR) for OS will be monitored during the course 
of the study. Hazard functions for OS and HR for OS will be estimated. As an 
approximate guideline, the HR for OS < 0.75 or > 1.33 will prompt a discussion of 
the ECOG-ACRIN DSMC. The main purpose of monitoring is for the safety 
reason in earlier part of the study. When the formal interim analysis begins based 
on the 2-year OS rate (after 2.52 years), it is not likely this safety-based 
monitoring will indicate a conflicting result. However this issue will be reported 
and discussed at the ECOG-ACRIN DSMC. The ECOG-ACRIN DSMC will also 
monitor the feasibility of cross-over from one arm to the other and completing at 
least an initial course of treatment after cross-over. If less than 50% of patients 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
140 
can safely cross over from one therapy to this other, accrual will be halted and 
the feasibility of the alternative treatment schedules will be evaluated. 
9.4 
Statistical Analysis Plan 
The primary (2-year OS rate) and secondary efficacy (OS, 3-year OS rate) 
analyses will include all randomized patients (intent-to-treat analysis). Toxicity 
analysis will be based on all cases who received the treatment regardless of 
eligibility. 
The primary endpoint, 2-year OS rate will be estimated (proportion of patients 
alive after 2 years of follow-up time) and will be compared between the two arms 
using the Mantel-Haenszel test (stratified by ECOG PS and LDH) based on two-
sided overall type I error rate of 0.05 adjusting for two-interim analysis. Mantel-
Haenszel test will compare the 2-year OS rates while controlling for the 
stratification factors. The difference in 2-year OS rates in arms A and B will be 
estimated and presented with 95% repeated confidence interval of Jennison-
Turnbull. In addition, OS distribution will be estimated using the Kaplan-Meier 
method. The distribution of OS will be compared using the stratified log rank test. 
Hazard of OS will be estimated as a function of time in arm A and in arm B (as 
randomized in step 1 to arm A vs. B) and presented graphically. 
In PFS distribution will be estimated using the Kaplan-Meier method. 
PFS distributions will be compared using the log rank test and response rates will 
be compared using the Mantel-Haenszel test (stratified by ECOG PS and LDH) 
test in arms A vs. B. 3-year OS rate (proportion of patients alive after 3 years of 
follow-up) will be estimated by treatment arms and will be compared using the 
Mantel-Haenszel test (stratified by ECOG PS and LDH) in arms A vs. B. Cases 
censored before 3-year will not be included in this analysis, but this number is 
expected to be minimal. 
Response rate and PFS for patients who are treated with Ipilimumab/Nivolumab 
before crossover (arm A) vs. for patients who were initially treated with 
dabrafenib/trametinib and crossed over to Ipilimumab/Nivolumab will be 
compared (arm D). For the latter group, PFS will be defined as the time from 
cross-over until progression or deaths without progression. Tumor response will 
be assessed from the start of a particular therapy and baseline will be 
recalculated at time of cross over therapy. Patients without RECIST defined 
measurable disease at time of crossover will be excluded from the response 
assessment. Response rates will be compared using the Fisher’s exact test and 
PFS will be compared using the log-rank test. Safety profile of these two groups 
will also be compared using the Chi-square or Fisher’s exact test. Analyses 
specified in this paragraph will be repeated for arms B vs. C comparison. 
Toxicity rate for individual AEs, categorized AEs and worst degree AEs will be 
compared in arms A vs. B and in arms C vs.D using the Chi-square of Fisher’s 
exact test. Two-sided p-values will be reported for these comparisons. 
In the event of missing data, it will be assumed that the data will be missing at 
random and no imputation will be performed.  
Subset analyses are planned for all stratification factors (ECOG PS, LDH) and 
well known prognostic factors such as age, sex, ulceration, etc. Subset analyses 
are considered to be exploratory in nature. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
141 
9.5 
Sex and Ethnicity  
Based on previous data from E1608, E2603 the anticipated accrual in subgroups 
defined by sex and race is: 
Ethnic Category 
Sex 
Females 
Males 
Total 
Hispanic or Latino 
0 
1 
1 
Not Hispanic or Latino 
106 
193 
299 
Ethnic Category: Total of all subjects 
106 
194 
300 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
3 
0 
3 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
103 
194 
297 
Racial Category: Total of all subjects 
106 
194 
300 
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 
targets. 
9.6 
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 ECOG-ACRIN Operations Office – Boston. 
9.7 
Correlative Objectives 
Genetic associations with irAE status will be assessed using Fisher’s exact test, 
one-degree-of-freedom genotypic trend test (analogous to the Cochran-Armitage 
test) or the two-degrees-of-freedom chi-squared test of independence at each 
individual SNP marker. Tests of association will be adjusted for age, sex, center 
or clinical protocol, and dose as well as AJCC stage, ulceration, performance 
status, lactase dehydrogenase (LDH) level, number of involved sites, using 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
142 
logistic regression modeling assuming an additive genetic model. Within distinct 
genetic pathways or regions, P-values of individual SNP marker associations will 
be adjusted for multiple testing by controlling the false discovery rate (FDR).   
Analysis for survival outcomes will occur within the framework of Cox 
proportional hazards, although otherwise similar to analyses described above for 
irAEs. In addition to adjusting for age at diagnosis, sex, center, clinical trial and 
dose, adjustment for variables potentially associated with prognosis including 
AJCC stage, ulceration, performance status, lactase dehydrogenase (LDH) level, 
number of involved sites, will also be made. 
For replication phase irAE outcomes, the study has 80% power to detect a per-
allele RR of 2.90 or greater for SNP markers with a MAF of at least 0.10. For 
analysis of 2 year survival, the study has 80% power to detect a per-allele HR of 
1.83 or greater for SNP markers with a MAF of at least 0.10. These detectable 
measures of effect compare favorably to point estimates we found in our small 
preliminary study. 
9.8 
Patient Reported Outcomes (PROs) Objectives 
All enrolled patients will participate in the PROs component of the study. Only 
those who receive at least one dose of protocol treatment (i.e., all treated 
patients) will be included in the PROs analysis. 
Several objectives are proposed in the patient-reported outcomes (PROs) 
assessment study: (a) to compare quality-adjusted time without symptoms or 
toxicity at 2 years between initial treatments (i.e., arm A: ipilimumab + nivolumab 
(with subsequent dabrafenib + trametinib) vs. arm B: dabrafenib + trametinib 
(with subsequent ipilimumab + nivolumab)); (b) to compare overall function 
between initial treatment (i.e., arm A: ipilimumab- + nivolumab (with subsequent 
dabrafenib + trametinib) vs. arm B: dabrafenib + trametinib (with subsequent 
ipilimumab- + nivolumab) at baseline, weeks 6, 12, months 6, 12, 18, and 24 
from study entry); and (c) to assess function and patient-reported symptoms by 
treatment sequence for ipilimumab +nivolumab (arm A vs. D), and dabrafenib + 
trametinib, (arm B vs. C) at baseline, 6-, 12-weeks, and 6-months after the 
initiation of treatment in each step. 
9.8.1 
Statistical consideration for PROs  
The primary objective is to compare the overall clinical benefit 
between initial treatments (i.e., arm A: ipilimumab + nivolumab (with 
subsequent dabrafenib + trametinib) vs. arm B: dabrafenib + 
trametinib (with subsequent ipilimumab + nivolumab)), accounting for 
toxicities and overall survival. The quality-adjusted time without 
symptoms of disease progression or toxicity of treatment (Q-TWiST) 
analysis will be used to provide an integrated measure of quality and 
quantity of survival time. The Q-TWiST score based on overall 
survival at 2 years will be computed and compared, with the details of 
the Q-TWiST score described in the following section. A clinically 
important difference (CID) in the Q-TWiST score is recommended to 
be 10% of median survival in the control group.44 It is hypothesized in 
this trial that the 2-year OS rate is 70% for Arm A and 50% for Arm B, 
the CID for Q-TWiST is thus estimated to be 2.4 months in this study 
for the Q-TWiST power calculations. A standard deviation of 4.0 was 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
143 
estimated based on the difference of 1.5 months, together with its 
95% confidence interval of (-6.3, 9.3), in the duration of the TWiST 
state between high-risk melanoma patients receiving IFNα2b and 
those on observation.45 The table below lists the power, using an 
independent-sample t-test with a two-sided type I error of 0.05, based 
on various projected standard deviation in the Q-TWiST score 
assuming different number of patients in each comparison arm. As 
shown in the table, with 135 patients in each group (as proposed for 
the 2-year OS primary endpoint), we have 80% power to detect a CID 
of 2.4 months in the Q-TWiST score with a standard deviation of 7 in 
the Q-TWiST score. The power drops to 50% with 135 patients in one 
group and a standard deviation of 10 in the Q-TWiST score. We 
acknowledge that the actual standard deviation of the Q-TWiST score 
could be quite a bit different here because the variance of the Q-
TWiST score will depend on the joint distribution of the 5 restricted 
mean estimates, which will depend on the actual distributions, as well 
as on the utility weights for the different states.  
Clinically 
Important 
Difference 
Standard 
Deviation 
N  
(per group) 
Power 
2.4 
5 
135 
97 
2.4 
6 
135 
90 
2.4 
7 
135 
80 
2.4 
8 
135 
69 
2.4 
9 
135 
58 
2.4 
10 
135 
50 
2.4 
5 
120 
95 
2.4 
6 
120 
86 
2.4 
7 
120 
75 
2.4 
8 
120 
63 
2.4 
9 
120 
53 
2.4 
10 
120 
45 
9.8.2 
Analysis plan for PROs 
Primary Q-TWiST Analysis. Due to the complexity of the current 
study (with the subsequent treatment after disease progression on the 
initial treatment), the basic 3-state Q-TWiST model is extended to a 5-
state model in order to calculate the Q-TWiST score. For each initial 
treatment group, overall survival will be partitioned into five distinct 
clinical health states as listed below:  
• 
TOX1: Toxicity with initial treatment (during step 1) is defined as 
the time spent with grade 3 or 4 toxicities prior to disease 
progression on the initial treatment. The start and end date for 
each adverse event will be captured. A day with multiple qualifying 
adverse events will only be counted once. For patients with severe 
toxicities reported in step 1 but no end date reported, TOX1 will be 
capped at the date of disease progression in step 1 or death 
without progression. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
144 
• 
TWiST1: Time without symptoms of disease progression or 
toxicity of initial treatment is defined as the number of days in step 
1 prior to disease progression and with no grade 3 or 4 toxicities 
reported. Specifically, this is the time from study entry to disease 
progression on the initial treatment or death without progression, 
minus TOX1.  
• 
TOX2: This toxicity period is defined as the time spent with grade 
3 or 4 toxicities after disease progression on the initial treatment 
(in step 1) and prior to 2nd disease progression on the 
subsequent treatment (in step 2). The start and end date for each 
adverse event will be captured. A day with multiple qualifying 
adverse events will only be counted once. For patients with severe 
toxicities reported during this period but no end date reported, 
TOX2 will be capped at the date of disease progression on the 
subsequent treatment or death without progression.  
• 
TWiST2: Time without symptoms of 2nd disease progression or 
toxicity of subsequent treatment is defined as the number of days 
after disease progression on the initial treatment and prior to the 
2nd disease progression on the subsequent treatment and with no 
grade 3 or 4 toxicities experienced during this time period. 
Specifically, this is the time from 1st disease progression to 2nd 
disease progression or death without progression, minus TOX2.  
• 
PROG: This progression health state is defined as the time from 
the last disease progression on the study to death from any 
cause. 
The above health states are progressive, but it is not required for all 
patients to go through all the 5 states. For example, for patients 
without disease progression on the initial treatment, they will not enter 
TOX2, TWiST2, and PROG states. 
The Q-TWiST score is obtained by summing the weighted clinical 
health state durations. The Q-TWiST score for each treatment arm will 
be calculated using the following formula: 
where uTOX1, uTWiST1, uTOX2, uTWiST2, uPROG represent the average group 
utility weight for each health state for that arm; TOX1, TWiST1, TOX2, 
TWiST2, and PROG represent the mean duration of the health state 
of that arm .  
In the Q-TWiST analysis, each health state is assigned a weight 
ranging from 0 (representing death) to 1 (indicating perfect health). 
These weights are called utility scores as well. For each patient, EQ-
5D will be administered multiple times (at baseline, at each cycle 
while during the initial and subsequent treatment period, then every 3 
months up to 2 years from study entry if patients are off protocol 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
145 
treatment and not receiving non-protocol therapy, at end of treatment 
in each step (before and after crossover), and at dose modification) 
and its score will be used to derive the utility score. In this study, the 
utility score is conditional on the patient-reported health state on the 5 
dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) captured in EQ-5D. A number ranging from 1 to 5 
will be assigned to each level in each of the 5 dimensions. A patient’s 
health state thus can be labeled using a 5-number descriptor ranging 
from 11111 to 55555. A utility score corresponding to each possible 
descriptor elicited from general population samples (by country) was 
provided in the file “EQ-5D-5L_Crosswalk value sets” posted in the 
website of www.euroqol.org.46 We are going to use the value set 
elicited from US subjects for our patients in this study. For instance, a 
health state with a descriptor of “11111” is given a utility score of 
1.000, “12111” is assigned a utility value of 0.854, and “43333” is with 
a utility score of 0.573. 
The average EQ-5D utility score for a patient’s individual health state 
will be computed across all utility scores collected during that health 
state. For instance, EQ-5D scores for all visits during which a grade 3 
or 4 adverse event is reported before the patient experiences disease 
progression on initial treatment will be averaged to form that patient’s 
TOX1 utility score. All EQ-5D scores for visits without either grade 3 
or 4 adverse events or disease progression on initial treatment will be 
averaged to form the patient’s TWiST1 utility score. Similar definition 
and computation apply for TOX2 and TWiST2 with respect to the 
subsequent treatment. All EQ-5D scores for visits after last disease 
progression will be averaged to form that patient’s PROG utility score. 
For each health state, the average group utility score is the mean of 
that health state within each treatment arm. 
The restricted mean amount of time for each health state will be 
estimated using the Kaplan-Meier method, with time limit set at 2 
years for computation of all restricted means. The duration of each 
health state is defined as follows: 
• 
Mean duration of TWiST1 = mean PFS1 – mean TOX1, 
• 
Mean duration of TWiST2 = mean PFS2 – mean TOX2, 
• 
Mean duration of PROG = mean OS – mean PFS2, 
where PFS1 is defined as the time from study entry to the first disease 
progression on the initial treatment. For patients alive without first 
disease progression, PFS1 will be censored at the date of last 
disease evaluation in step 1. PFS2 is defined as the time from study 
entry to the second disease progression on the subsequent treatment 
(in step 2). For patients enrolled into step 2, if they are alive without 
disease progression in step 2, PFS2 will be censored at the date of 
last disease evaluation in step 2. For patients not enrolled into step 2, 
PFS2 will be censored at the date of last disease evaluation in step 1. 
OS is defined as the time from study entry to death from any cause, 
censored at the date of last contact. TOX1 is defined as the days 
spent with grade 3 or 4 toxicities prior to disease progression on the 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
146 
initial treatment (in step 1). For patients with severe toxicities reported 
in step 1 but no end date reported, TOX1 will be capped at the date of 
disease progression in step 1 or death without progression. TOX2 is 
defined as the number of days with grade 3 or 4 toxicities reported 
after the first disease progression on the initial treatment (in step 1) 
and prior to the second disease progression on the subsequent 
treatment (in step 2). For patients with severe toxicities reported 
during this period but no end date reported, TOX2 will be capped at 
the date of disease progression on the subsequent treatment or death 
without progression. For patients not receiving the subsequent 
treatment, TOX2 is counted as 0. 
There are a couple of special notes for this expanded Q-TWiST 
analysis. If patients die during an early state and EQ-5D is not 
administered thereafter, the utility score in each of subsequent states 
will be defined as 0. If patients withdraw or lost to follow-up during an 
earlier state, the utility score in subsequent states will be assigned 0.. 
Finally, since Q-TWiST is being computed for 2 years in this study, 
once the duration of earlier states reach 2 years, the utility score 
collected in subsequent states will be used for these patients in the 2-
year Q-TWiST analysis.  
The mean amount of time for each health state and the average group 
utility scores will be summarized by initial treatment (i.e., arm A: 
ipilimumab + nivolumab (with subsequent dabrafenib + trametinib) vs. 
arm B: dabrafenib + trametinib (with subsequent ipilimumab + 
nivolumab)). The Q-TWiST subscore and the overall Q-TWiST score 
will then be reported by initial treatment. Differences between 
treatment groups in the mean Q-TWiST score (including the overall 
score and the subscore) will be calculated. For each score, a 95% 
confidence interval (CI) and two-sided P-value for testing the null 
hypothesis of no difference between treatment groups will be 
conducted using a Z-test (with normal approximation), with standard 
errors calculated by the bootstrap method. The bootstrap will be 
performed by repeated sampling, with replacement, from the sample 
of patients enrolled in this study, to obtain a new sample. The means 
for the new sample will be calculated using the same method as 
described above. This process will be repeated 1000 times. Based on 
the means obtained by the bootstrap method, the standard errors can 
be calculated. 
Due to the multiple assessment timepoints for EQ-5D (at baseline, at 
each cycle while during the initial and subsequent treatment period, 
then every 3 months up to 2 years from study entry if patients are off 
protocol treatment and not receiving non-protocol therapy, at end of 
treatment in each step (before and after crossover), and at dose 
modification), we do not expect too many patients that reach a state 
but do not get any EQ-5D evaluation for the utility calculations. If this 
indeed occurs, it suggests that the reached state is rather short. For 
the primary Q-TWiST analysis, we assume these data will be missing 
at random then compute the average group utility weight for each 
health state based on patients with nonmissing data on the reached 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
147 
states. If more than 20% of the cases have missing data, with respect 
to any reached health state, a sensitivity analysis will be performed 
with missing utility scores on a reached state being replaced by the 
average EQ-5D utility score from these patients’ preceding health 
state. In case of discrepancies between the primary analysis and the 
sensitivity analysis, possible explanations will be discussed. 
Secondary PRO Analysis. Overall function will be assessed (at 
baseline, weeks 6 (end of cycle 1), weeks 12 (end of cycle 2), and 
months 6 (disease stability)) while during the initial and subsequent 
treatment period (at 6-week, 12-week, months 6, 12, 18, and 24 from 
study entry (even off study treatment)) using PROMIS PROFILE-29. 
This instrument, consists of 7 short forms (Depression, Anxiety, 
Physical Function, Pain Interference, Fatigue, Sleep Disturbance, and 
Ability to Participate in Social Roles and Activities, with 4 items in 
each short form) together with one Pain Intensity item. Each item has 
five response options ranging in value from 1 to 5, except for the Pain 
Intensity item which has eleven response options ranging in value 
from 0 to 10. A raw score can be computed for each short form by 
summing the values of the response to each question within each 
domain. 
The total raw score for each short form can then be converted into a 
standardized T-score with a mean of 50 and a standard deviation of 
10. As to the Pain Intensity item, the raw response (0-10) can be used 
directly in data analyses. 
Given differential attrition might exist in the two treatment groups and 
a high level of missing data is expected toward the end of the two-
year PRO period with advanced melanoma patients (2-year OS rate 
expected to be 70% vs. 50% for arm A and arm B, respectively), a 
log-normal survival model will be implemented to adjust for potentially 
informatively censored data, using the expectation-maximization (EM) 
algorithm, as describled in Schluchter (1992).47 A log-normal survival 
model for analyzinag longitudinal data (collected at baseline, 6-week, 
12-week, months 6, 12, 18, and 24 from study entry) which 
incorporates the non-ignorable censoring mechanism will be fitted for 
each short form T-score and pain intensity, separately, to assess 
initial treatment effect (i.e., arm A: ipilimumab + nivolumab (with 
subsequent dabrafenib + trametinib) vs. arm B: dabrafenib + 
trametinib (with subsequent ipilimumab + nivolumab)) on each 
function. 
To evaluate the effect of treatment sequence on patient function, each 
of the PROMIS short form T-score and pain intensity (with longitudinal 
data collected at baseline, 6-, 12-weeks, and 6-months after the 
initiation of treatment in each step) will be compared by treatment 
sequence for ipilimumab + nivolumab (arm A vs. D) and for 
dabrafenib + trametinib (arm B vs. C), using a log-normal survival 
model as described above. 
PRO-CTCAE consisting of 17 symptoms (rash, headache, muscle 
pain, joint pain, decreased appetite, nausea, vomiting, constipation, 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
148 
diarrhea, fatigue, cough, chills, itching, abdominal pain, shortness of 
breath, swelling, and increased sweating) will be administered 
multiple times (at baseline, at each subsequent cycle while during the 
initial and subsequent treatment period, at end of treatment in each 
step (before crossover and after crossover), and at dose 
modification). 
PRO-CTCAE measures, if applicable, patient-reported presence (yes 
or no), frequency (never, rarely, occasionally, frequently, or almost 
constantly) and severity (none, mild, moderate, severe, very severe) 
on each of the specified symptoms. To evaluate the effect of 
treatment sequence on symptoms, summary statistics (frequency (N) 
and percentage (%)) will be reported with respect to presence, 
frequency and severity (if applicable) for each symptom by treatment 
sequence for ipilimumab + nivolumab (arm A vs. D), and for 
dabrafenib + trametinib (arm B vs. C) at baseline, 6-, 12-weeks, and 
6-months after the initiation of the first treatment and the secondary 
treatment. 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
149 
10. 
Biological Sample Submissions 
Diagnostic material from previously collected tissue must be submitted for central 
diagnostic review and retention of a portion for defined immune biomarker assays and 
future undefined research studies such as PDL-1 and other bio-markers (per patient 
consent). Peripheral blood is to be submitted from consenting patients for defined 
laboratory research studies. 
It is required that all samples submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (see Section 10.4). An STS shipping manifest 
form is to be included with every submission. 
All samples must be labeled clearly with the ECOG-ACRIN protocol number (EA6134), 
ECOG-ACRIN patient sequence number, patient’s initials, date of collection and sample 
type. 
10.1 
Sample Collection and Submission Schedule 
Samples are to be submitted as follows: 
• 
Pretrial diagnostic pathology samples must be submitted within one (1) month 
of registration. See Section 10.2. 
• 
Peripheral blood samples are to be submitted as outlined in Section 10.3 on 
the day of collection. Samples are to be collected at the following time points 
for each tube type: 
• 
Prior to start of treatment (yellow top at baseline only) 
• 
Every week for patients with grade 3 or 4 irAEs until the irAE resolves to 
grade 1 and then at the patients’ regularly scheduled vistis until they are 
tapered off 
• 
Every six (6) weeks (initial and crossover) 
• 
Time of Crossover 
• 
Time of Progression 
10.2 
Submissions to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF) 
Submitting pathologist and clinical research associate may refer to Appendix I 
which outlines the Pathology Submission Guidelines. Submission of pretrial 
diagnostic pathology samples from all patients is mandatory. Failure to submit 
the required materials may render the patient’s data unevaluable.  
The tissue samples are to be labeled with the Pathology ID as well as the 
information above. 
10.2.1 
Required Materials 
Forms: Must be submitted with all tissue submissions. 
• 
STS generated shipping manifest form 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
completed. Please identify the clinical status of the submitted 
material (i.e., pretreatment as opposed to remission and relapse). 
• 
Copy of the pathology report 
Rev. 6/16 
Rev. Add10 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
150 
Pathological Material Submission: 
• 
Representative diagnostic FFPE primary and metastatic tumor 
tissue blocks 
NOTE: 
If a block is unavailable for submission, cores and slides 
are to be submitted. All cores and slides must be 
adequately labeled, with slides numbered sequentially in 
the order cut. Alternative submission per tissue availability: 
• 
One (1) H&E slide from each source block, and 
• 
Ten (10) - twenty (20) 5 µm unstained, uncharged, air-
dried plus slides from the thickest part of the tumor, 
and 
• 
One (1) or more core punches (minimum of 4mm 
diameter). If core punch tool is unavailable, request 
core punch kit from the ECOG-ACRIN CBPF 1-844-
744-2420. Adequately label every slide and core 
submitted. 
If these criteria cannot be met, please contact the ECOG-ACRIN 
Central Biorepository and Pathology Facility (CBPF) 
(eacbpf@mdanderson.org) to obtain alternative submission 
requirements. 
10.2.2 
Shipping Procedures 
Pathology materials are to be shipped at ambient temperature within 
one (1) month following patient registration.  
Ship using the CBPF’s FedEx account using the FedEx on-line ship 
manager. 
Ship to: 
MD Anderson Cancer Center CBPF 
Mike Balco 
Life Science Plaza - Suite 910 
2130 West Holcombe Boulevard, LSP9.4227 
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 
Access to the FedEx shipping account for shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained 
by logging onto fedex.com with an account issued by the ECOG-
ACRIN CBPF. For security reasons, the account number will no 
longer be 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 
Pretrial diagnostic pathology materials will be forwarded to Dr. Brent 
Harris for central review. 
Rev. 6/16 
Rev. Add10 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
151 
10.3 
Submissions to Immunologic Monitoring and Cellular Products Laboratory 
(IMCPL) 
Blood samples should be shipped the day they are drawn. If you have any 
questions concerning sample collection and shipment, please contact the ECOG-
ACRIN Study Coordinator at (412) 624-0078 at the IMCPL. 
NOTE: 
Blood should NOT be collected or shipped on Fridays. 
Instructions to order kits are outlined in Section 10.3.1.1. 
Submit from patients who answer “Yes” to “I agree to have my samples collected 
and I agree that my samples and related information may be used for the 
laboratory studies described above.”  
10.3.1 
Sample Preparation Guidelines 
Please completely fill all blood tubes as full as possible and 
collect the correct number and tube type as outlined below. 
Each tube must be clearly labeled to include: 
• 
ECOG-ACRIN protocol number EA6134 
• 
ECOG-ACRIN five-digit patient sequence number 
• 
Patient initials 
• 
Originating institution/investigator name  
• 
Date and time drawn 
• 
Collection time point 
At EACH time point please submit the following: 
• 
TWO (2) FULL 10 cc RED top tubes (BD cat #367820 or SST 
367988 gel separator/gold top/tiger tubes if the center can 
centrifuge them) 
• 
Five (5) FULL 10 cc GREEN top heparin tubes (BD cat # 366480) 
At Prior to Start of Treatment ONLY please submit the following: 
• 
One (1) FULL 10 cc YELLOW top ACD tube (BD cat # 364606) 
10.3.1.1 
Shipping Kits  
Shipping kits are available to order for the collection of the 
blood samples, and will contain the supplies and 
instructions for collecting, processing, and shipping the 
samples. To order kits please fax the request using the 
Shipping Kit Request Facsimile Form (Appendix VII) to 
(412) 623-6625 or call the IMCPL at (412) 624-0078. 
Please allow ten (10) 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. 
Rev. 6/16 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
152 
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 
10.3.2 
Shipping Procedures 
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) and the red and 
yellow top 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 1.31 
ECOG-ACRIN Study Coordinator 
Hillman Cancer Center 
5117 Centre Avenue, L 1.31 
Pittsburgh, PA 15213 
Tel: (412) 624-0078 
FAX: (412) 623-6625 
Federal Guidelines for the Shipment of Blood Products: Sites should 
follow IATA regulations for Packaging UN3372 shipments. Please 
refer to FedEx guidelines. 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.  
10.4 
ECOG-ACRIN Sample Tracking System  
It is required that all specimens 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 specimens 
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 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
153 
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 shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@ecog-acrin.org. 
Study Specific Notes 
Generic Specimen Submission Form (#2981v2) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. For specimen 
submissions to the IMCPL, notify the ECOG-ACRIN Study Coordinator by FAX 
(412) 623-6625 using the Specimen Shipment Requisition Form (Appendix VIII). 
If you are unable to get through to the laboratory by FAX, telephone the ECOG-
ACRIN Study Coordinator at (412) 624-0078 and provide the tracking number. 
Indicate the appropriate Lab ID# on the submission form: 
• 
ECOG-ACRIN CBPF 
• 
0009= ECOG-ACRIN Immunologic Monitoring and Cellular Products 
Laboratory 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.5 
Use of Specimens in Research 
Pathological materials will be distributed to investigators for central diagnostic 
review and immune bio-marker studies. 
Specimens from patients who consented to allow their specimens to be used for 
future ECOG-ACRIN approved research studies, including residuals from the 
mandatory diagnostic review, will be retained in an ECOG-ACRIN designated 
central repository. 
For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility and the ECOG-ACRIN Immunologic 
Monitoring and Cellular Products Laboratory.  
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microarrays (TMAs). DNA, 
RNA, serum, and plasma (if appropriate) will be isolated from the submitted 
peripheral blood specimens. 
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 specimens will be 
removed from consideration for use in any future research study. Pathology 
materials may be retained for documentation purposes or returned to the site. All 
other specimens will be destroyed per guidelines of the respective repository. 
Rev. Add10 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
154 
10.6 
Sample Inventory Submission Guidelines  
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of samples forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office - Boston. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
155 
11. 
Correlative Studies 
The results of these studies are for the purposes of the trial only and will not be returned 
to the site or reported to the patient. 
11.1 
Pathology Review (MANDATORY) 
The appropriate representative tumor tissue samples will be forwarded to Brent 
Harris, MD, PhD for central diagnostic review and classification to confirm the 
diagnosis. This is done as a retrospective review to determine the evaluability of 
the patient’s data for analysis and to classify the tumor for analysis in the 
secondary aims. The results of the review are for the purposes of the trial only 
and will not be returned to the site. 
11.2 
Association of Inherited Variation with Immune Mediated Adverse Events and 
Response to Ipilimumab/Nivolumab 
11.2.1 
Correlative Study Design:  
From all patients prior to receiving treatment on each arm of the 
study, buffy coats will be extracted from venous bloods and stored. 
Stored buffy coats will be shipped in batches on dry ice to the 
laboratory of Dr. Katherine Nathanson at the University of 
Pennsylvania for isolation of germline DNA and subsequent 
genotyping.   
ECOG-ACRIN data items listed below will be requested for the 
analyses at University of Pennsylvania. The focus will be on the 
ipi/nivo treatment either as initial therapy or administered following 
dabrafenib/trametinib resistance. Measures of irAEs will include any 
irAE grade 3 or higher (yes/no); any gastrointestinal irAE (e.g. 
diarrhea, colitis; yes/no), any hepatic irAE (e.g. hepatitis, abnormal 
liver function tests; yes/no), any endocrine irAE (e.g. hypophysitis, 
hypopituitarism, yes/no) and any other irAE (yes/no)]. Information for 
survival outcomes will include duration of follow-up post treatment, 
vital status at time of last follow-up, and cause of censoring (death 
due to disease or otherwise), from which measures of survival status 
at one year (alive/dead/censored) and two years 
(alive/dead/censored) post treatment will be derived. Information on 
tumor response (complete remission/partial remission/stable 
disease/progressive disease) at 6 months will also be provided. 
Additional data on clinical covariates including sex, race/ethnicity, age 
at diagnosis, AJCC stage, ulceration (no/yes/unknown), performance 
status, LDH (normal/elevated), number of involved sites (1, 2-3, ≥4) 
and number of prior therapies will be requested. 
11.2.2 
Specific Hypotheses: 
Multiple lines of evidence suggest that inherited genetic variation may 
play a role in response to immunotherapies, such as ipilimumab, but 
also in the development of irAEs. To address the hypothesis that 
inherited variation is a determinant of both response and irAEs, the 
University of Pennsylvania investigators have identified patients 
Rev. Add10 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
156 
treated on ipilimumab clinical trials from 10 academic contributing 
sites, two ECOG-ACRIN clinical trials and Bristol-Myers Squibb for a 
total of 716 and 1035 patients treated with 3mg/kg and 10mg/kg, 
respectively. We propose to determine the association of inherited 
variation with 1) irAEs and 2) overall survival at 1 and 2 years. In a 
discovery phase, we will perform candidate-based gene and pathway 
analyses of genes involved in lymphocyte activation, cytokines, 
cytokine receptors and within the MHC region, as well as an agnostic 
genome-wide SNP-based approach to discover novel genetic markers 
associated with our outcomes of interest. In a replication phase, we 
will replicate our findings in an independent sample set. 
The aims of the whole project are described below. Biosamples and 
clinical information provided from EA6134 will contribute to the 
replication/validation step (Aim 3 below) for which a total of 950 
melanoma patients treated with ipilimumab containing regimens are 
anticipated. It is expected that 210 of 300 patients from EA6134 will 
participate in Aim 3. 
Aim 1: To determine the association of inherited genetic variation and 
immune-associated adverse events in patients with metastatic 
melanoma treated with ipilimumab containing regimens by 
completing: Aim 1a: Candidate-based gene and pathway analyses of 
genes involved in lymphocyte activation, cytokines, cytokine receptors 
and within the MHC region. 
Aim 1b: An agnostic genome-wide SNP-based approach. 
Aim 2: To investigate the association between inherited genetics and 
survival in patients with metastatic melanoma treated with ipilimumab 
containing regimens by completing. 
Aim 2a: Candidate-based gene and pathway analyses of genes 
involved in lymphocyte activation, cytokines, cytokine receptors and 
within the MHC region. 
Aim 2b: An agnostic genome-wide SNP-based approach. 
Aim 3: To replicate genomic markers identified in Aims 1 and 2 in an 
independent sample set of patients treated with ipilimumab containing 
regimens and preliminary characterize their potential functional role. 
Aim 3a: Replication of variation identified in Aims 1 and 2 as 
associated with irAEs and survival. 
Aim 3b: Bioinformatic assessment of genomic markers. 
11.2.3 
Background: 
Response to ipilimumab therapy can be quite durable with 24-30% of 
patients being alive at two years following treatment initiation; 
however, treatment with ipilimumab is associated with significant rates 
of immune related adverse events. Preliminary data from the 
ipilimumab/nivolumab combination suggests that response rates are 
greater and the responses occur more quickly and are more robust. 
Similarly, the irAEs associated with ipilimumab occur to a similar 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
157 
extent with the ipi/nivo combination but can be more rapid and severe. 
It is therefore crucial to delineate both those at highest risk of irAEs 
and those that will most benefit from therapy with ipilimumab +/- 
nivolumab in order to direct this therapy to those most likely to receive 
benefit and avoid side effects and/or inform management. Of 
particular importance is identifying those patients who are unlikely to 
respond to the ipilimumab +/- nivolumab, who might be better treated 
with alternative agents or enrolled on other clinical trials. The lack of 
biomarkers (which includes genetic polymorphisms) for 
immunotherapies is well recognized, despite substantial efforts to 
date. As inherited polymorphisms do not vary and if they can serve as 
biomarkers, immune monitoring could be circumvented. 
The genetic association study proposed by the University of 
Pennsylvania group is the first step in the identification of potential 
biomarkers. Multiple lines of evidence from other chemo- and 
immunotherapies as well from ipilimumab treatment, demonstrate the 
importance of inherited genetic variation to response and adverse 
events. Studies focusing on bevacizumab in breast and colorectal 
cancers have identified single nucleotide polymorphisms (SNPs) 
associated with a 60-90% increased overall survival; and 
polymorphisms in immunoglobin G fragment C receptor (FcγRIIa), 
which plays a role in antibody-dependent cellular cytotoxicity, have 
been associated with response rates for cetuximab in colorectal 
cancer, trastuzumab in breast cancer, and rituximab in follicular 
lymphoma. Importantly, SNPs in and haplotypes of CTLA4 itself have 
been shown to be strongly associated (odds ratio (OR) 4.1, 95% 
confidence interval (CI) 1.2, 15 for the risk haplotype) with complete 
and partial response to treatment with ipilimumab in 152 patients with 
metastatic melanoma 
 
A preliminary genome-wide association study of irAE and outcome for 
patients treated with ipilimumab was completed. DNA from 73 patients 
with resected stage IIIc/IV melanoma (25) treated with either 3 mg/kg 
(approximately 33% of patients) or 10 mg/kg ipilimumab at the H. Lee 
Moffitt Cancer Center was genotyped on the Illumina Human660W-
Quad BeadChip. After quality control filters, the final sample set from 
MSKCC consisted of DNA from 44 melanoma patients. Because of 
differences in the definition of irAE (grade 2 and higher requiring 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
158 
treatment vs. any grade 3 and higher) and types of patients (resected 
vs. non-resectable) between the two patient sets, samples from Moffitt 
were used to identify novel genetic associations (i.e. discovery phase) 
and samples from MSKCC were used to independently confirm 
observed top association (i.e. replication phase). In both sample sets, 
SNP markers with a call rate <0.98 were excluded from analysis. 
 
The most significant observed associations for irAE were for 
rs2466176 (P = 1.25 x 10-6; OR = 4.84), rs416011 (P = 4.24 x 10-6, 
OR = 3.85) and rs375071 (P = 6.97 x 10-6; OR = 3.70) (Figure 1). 
rs2466176 maps to an intronic region of PEBP4, while rs375071 and 
rs2466176 are two closely-clustered SNP markers at 8q21.3 located 
between CNBD1 and DCAF4L2. Although associations did not reach 
genome-wide significance in this small sample set, the strength of the 
observed associations were quite impressive.   
For response, two outcomes were examined 1) disease-free survival 
at the time of last follow-up; and (2) overall survival at time of last 
follow-up. Post-treatment follow-up at the time of analysis ranged from 
seven to 69 months. For relapse, the most statistically significant 
result (P = 4.32 x 106, OR = 3.6) was at rs6046009 in an intron 
SLC24A3, a plasma membrane sodium/potassium/calcium exchanger 
(Figure 2). In total, eight SNP markers at this locus had P values  
< 1 x 10-4 and were ranked within the top 50 hits. We observed the 
association with rs6046009 both in the Moffitt and MSKCC sample 
sets, suggesting that the association is not being driven by differences 
in a study-specific manner, i.e. by differences in outcome definition or 
individual treatment regimens. Additional loci on chromosomes 8, 15, 
and 16 have more than 2 SNP markers that surpassed a significance 
threshold of P < 1 x 10-4. Our preliminary data provide evidence that 
we will successfully identify novel genetic markers associated with 
ipilimumab-induced irAE and response. 
11.2.4 
Statistical Design: 
Genetic associations with irAE status will be assessed using Fisher’s 
exact test, one-degree-of-freedom genotypic trend test (analogous to 
the Cochran-Armitage test) or the two-degrees-of-freedom chi-
squared test of independence at each individual SNP marker. Tests of 
association will be adjusted for age, sex, center or clinical protocol, 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
159 
and dose as well as AJCC stage, ulceration, performance status, 
lactase dehydrogenase (LDH) level, number of involved sites, BRAF 
mutation status (when available) and number of prior therapies using 
logistic regression modeling assuming an additive genetic model. 
Within distinct genetic pathways or regions, P-values of individual 
SNP marker associations will be adjusted for multiple testing by 
controlling the false discovery rate (FDR).   
Analysis for survival outcomes will occur within the framework of Cox 
proportional hazards analysis, otherwise similar to analyses described 
above for irAEs. In addition to adjusting for age at diagnosis, sex, 
center, clinical trial and dose, adjustment for variables potentially 
associated with prognosis including AJCC stage, ulceration, 
performance status, lactase dehydrogenase (LDH) level, number of 
involved sites, BRAF/NRAS/WT tumor mutation status, and number of 
prior therapies will also be made. 
Study Power: For replication phase irAE outcomes, the study has 
80% power to detect a per-allele RR of 2.90 or greater for SNP 
markers with a MAF of at least 0.10. For analysis of 2 year survival, 
the study has 80% power to detect a per-allele HR of 1.83 or greater 
for SNP markers with a MAF of at least 0.10. These detectable 
measures of effect compare favorably to point estimates we found in 
our small preliminary study. 
11.3 
Evaluation of the Utility of Circulating BRAF Levels in Determining the Response 
and Resistance to Either BRAF Directed and/or Immunotherapy in Patients with 
BRAF Mutant Melanoma 
11.3.1 
Correlative Study Design: 
To define the dynamic and kinetic effects of systemic therapy on 
peripheral blood BRAFV600 mutation detection, we will test isolated 
PBL and serum from samples obtained from patients prior to receiving 
treatment on each arm of the study. As part of trial eligibility, patients 
will have been previously identified as being positive for a BRAFV600 
mutation based on the results of the testing of their tumor tissue 
(either primary tumor or nodal/systemic metastasis) in a CLIA-
approved laboratory for BRAFV600 sequencing analysis. Heparinized 
blood will be collected on each patient at baseline and every 6 weeks 
on both initial and crossover therapy and at the time of both RECIST 
defined progression and crossover to the alternative therapy. Blood 
samples will be shipped overnight at room temperature to the ECOG-
ACRIN melanoma immunotherapy laboratory at the Pittsburgh Cancer 
Institute for ficoll to isolate PBMC. Samples will be labeled and stored 
at minus 80 for batch analysis. 
11.3.2 
Specific Hypotheses: 
a) To determine if changes in blood BRAF levels utilizing peripheral 
blood BRAFV600 mutational testing in patients with Stage IV BRAF 
mutant melanoma correlate with response and resistance to 
combination BRAF/MEK directed therapy.  

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
160 
b) To determine if changes in blood BRAF levels utilizing peripheral 
blood BRAFV600 mutational testing in patients with Stage IV BRAF 
mutant melanoma correlate with response and resistance to 
combination immunotherapy.  
c) To compare the kinetics of peripheral blood BRAFV600 levels 
during response and resistance in groups of patients receiving 
BRAF targeted therapy or combination immunotherapy as initial 
therapy.  
d) To compare the kinetics of peripheral blood BRAFV600 levels 
during response and resistance to combination BRAF targeted 
therapy or combination immunotherapy in individual patients 
(initial treatment vs. crossover treatment). 
11.3.3 
Background: 
 
Sullivan, Panka and colleagues have developed and optimized an RT-
PCR-based technique that takes advantage of an unique restriction 
enzyme site present in wild-type (WT) but not the mutant BRAF to 
enrich the sample for the mutant form initially and then inserts a 
restriction site into the mutant but not WT BRAF to allow for detection 
and quantification of mutant BRAF.1 As outlined in our original 
description of this technique1 and the second generation assay the 
protocol (Figure 1A) involves a series of PCR amplifications and 
restriction digestions that discriminate between WT and mutant BRAF 
at amino acid position 600. An initial RT-PCR is followed by digestion 
with TspR1 that preferentially digests the WT product but not the 
BRAFV600 PCR product. A second PCR using nested PCR primers 
with the digested 1st round PCR product as template follows. This 
PCR product may be subjected to sequencing using a nested 
oligonucleotide (Figure 1B), however, since the TspR1 digestion does 
not lead to complete elimination of WT BRAF, this PCR product is 
then subjected to a second TspR1 digest to further enrich for mutant 
BRAFV600. Next, Real-Time PCR is performed on the second TspR1 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
161 
digest product using primers designed to amplify BRAFV600E. Purified 
first round PCR product with a known concentration is run through the 
assay along with test samples and is used to create a standard curve 
with each batched analysis of patient samples (Figure 1C). Using the 
standard curve the amount of end product is determined and 
BRAFV600E levels are determined. 
 
In practice, the assay is highly sensitive and specific when used to 
analyze isolated PBMCs from patients with Stage IV melanoma. In 
particular, the sensitivity and specificity of the assay, using a cut off 
for positivity of 10 pg, is 93% and 100%, respectively (Figure 2A 
shows the box plot of BRAF values in patients with melanoma and 
known tissue BRAF status or people without melanoma). The average 
BRAF level in stage IV melanoma patients with tissue confirmed 
BRAF mutation is higher than the average BRAF level in patients with 
Stage II and III patients who have a positive blood BRAF level using 
the cutoff of ≥ 10 pg (Figure 2B), suggesting that the assay may 
reflect tumor burden. Lastly, when patients on BRAF inhibitor therapy 
were followed with serial sampling, the assay is reflective of disease 
response and disease progression. Specifically, BRAF levels 
generally reduce with treatment initiation and then increase at the time 
of or, in many cases, prior to radiographic progression. 
 
A first generation peripheral blood BRAF assay had been utilized to 
follow serial circulating BRAF levels in several patients treated with 
either vemurafenib or the combination of dabrafenib with trametinib. In 
each patient, who had a known BRAF mutation detected in tissue 
from a CLIA approved laboratory, peripheral blood BRAF levels were 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
162 
detected and reduced more profoundly and durably with dabrafenib 
plus trametinib therapy than it did with single-agent vemurafenib 
(Figure 3); similar findings to a randomized Phase II study of single-
agent dabrafenib versus the combination of dabrafenib and trametinib. 
Further, this reduction in blood BRAFV600 level correlated with disease 
response on imaging, and more importantly, the blood BRAFV600 level 
has risen to at least double the nadir in 5 of the 7 patients in whom we 
had serial blood draws from baseline to time of progression. Figure 4 
charts the blood BRAF values of four representative patients. In 
patients PLX-004 and MAB212 (A&B), levels rose well in advance of 
progression imaging (42 and 57 days, respectively). In patient MGH-
MEL2 (C), the BRAF level oscillated until patient had maximal tumor 
response and remained stable even in the presence of CNS 
recurrence, a sign that disease in the CNS may not shed mutant 
BRAF as readily in the blood. Lastly, patient MGH-MEL5 (D) 
represents an interesting case of a patient with a known double 
mutant, BRAFV600E and BRAFV600K, whose blood BRAF level falls 
throughout treatment, though he then progresses. Since one of the 
limitations of our assay is that it only measures BRAFV600E levels, it is 
likely that his progressing disease was dominated by BRAFV600K; a 
subtype of BRAF mutant melanoma that is associated with less 
profound and durable responses to BRAF-directed therapy. These 
results suggest that BRAF levels determined via our assay effectively 
reflects dynamics in tumor volume and might be an early predictor of 
non-CNS, disease progression in patients treated with BRAFV600E 
melanoma on BRAF-directed therapy.  
 
11.3.4 
Statistical Design: 
Aim 2a: The change in blood BRAF levels between week 12 (after 
initiation of therapy) and baseline (before BRAF/MEK therapy begins) 
will be used. It is expected a total of 250 patients (150 first-line 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
163 
dabrafenib/trametinib and 100 second-line dabrafenib/trametinib 
treated) will be included in this analysis. Of these, we hypothesize 
50% will have a favorable outcome (CR+PR and their blood BRAF 
level will decrease at least by 50% from the baseline value. The 
change in blood BRAF level between week 12 and baseline will be 
compared among patients with favorable outcome vs. no favorable 
outcome (SD or PD). Two-sample t-test will be used to compare the 
changes in the blood BRAF levels among responders (n=125) and 
non-responders (n=125). If the standardized difference is 1.38, there 
will be 85% power. This is based on a two-sided type I error rate of 
0.05. If the normality assumption is not appropriate, Wilcoxon rank-
sum test will be used in the analysis. 
For assessment of association with resistance, the change in blood 
BRAF level on the most recent test done prior to documentation of 
RECIST defined disease progression on CT scan relative to the nadir 
level will be used. It is expected that a total of 200 patients (125 first-
line dabraf/tramet and 75 second-line dabraf/tramet treated) will be 
included in this analysis. Of these we hypothesize that pre-
progression samples will show a 50% increase from the nadir sample. 
The changes from the nadir sample will be summarized using the 
descriptive statistics. Also the proportion of patients who had at least 
50% increase will be summarized. With a sample size of 200, 95% 
confidence interval will not be wider than 14%.  
Aim 2b: The change in blood BRAF levels between week 12 (after 
initiation of therapy) and baseline (before BRAF/MEK therapy begins) 
will be used. It is expected a total of 250 patients (150 first-line ipi/nivo 
and 100 second-line ipi/nivo treated) will be included in this analysis. 
Of these, we hypothesize 5% will have a favorable outcome (CR+PR) 
and their blood BRAF level will decrease at least by 50% from the 
baseline value. The change in blood BRAF level between week 12 
and baseline will be compared among patients with favorable 
outcome vs. no favorable outcome (SD or PD). Two-sample t-test will 
be used to compare the changes in the blood BRAF levels among 
responders (n=135) and non-responders (n=115). If the standardized 
difference is 1.38, there will be 85% power. This is based on a two-
sided type I error rate of 0.05. If the normality assumption is not 
appropriate, Wilcoxon rank-sum test will be used in the analysis. 
For assessment of association with resistance, the change in blood 
BRAF level on the most recent test done prior to documentation of 
RECIST defined disease progression on CT scan relative to the nadir 
level will be used. It is expected that a total of 200 patients (125 first-
line dabraf/tramet and 75 second-line dabraf/tramet treated) will be 
included in this analysis. Of these we hypothesize that pre-
progression samples will show a 50% increase from the nadir sample. 
The changes from the nadir sample will be summarized using the 
descriptive statistics. Also the proportion of patients who had at least 
50% increase will be summarized. With a sample size of 200, 95% 
confidence interval will not be wider than 14%.  

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
164 
Aim 2c: Similar analyses as described under 2a/2b will be conducted 
in 150 patients with first-line therapy and 100 patients with second-line 
therapy in each group.   
Aim 2d: The change in blood BRAF levels between week 12 and 
baseline will be compared between 150 patients receiving the first-line 
immune therapy vs.150 patients receiving the first-line targeted 
therapy (at the time of response and progression as described in 
2a/2b). A similar comparison will be made among 100 patients 
receiving second-line immune therapy vs. 100 patients receiving the 
second-line targeted therapy (at the time of response and progression 
as described in 2a/2b).   
11.4 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secure data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
165 
12. 
Electronic Data Capture 
Please refer to the EA6134 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed in Medidata Rave and EASEE-PRO (for 
tobacco use assessment). 
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. Siegel et al. Cancer Statistics, 2011. CA Cancer J Clin. 2011; 61:212-236. 
2. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med 2010; 363: 711-23. 
3. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma.  N Engl J Med 2011;  364(26):2517-26 
4. Schadendorf D, et al. Eur J Cancer 2013; 49(suppl 2): abstract 24LBA]. 
5. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and 
brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012; 13:459. 
6. Shababi V et al Cancer Immunol Immunother 2012, 61:733-37 
7. Simeone E. et al Proc ASCO 2013 Abstract no.  
8. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med  2013 369(2):122-33 
9. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced 
melanoma treated with vemurafenib. N Engl J Med 2012; 366:707 
Rev. 5/17 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
166 
10. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic 
melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 
2012; 380:358. 
11. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Engl J Med 2011, 364:2507-2516. 
12. Chapman PB, et al. Updated overall survival (OS) results for BRIM-3, a phase III 
randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib 
(vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-
mutated melanoma. J Clin Oncol 2012. 
13. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in 
melanoma with BRAF V600 mutations. N Engl J Med 2012; 367:1694. 
14. Ackerman A, Klein O, McDermott DF et al Outcomes of patients with metastatic 
melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014  
(Epub ahead of print)  
15. Ascierto PA, Simeone E, Sileni VC et al Sequential Treatment with Ipilimumab and 
BRAF Inhibitors in Patients with Metastatic Melanoma: Data from the Italian Cohort 
of the Ipilimumab Expanded Access Program. Cancer Invest 2014: 32(4):149-9 
16. Wolchok JD, Weber JS, Hamid O, et al  Ipilimumab efficacy and safety in patients 
with advanced melanoma: a retrospective analysis of HLA subtype from four trials. J 
Cancer Immun. 2010;10:9. 
17. Wolchok JD, Hoos A, O'Day S, et al  Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 
2009;15(23):7412. 
18. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443. 
19. Topalian SL, Sznol M, McDermott DF et al. Survival, durable tumor remission and 
long-term safety in patients with advanced melanoma receiving nivolumab J Clin 
Oncol 2014 32(10):1020-30. 
20. Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, 
randomized trial: Dabrafenib versus dacarbazine in patients with BRAF V600E-
positive mutation metastatic melanoma Proc  ASCO 2013, Abstract no. xx 
21. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in 
BRAF-mutated melanoma. N Engl J Med 2012; 367:107. 
22. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by 
BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-
4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL) 
(abstract LBA9003). 2014 American Society of Clinical Oncology (ASCO) meeting. 
23. Long GV, Stroyakovsky DL, Gogas H, et al. COMBI-d: A randomized, double-
blinded, Phase III study comparing the combination of dabrafenib and trametinib to 
dabrafenib and trametinib placebo as first-line therapy in patients (pts) with 
unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma 
(abstract 9011).. 2014 American Society of Clinical Oncology meeting 
24. Hodi FS, Sznol M, Kluger HM, et al. Long-term survival of ipilimumab-naive patients 
(pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-
936558, ONO-4538) in a phase I trial (abstract 9002). 2014 American Society of 
Clinical Oncology (ASCO) meeting. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
167 
25. Flaherty K, Daud A, Weber J, Updated Overall Survival for BRF113220: 
A Phase 1-2 study of dabrafenib alone vs. combined dabrafenib and trametinib in 
patients with BRAF V600 mutation-positive metastatic melanoma  (Abstract 90xx). 
2014 American Society of Clinical Oncology (ASCO) meeting. 
26. Panka DJ, Sullivan RJ, Mier JW: An inexpensive, specific and highly sensitive 
protocol to detect the BrafV600E mutation in melanoma tumor biopsies and blood. 
Melanoma Res 2010, 20:401-407.  
27. Panka DJ, Buchbinder E, Giobbie-Hurder A, Montaser L, Sepehr A, Lawrence DP, 
McDermott DF, Cohen R, Carlson A, Wargo JA, Merritt R, Seery VJ, Hodi FS, 
Gunturi A, Frederick D, Atkins MB, Iafrate AJ, Flaherty KT, Mier JW, Sullivan RJ. 
Clinical utility of a blood-based BRAFV600E mutation assay in melanoma. Submitted 
2014. 
28. Cella, D.F., Tulsky, D.S., Gray, G., Sarafian, B., Lloyd, S., Linn, E., Bonomi, A., 
Silberman, M., Yellen, S.B., Winicour, P., Brannon, J., Eckberg, K., Purl, S., 
Blendowski, C., Goodman, M., Barnicle, M., Stewart, I., McHale, M., Bonomi, P., 
Kaplan, E., Taylor, S., Thomas, C., & Harris, J. (1993). The Functional Assessment 
of Cancer Therapy (FACT) scale: Development and validation of the general 
measure. Journal of Clinical Oncology, 11(3), 570-579. 
29. Peipert JD, Beaumont JL, Bode R, Cella D, Garcia SF, Hahn EA. Development and 
validation of the functional assessment of chronic illness therapy treatment 
satisfaction (FACIT TS) measures. Qual Life Res. 2014 Apr;23(3):815-24. 
30. Ribas, Flaherty personal communications 
31. Chapman, P.B., A. Hauschild, C. Robert, et al.  (2011).  Improved survival with 
vemurafenib in melanoma with BRAF V600E mutation.  N Engl J Med.  364:2507-
2516. 
32. Kopetz, S., J. Desai, E. Chan, et al.  (2010).  PLX4032 in metastatic colorectal 
cancer patients with mutant BRAF tumors.  J Clin Oncol.  28:Abstract 3534. 
33. FDA.  (2014).  FDA approves Mekinist in combination with Tafinlar for advanced 
melanoma.  January 10, 2014. 
34. Revicki DA, van den Eertwegh AJ, Lorigan P, Lebbe C, Linette G, Ottensmeier CH, 
Safikhani S, Messina M, Hoos A, Wagner S, Kotapati S. (2012). Health related 
quality of life outcomes for unresectable stage III or IV melanoma patients receiving 
ipilimumab treatment. Health Qual Life Outcomes. 2012 Jun 13;10:66. 
35. Grob JJ, Amonkar MM, et al. Ann Oncol. 2014 Jul;25(7):1428-36. doi: 
10.1093/annonc/mdu154. Epub 2014 Apr 25. 
36. Schadendorf D1, Amonkar MM, Milhem M,, et al. Ann Oncol. 2014 Mar;25(3):700-6. 
doi: 10.1093/annonc/mdt580. Epub 2014 Feb 6. 
37. Weber et al ESMO 2014 
38. FDA.  (2013).  FDA approves two drugs, companion diagnostic test for advanced 
skin cancer.  May 29, 2013. 
39. Balagula, Y., K. Barth Huston, K.J. Busam, et al.  (2010).  Dermatologic side effects 
associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886).  Invest 
New Drugs.  29:1114-1121. 
40. Cella D1, Yount S, Rothrock N, Gershon R, Cook K, Reeve B, Ader D, Fries JF, 
Bruce B, Rose M; PROMIS Cooperative Group. Med Care. 2007 May;45(5 Suppl 
1):S3-S11. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
168 
41. DeWalt DA1, Rothrock N, Yount S, Stone AA; PROMIS Cooperative Group. Med 
Care. 2007 May;45(5 Suppl 1):S12-21. 
42. Cella D1, Riley W, Stone A, Rothrock N, Reeve B, Yount S, Amtmann D, Bode R, 
Buysse D, Choi S, Cook K, Devellis R, DeWalt D, Fries JF, Gershon R, Hahn EA, Lai 
JS, Pilkonis P, Revicki D, Rose M, Weinfurt K, Hays R; PROMIS Cooperative Group. 
J Clin Epidemiol. 2010 Nov;63(11):1179-94. doi: 10.1016/j.jclinepi.2010.04.011. 
Epub 2010 Aug 4. 
43. Shaw JW1, Johnson JA, Coons SJ. Med Care. 2005 Mar;43(3):203-20. 
44. Revicki DA, Feeny D, Hunt TL, Cole BF. Analyzing o120ncology clinical trial data 
using the Q-TWiST method: Clinical importance and sources for health state 
preference data. Quality of Life Research 2006, 15: 411-423. 
45. Kilbridge KL, Cole BF, Kirkwood JM et al. Quality-of-life-adjusted survival analysis of 
high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using 
intergroup clinical trial data. J Clin Oncol 2002; 20: 1311-1318. 
46. Brooks R. Introduction. In Brooks R, Rabin R, and Charro RD, editors. The 
Measurement and Valuation of Health Status Using EQ-5D: A European 
Perspective. Netherlands: Kluwer Academic Publishers; 2003: 1-5. 
47. Schluchter, M.D. Methods for the analysis of informatively censored longitudinal 
data. Stat Med 1992; 11: 1861-1870. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
169 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. 
List of Required Materials for EA6134 
2. 
Instructional memo to submitting pathologists 
3. 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
Rev. 6/16 
Rev. Add10 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
170 
List of Required Material 
EA6134: A Randomized Phase III trial of Dabrafenib + Trametinib followed by Ipilimumab 
+ Nivolumab at Progression vs. Ipilimumab + Nivolumab followed by Dabrafenib 
+ Trametinib at Progression in Patients With Advanced BRAFV600 Mutant 
Melanoma 
The following materials are to be submitted within one (1) month of registration:  
1. Required Diagnostic Materials 
• 
Pretrial Diagnostic Pathology Materials (MANDATORY): Representative diagnostic 
primary and metastatic tumor tissue blocks  
NOTE: If a block is unavailable for submission, cores and slides are to be submitted. All 
cores and slides must be adequately labeled, with slides numbered sequentially 
in the order cut. Alternative submission per tissue availability: 
• 
One (1) or more core punches (minimum of 4mm diameter). If core punch 
tool is unavailable, request core punch kit from the ECOG-ACRIN CBPF 1-
844-744-2420 
• 
One (1) H&E slide from each source block, and  
• 
Ten (10) to twenty (20) 5 µm unstained, uncharged air-dried plus slides from 
the thickest part of the tumor 
If these criteria cannot be met, please contact the ECOG-ACRIN Central Biorepository 
and Pathology Facility (CBPF) (eacbpf@mdanderson.org) to obtain alternative submission 
requirements. 
2. Forms and Reports: 
NOTE: Adequate patient identifying information must be included with every submission. 
It is strongly recommended that full patient names be provided. The information 
will be used only to identify patient materials, and will help to expedite any 
required communications with the institution (including site pathologists). 
The following items are to be included with the pathology materials: 
• 
Institutional Pathology Report 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981) (if STS unavailable) 
• 
Sample Tracking System (STS) Shipping Manifest Form 
3. 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 G1.3598 
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 
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-
844-744-2420 or email eacbpf@mdanderson.org. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
171 
MEMORANDUM 
TO:  
______________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
_______________________ 
SUBJECT: 
Submission of Pathology Materials for EA6134: A Randomized Phase III Trial of 
Dabrafenib + Trametinib followed by Ipilimumab + Nivolumab at Progression vs. 
Ipilimumab + Nivolumab followed by Dabrafenib + Trametinib at Progression in 
Patients with Advanced BRAFV600 Mutant Melanoma 
 
A patienthas been entered onto an ECOG-ACRIN protocol by 
______________________________ (ECOG-ACRIN Investigator). This protocol requires the 
submission of pathology materials for pathology review and future undefined research studies. 
Please complete the Submission Form. 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 materials to the Clinical Research Associate (CRA). The CRA will forward all required 
pathology materials 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 
Biorepository for undefined future research studies. Paraffin blocks will be returned upon written 
request for purposes of patient management. 
If you have any questions regarding this request, please contact the Central Biorepository and 
Pathology Facility at 1-844-744-2420or email eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: ________________________________________  
Address: _______________________________________  
Phone: ________________________________________  
 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
173 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the 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 hope to 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 ECOG-ACRIN Cancer Research Group, we thank you 
again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
174 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix III 
 
Patient Medication Calendar for Dabrafenib/Trametinib 
 
Medication Calendar Directions 
1. Take your scheduled dose of each medication. 
2. If you forget, the missed medications will not be taken later. 
3. Please bring the empty bottle or any leftover tablets and your  
medication calendar to your next clinic visit. 
 
 
Rev. 6/16 
Rev. 11/16 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
175 
Patient Medication Calendar for Dabrafenib/Trametinib 
This is a calendar on which you are to record the time and number of tablets and capsules you take each day. You should take your 
scheduled dose of each medication. Note the times and the number of tablets and capsules that you take each day. If you 
develop any side effects, please record them and anything you would like to tell the doctor in the space provided. Bring any unused 
tablets and capsules and your completed medication calendar to your doctor’s visits. 
Patient Medication Diary for Dabrafenib/Trametinib 
(Please bring this diary and any unused Dabrafenib and Trametinib to your study doctor’s office on each visit. 
Patient ID #   __________ 
Start Date 
____ /_____ /______  
Next Visit Date: ____ /_____ /______ 
Dabrafenib  ____ mg capsules  /_______ bottles 
Trametinib  ____ mg tablets /_______ bottles 
Instructions: 
1. 
Take Dabrafenib and Trametinib on an empty stomach, one hour before or two hours after a meal. 
2. 
Take Dabrafenib and Trametinib with about 200 mL (1 cup) of water. 
3. Please call  ___________________________,  if you have any questions regarding the study medications. 
Day 
Date Taken 
Trametinib Tablets 
(Please take _____ tablets 
only once a day) 
(and keep drug refrigerated) 
Dabrafenib Capsules  
(Please take ______ capsules every 12 hours) 
Please note any unusual symptoms 
or side effects and questions for 
study Doctor or Nurse 
Month/Day 
Time (Please 
circle AM or PM) 
Number of 
tablets taken 
Time 
Taken in 
AM 
Number of 
capsules taken 
Time 
Taken in 
PM 
Number of 
capsules taken 
1 
  
AM or PM  
AM 
   
PM 
 
 
2 
 
AM or PM 
 
AM 
 
PM 
 
3 
 
AM or PM 
 
AM 
 
PM 
 
4 
 
AM or PM 
 
AM 
 
PM 
 
5 
 
AM or PM 
 
AM 
 
PM 
 
6 
 
AM or PM 
 
AM 
 
PM 
 
 
7 
 
AM or PM 
 
AM 
 
PM 
 
 
8 
 
AM or PM 
 
AM 
 
PM 
 
 
9 
 
AM or PM 
 
AM 
 
PM 
 
 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
176 
Day 
Date Taken 
Trametinib Tablets 
(Please take _____ tablets 
only once a day) 
Dabrafenib Capsules 
(Please take ______ capsules every 12 hours) 
Patient ID # ______________ 
Month / 
Day 
Time (Please 
circle AM or PM) 
Number of 
tablets 
taken 
Time 
Taken in 
AM 
Number of 
capsules 
taken 
Time 
Taken in 
PM 
Number of 
capsules 
taken 
Please note any unusual symptoms 
or side effects and questions for 
study Doctor or Nurse 
10 
 
AM or PM 
 
AM 
 
PM 
 
 
11 
 
AM or PM 
 
AM 
 
PM 
 
 
12 
 
AM or PM 
 
AM 
 
PM 
 
 
13 
 
AM or PM 
 
AM 
 
PM 
 
 
14 
 
AM or PM 
 
AM 
 
PM 
 
 
15 
 
AM or PM 
 
AM 
 
PM 
 
16 
 
AM or PM 
 
AM 
 
PM 
 
17 
 
AM or PM 
 
AM 
 
PM 
 
18 
 
AM or PM 
 
AM 
 
PM 
 
19 
 
AM or PM 
 
AM 
 
PM 
 
20 
 
AM or PM 
 
AM 
 
PM 
 
21 
 
AM or PM 
 
AM 
 
PM 
 
22 
 
AM or PM 
 
AM 
 
PM 
 
23 
 
AM or PM 
 
AM 
 
PM 
 
24 
 
AM or PM 
 
AM 
 
PM 
 
25 
 
AM or PM 
 
AM 
 
PM 
 
26 
 
AM or PM 
 
AM 
 
PM 
 
27 
 
AM or PM 
 
AM 
 
PM 
 
28 
 
AM or PM 
 
AM 
 
PM 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
177 
Day 
Date Taken 
Trametinib Tablets 
(Please take _____tablets 
only once a day) 
Dabrafenib Capsules 
(Please take ______ capsules every 12 hours) 
Patient ID # ______________ 
Month / 
Day 
Time (Please 
circle AM or PM) 
Number of 
tablets 
taken 
Time 
Taken in 
AM 
Number of 
capsules 
taken 
Time 
Taken in 
PM 
Number of 
capsules 
taken 
Please note any unusual symptoms 
or side effects and questions for 
study Doctor or Nurse 
29 
 
AM or PM 
 
AM 
 
PM 
 
 
30 
 
AM or PM 
 
AM 
 
PM 
 
 
31 
 
AM or PM 
 
AM 
 
PM 
 
 
32 
 
AM or PM 
 
AM 
 
PM 
 
 
33 
 
AM or PM 
 
AM 
 
PM 
 
 
34 
 
AM or PM 
 
AM 
 
PM 
 
 
35 
 
AM or PM 
 
AM 
 
PM 
 
 
36 
 
AM or PM 
 
AM 
 
PM 
 
 
37 
 
AM or PM 
 
AM 
 
PM 
 
 
38 
 
AM or PM 
 
AM 
 
PM 
 
 
39 
 
AM or PM 
 
AM 
 
PM 
 
 
40 
 
AM or PM 
 
AM 
 
PM 
 
 
41 
 
AM or PM 
 
AM 
 
PM 
 
 
42 
 
AM or PM 
 
AM 
 
PM 
 
 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
178 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix IV 
 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” (http://ctep.cancer.gov/industry) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected , used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
179 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to submission 
for publication. Collaborator(s) will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in 
addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts 
must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as 
possible and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
180 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix V 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
181 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix VI 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) must be reported in an expeditious manner.  This 
includes all pregnancies or suspected pregnancies occurring in: 
• 
a female patient while she is on protocol treatment, or within 90 days of the female 
patient’s last dose of protocol treatment, and  
• 
a female partner of a male patient while he is on protocol treatment, or within 90 
days of the male patient’s last dose of protocol treatment.  
The outcome of the pregnancy and neonatal status must also be reported. 
Where should the pregnancy be reported? 
The pregnancy or suspected pregnancy (including a positive or inconclusive pregnancy test 
must be reported via the CTEP’s Adverse Event Reporting System (CTEP-AERs) website 
accessed here: http://ctepcore.nci.nih.gov/ctepaers/security/login.  
When does a pregnancy need to be reported? 
Due to risk of intrauterine exposure to the fetus with the study agents, an initial report must 
be done within 24 hours of the Investigator’s learning of the pregnancy or suspected 
pregnancy (including a positive or inconclusive pregnancy test), followed by a complete 
expedited CTEP-AERs report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
• 
The pregnancy or suspected pregnancy (including a positive or inconclusive pregnancy 
test) itself must be reported as a Grade 3 “Pregnancy, puerperium and perinatal 
conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
• 
The start date should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s), chemotherapy 
agent(s), or other protocol therapy must be documented in the “Description of Event” 
section of the CTEP-AERs report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status. Newborn infants should be 
followed until 30 days old.  
• 
The Investigator must solicit information and report information about the pregnancy or 
pregnancy outcome from the study participant only (the female or male patient and not 
the female partner of a male patient).  The female partner should not be consented or 
contacted, not should her medical records directly accessed.  The Investigator must 
make best efforts to collect the deidentified information from the study participant only.  
Rev. 12/15 
Rev. 11/16 
Rev. Add10 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
182 
• 
It is recommended the female patient or female partner of a male patient be referred to 
an obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling.  
How should the outcome of a pregnancy be reported? 
If the outcome of the pregnancy occurs on the same cycle of treatment as the pregnancy 
itself, the outcome should be reported as an amendment to the initial CTEP-AERs report 
(using the same ticket number) within 24 hours of the time the outcome becomes known.  
However, if the outcome of the pregnancy occurs on a subsequent cycle, the outcome 
should be reported on a new and separate CTEP-AERs report (with a new ticket number) 
via the CTEP-AERS website. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects. For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis. 
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
The pregnancy loss must be reported via the CTEP-AERS website as a Grade 4 “Pregnancy 
Loss” under the System Organ Class (SOC) “Pregnancy, puerperium and perinatal 
conditions”. 
A pregnancy loss should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A death occurring during the first 28 days after 
birth” that is felt by the investigator to be at least possibly due to the protocol treatment. 
However, any neonatal death that occurs within 28 days of birth, without regard to causality, 
must be reported via the CTEP-AERS website AND any infant death after 28 days that is 
suspected of being related to the in utero exposure to any of the agents on protocol 
treatment must be reported via the CTEP-AERS website as a Grade 4 “Death neonatal” 
under the System Organ Class (SOC) “General disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting a CTEP-AERs report for a pregnancy, pregnancy loss, or neonatal loss, 
the “CTEP Clinical Trial Pregnancy and Lactation Information Form” must be completed 
and faxed along with any additional medical information to CTEP (301-897-7404).  
This form must also be used for lactation exposure.  
This form is available on CTEP's website 
(https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/CTEP Pregnanc
y Report Form.pdf) 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
183 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix VII 
 
Shipping Kit Request Facsimile Form 
ECOG-ACRIN PROTOCOL EA6134 
Immunologic Monitoring and 
Cellular Products Laboratory 
UPCI Research Pavilion at the Hillman Cancer Center 
Room L 1.31 
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:  
Prior to Start of Treatment (5GT/2RT/1YT)  
_______________________ 
Every Week for Patients with Grade 3 or 4 irAEs until the irAE Resolves to Grade 1 and then 
at their regularly Scheduled Visits until they are Tapered Off of Immunosuppressive Agents 
(2RT)  
 
 
 
 
______________________________ 
Every Six Weeks (5GT/2RT)  
 
______________________________ 
Time of Crossover (5GT/2RT) 
 
 
 ______________________________ 
Time of Progression (5GT/2RT) 
 
 ______________________________ 
Shipping Address:  _______________________________________ 
 
 
 
_______________________________________ 
 
 
 
_______________________________________ 
PLEASE ALLOW 10 WORKING DAYS FOR RECEIPT OF SHIPPING KITS 
NOTE: To order collection and shipping kits for EA6134, patients must be registered to or 
in the process of being worked up for the EA6134 trial.  Due to funding restrictions 
institutions cannot order multiple collection and shipping kits in advance. 
 
This message is intended only for the use of the individual or entity to which it is addressed and may contain 
information that is privileged, confidential, and exempt from disclosure under applicable law.  If the reader of this 
message is not the intended recipient or the employee or agent responsible for delivering the message to the 
intended recipient, you are hereby notified that any dissemination, distribution, or copying of this communication 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. 6/16 
Rev. Add10 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
184 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix VIII 
 
Specimen Shipment Requisition Form 
ECOG-ACRIN – PROTOCOL EA6134 
It is required that samples submitted from patients participating in EA6134 be entered 
and tracked via the online ECOG-ACRIN Sample Tracking System. This form is used 
only in the event that the STS is inaccessible and then the shipments are to be logged in 
retroactively, indicating the actual dates of collection and shipment. 
 
Immunologic Monitoring and 
Cellular Products Laboratory 
UPCI Research Pavilion at the Hillman Cancer Center 
Room L 1.31 
5117 Centre Avenue 
Pittsburgh, PA  15213-1863 
Telephone: 412-624-0078 
FAX:  412-623-6625 
 
Ship samples by FedEx Priority Overnight to arrive the next morning unless otherwise 
directed by the protocol. Do NOT ship on Friday or Saturday, or the day before a legal 
holiday. 
Call the IMCPL ECOG-ACRIN Study Coordinator at 412-624-0078 with questions on 
collection and shipping. 
Please complete the following information and include this form in the shipment. 
 
ECOG-ACRIN Patient Sequence Number:  _________________    
ECOG-ACRIN Patient Initials: __________ 
 
 
 
            Last    First 
Clinical Site:_____________________________    
Site Contact: __________________________ 
Telephone Number:  ______________________     
Fax Number: _________________________ 
Federal Express® Air Bill No.: ________________________   
Date of Shipment: _____________ 
Specimen 
Collection Date 
 
___/___/___ 
MM/DD/YY 
Specimen 
Collection Time:  
 
____ ____:____ ____ 
(24 hour clock) 
 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
185 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix IX 
 
New York Heart Association (NYHA) Classification System 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is 
increased. 
 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
186 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix X 
 
MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, GASTROINTESTINAL, HEPATIC, 
NEUROLOGICAL, PULMONARY, RENAL, AND SKIN ADVERSE EVENTS 
 
NOTE: 
In the event that the dosing management outlined in Section 5.4.2 conflicts 
with Appendix X Management Algorithms, the EA6134 reccomendation is to 
follow the Section 5.4.2 management guidelines. 
Rev. 12/15, 6/16 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
187 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
188 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
189 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
190 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
191 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
192 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
193 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
194 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix XI 
 
Strong inducers of CYP3A4 or CYP2C8 
Any medications or substances that are strong inhibitors or inducers of CYP3A4 or 
CYP2C8 are ineligible. Current use of, or intended ongoing treatment with: herbal 
remedies (e.g., St. John’s wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) 
or breast cancer resistance protein 1 (Bcrp1) should also be excluded. 
Below are a few examples of the agents that are prohibited while on study treatment: 
PROHIBITED – strong inducers of CYP3A4 or CYP2C8, since concentrations of 
dabrafenib may be decreased 
Class/Therapeutic Area 
Drugs/Agents 
Antibiotics 
Rifamycin class agents (e.g., rifampin, rifabutin, 
rifapentine),  
Anticonvulsant 
Carbamazepine, oxcarbazepine phenobarbital, 
phenytoin, s-mephenytoin  
Miscellaneous 
bosentan, St. John’s wort 
PROHIBITED – Strong inhibitors of CYP3A4, or CYP2C8 since concentrations of 
dabrafenib may be increased 
Class/Therapeutic Area 
Drugs/Agents 
Antibiotics 
Clarithromycin, telithromycin, troleandomycin 
Antidepressant 
Nefazodone 
Antifungals 
Itraconazole, ketoconazole, posaconazole, 
voriconazole 
Hyperlipidemia 
Gemfibrozil  
Antiretroviral 
ritonavir, saquinavir, atazanavir 
Miscellaneous 
Conivaptan  
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list; medical reference texts such as the Physicians’ Desk 
Reference may also provide this information. As part of the enrollment/informed consent 
procedures, the patient will be counseled on the risk of interactions with other agents, 
and what to do if new medications need to be prescribed or if the patient is considering a 
new over-the-counter medicine or herbal product. 
Rev. 11/16 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
195 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix XII 
 
What to do if a patient comes in with possible immunotherapy-induced Myocarditis? 
Javid Moslehi and Doug Johnson (Vanderbilt) 
Detection: 
Troponin – screening per Section 7 
If troponin elevated, then obtain diagnostic workup, including: 
Clinical examination for signs of heart failure, ischemia, arrhythmia and skeletal muscle 
myositis.  
EKG, to rule out myocardial ischemia 
For myocarditis, special attention to heart block, PR prolongation, QRS duration 
CK (for concomitant myositis), CK-MB 
Assess cardiac function via cardiac imaging 
Echo (structural heart disease) 
Consider cardiac MRI if available  
Monitoring 
If troponin elevated but not symptomatic and no arrhythmia, then hold immunotherapy and 
obtain troponin every 2-3 days with concurrent CK, CK-MB, and EKG until normalized. If 
normalized within 2 weeks, may proceed with treatment otherwise hold further therapy.  
If troponin elevated and patient symptomatic and/or suspected myocarditis, admit to the 
hospital: 
Monitor troponin, CK, CK-MB 
Continuous cardiac monitoring 
EKG at least daily 
Cardiology consult 
If other cardiac causes for patient’s symptoms are ruled out, and the most likely diagnosis is 
myocarditis, a myocardial biopsy is strongly encouraged to confirm immune mediated 
myocarditis. Cardiac MRI may be an alternative to myocardial biopsy for diagnosis. 
Treatment of presumed or confirmed myocarditis 
Early cardiology consultation is strongly encouraged. Since most cardiologists are unaware of 
immune related adverse events, cardiology education about the therapies and adverse effects is 
important. Particularly, since EKG manifestations (specifically, heart block) appear to be an 
early manifestation of this entity, would favor consideration for pacemaker placement.  
The optimal approach for treatment of myocarditis has not been established. Since this toxicity 
has caused patient deaths aggressive management is encouraged. Corticosteroids (see below) 
may be started while pending definitive diagnosis, if myocarditis is suspected. 
Methylprednisolone 2mg/kg IV daily 
Alternatively, methylprednisolone 1g daily (dose used for acute allograft rejection in cardiac 
transplantation) could be considered. 
Rev. 11/16 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
196 
Based on the experience with other immune-related adverse events and cellular-mediated 
cardiac transplantation, other agents to consider include:  
Infliximab 
Anti-thymocyte globulin (ATG) 
Mycophenolate mofetil 
Tacrolimus 
Investigational Studies 
Defining mechanisms of toxicity is the best means to develop preventative and treatment 
strategies for immune mediated myocarditis.  
If myocardial biopsy is obtained, then should get the following: 
Formalin-fixed tissue (routinely done) 
Frozen tissue (or snap frozen tissue) 
In case of patient death, an autopsy can be helpful to help future cases 
Education in terms of getting autopsy 
Make sure whole set of organs is autopsied: skeletal muscle, endocrine (pituitary), liver, kidney 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
197 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix XIII 
 
Ancillary for Tobacco Use Assessment:  EAQ16T 
 
Study Co-Chairs: Elyse Park, Ilana Gareen, Lynne Wagner, Jamie Ostroff, Ben Herman 
Patients registered to the selected ECOG-ACRIN trials are eligible to participate in this ancillary 
study, once the appropriate amendment incorporating the study is activated. 
The Ancillary for Tobacco Use Assessment is a project that seeks to address questions about 
patient-reported tobacco use and smoking behaviors that may span several studies and/or 
diseases. The tobacco use ancillary is embedded into parent protocols, with participation in the 
ancillary informed in the parent consent form and participation determined via providing email 
address to the sites. The general objectives of the tobacco use ancillary are not specific to any 
single parent protocol; however, specific objectives may be included in the parent or related 
parent protocols. 
A significant proportion of cancer patients are current smokers at the time of cancer diagnosis,1–
5 and there are known risks associated with continued smoking following cancer diagnosis. 
These include decreased survival time; increased complications from surgery, radiation, and 
chemotherapy; and increased risk of second primary tumors.6–11 As such, the National 
Comprehensive Cancer Network (NCCN), the American Association of Cancer Research 
(AACR) and the American Society of Clinical Oncology (ASCO) have identified persistent 
smoking as a modifiable risk factor and recommend cessation counseling for cancer patients 
who smoke. Although evidence-based guidelines for treating tobacco dependence exist,12 they 
have not yet been well-integrated into cancer care settings. Moreover, knowledge regarding the 
scope and patterns of tobacco use among cancer patients is limited. As a critical step in closing 
this knowledge gap, the NCI-AACR Cancer Patient Tobacco Use Asssessment Task Force 
developed the Cancer Patient Tobacco Use 1–4,13,14 Questionnaire (C-TUQ). Through this 
ancillary, the modified C-TUQ measures will be administered to participants enrolling in selected 
Phase II and Phase III ECOG ACRIN (EA) therapeutic trials. 
The major questions may be summarized: 
1. What is the smoking status of cancer patients enrolled on EA clinical trials? 
2. Do patients quit smoking or try to quit smoking after receiving a cancer diagnosis? 
3. What forms of tobacco use do patients engage in? 
4. What assistance do patients use or receive to try to quit? 
5. How does tobacco use, other forms of tobacco use, and/or environmental tobacco exposure 
affect patient’s treatment toxicity, patient-reported physical and psychological symptoms, 
trial adherence, and therapeutic outcomes? 
When patients consent to participate, they will be asked to provide a contact email address and 
that address along with their registration information will be sent directly from the parent trial’s 
registration system to ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO), and the patient will be automatically registered into EASEE-PRO for 
participation. To activate their account for self-directed web entry of surveys, the system will 
send an activation message to the contact email address that will explain how to activate their 
Rev. 5/17, 
10/17 
Rev. Add10 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
198 
account for self-directed web entry of surveys. After their account is activated, the patient will be 
able to complete questionnaires using a secure browser interface from any web enabled 
computer, tablet, or mobile device. 
Measures 
The selected Core and Extension C-TUQ items will be assessed. The 4-item Short Form 
PROMIS® for anxiety and depression, the Lung Cancer Stigma Scale, and six symptom items 
(general pain, fatigue, nausea, cough, insomnia, shortness of breath) from FACIT (Functional 
Assessment of Chronic Illness Therapy) together with modifications of these same six questions 
to address the degree of bother associated with each symptom will be administered as well. 
Additionally, we will ask participants’ perceptions of how smoking improves or worsens each of 
the six symptom experience. All these items will be compiled into Survey of Tobacco Use (STU) 
(baseline and follow-up). 
Contents and Corresponding Questions in Survey of Tobacco Use (STU) 
Dimension 
Source of Measures 
Baseline STU 
Follow-up STU 
Basic Tobacco Use Information 
C-TUQ 
Q1 – Q5 
Q1-Q2 
Tobacco Use in Relation to Cancer 
Diagnosis and Treatment 
C-TUQ 
Q6 – Q7 
Q3 
Smoking Cessation, Cessation 
Products, and Assistance Methods 
C-TUQ 
Q8 – Q13 
Q4 – Q9 
Use of Other Products  
C-TUQ 
Q14 
Q10 
Second-Hand Smoke Exposure 
C-TUQ 
Q15-Q16 
Q11-Q12 
Psychological Symptoms 
PROMIS  
Lung Cancer Stigma 
Scale 
Q17-Q18 
Q13-Q14 
Physical Symptoms 
FACIT 
Q19 
Q15 
Sociodemographics 
 
Q20-21 
 
NOTE: 
In order to minimize ambiguity and assure that patients are oriented to answer 
appropriately, the specific phrasing of items may vary depending specific cancer type 
and treatment. 
Tobacco Use. The selected Core and Extension C-TUQ items (from categories of Basic 
Tobacco Use Information, Tobacco Use in Relation to Cancer Diagnosis and Treatment, 
Smoking Cessation/Cessation Products/Assistance Methods, Use of Other Products, and 
Second-Hand Smoke Exposure) will be assessed in the baseline and follow-up Survey of 
Tobacco Use. 
Oncology Provider Assistance. C-TUQ Question 13 assesses “cancer doctors” Advise. We 
will add 4 As to assess participants’ reported 5As (Ask (Q12a), Advise (Q12b), Assess (Q12c), 
Assist (Q12d-Q12f), and Arrange follow-up (Q12g), as in Baseline STU).80 
Psychological Symptom Assessment. Anxiety & Depression: (The Patient Reported 
Outcomes Measurement Information System (PROMIS®)). We will administer the 4-item Short 
Form PROMIS® for anxiety and depression (Q17 in Baseline STU). Stigma: The Lung Cancer 
Stigma scale measures the extent to which shame is internalized (Q18 in Baseline STU).81   
Physical Symptom Assessment Physical Symptom Assessment (Functional Assessment of 
Chronic Illness Therapy (FACIT)). FACIT, a measurement system with a collection of quality-of-

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
199 
life questionnaires, expands the more familiar FACT (Functional Assessment of Cancer 
Therapy) questionnaires into other chronic illness and conditions. FACIT consists of many 
individual questions to assess various symptoms from the patient perspective. We will use 6 
FACIT items, selected based on the therapeutic regimens, expected toxicity, and malignancy 
type of the parent trials. In addition, we have created modifications of these same six questions 
to address the degree of bother associated with each symptom” The symptoms of general pain, 
fatigue, nausea, cough, sleep difficulty, and shortness of breath will be assessed, first using the 
standard and validated FACT item, and then asking the degree of “bother” imposed by each 
symptom, on the same 5-point scale. These clusters of symptoms were specifically chosen 
based on potential interactions between tobacco use and longitudinal symptoms. 
Sociodemographic Variables. Sociodemographic variables, including age, sex, zip code, and 
race/ethnicity are collected for all NCTN trial participants at registration. At baseline, participants 
will provide information on marital status (Q20 in Baseline STU) and education level (Q21 in 
Baseline STU) as part of the tobacco supplemental assessment. 
Cancer Treatment Variables. Clinical variables including date of diagnosis, malignancy type 
(smoking related vs. non-smoking related, cancer stage), and treatment details (i.e. types and 
dates of surgery, chemotherapy, and/or radiation received), along with disease status and 
survival, will be captured in Medidata Rave via the parent protocol and will be available for 
analysis of the ancillary. Provider-assessed adverse events will also be captured via the parent 
protocol in Medidata Rave, using case report forms commonly used across the NCTN and using 
standard data elements. 
Assessments 
All items in Survey of Tobacco Use will be administered using the EASEE-PRO system. The 
advantage of our virtual electronic data capture system is that our proposed assessments will 
not be limited to, or dependent upon, patient trial visits. Confidential and potentially stigmatizing 
information can be provided without requiring direct contact with the care team. 
Timing of Assessments 
Given the critical questions that remain13 about the timing of conducting tobacco use 
assessments, we have carefully chosen to collect tobacco assessment data at trial enrollment, 3 
and 6 month follow-up. For tobacco treatment trials, 6 month follow-up is the recommended 
primary outcome time point. By 6 month follow-up, most cancer treatment-related quitting 
activity62, cancer treatment initiation of therapy, and FDA-approved smoking cessation 
medication regimens will be completed. Adverse events during treatment will have been 
observed. 
Statistical Considerations and Analysis Plans 
The analysis plans described below are planned for a combined analysis of the data from the 
selected ECOG-ACRIN trials. Consistency in the effects over the studies would be examined in 
this analysis. 
1. CHANGES IN SMOKING STATUS AND EXPOSURE. At baseline, combustible tobacco use 
(1a) will be characterized by smoking status (never smoker, former smoker, and current 
smoker based on Baseline STU Qs 1 and 5), other forms of tobacco use (1b) will be a 
composite variable determined by non-cigarette items (based on Baseline STU Q7 and 
Q14), and environmental tobacco smoke (ETS) level (1c) will be determined by current 
household and work exposure (Baseline STU Qs 15-16). At follow-up, combustible tobacco 
use (1a) will be examined by smoking status (Follow-up STU Qs 1 and 2), other forms of 
tobacco use (1b) will be determined by Follow-up STU Q10, and ETS level (1c) will be 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
200 
determined by 30 day household and work exposure (Follow-up STU Qs 11-12). We will 
examine tobacco use at baseline, 3 and 6 month follow-up, and change in status 
(abstinence in combustible tobacco, abstinence of other forms of tobacco use, and change 
in exposure to smoke-free home and work) using summary statistics (frequency and 
proportion). We will explore the effects of sociodemographic and cancer treatment factors 
on smoking status using logistic regression (comparing smokers and non-smokers). We will 
also evaluate factors associated with changes in smoking status. 
2. TREATMENT TOXICITY. The selected trials capture information about adverse events 
during treatment using NCI’s Common Terminology Criteria for Adverse Events, Version 4. 
Toxicities are measured at each treatment visit and graded according to severity, with grade 
1 corresponding to mild toxicity and grade 5 signifying a lethal adverse event. We will 
determine each patient’s worst degree toxicity across all event types and treatment visits 
and will compare the distribution of worst degree grades between smokers and non-
smokers and between patients with environmental tobacco exposure and those without 
exposure using exact tests. We will also examine the distribution of worst degree grades 
between users with different form of tobacco use. In addition, we will explore the effects of 
tobacco use on dose modifications (yes vs. no) using logistic regression, with each patient’s 
dose modification status determined across all treatment visits. 
3. SYMPTOM BURDEN. Tobacco variables will be conceptualized as described in the section 
of CHANGES IN SMOKING STATUS AND EXPOSURE. Tobacco use status (as measured 
at baseline, 3 and 6 month follow-up) will be compared to physical and psychological 
symptom burden (as measured at each corresponding time points). At 3 and 6 month follow-
up, we will also examine the association between tobacco use changes and changes in 
symptom burden. We will explore the effects of sociodemographic and cancer treatment 
factors on symptom burden using repeated measures mixed effects models. As an example 
of statistical power, we consider the PROMIS SF-4 depression measure. We assume that 
1500 patients will be enrolled across the 8 parent studies over 13 months, and that 20% are 
smokers. We assume that 85% of patients will have assessments at 6 months. Given 
groups of these sizes (26 quitters and 230 still-smokers) and standard deviation of 4.08 for 
the PROMIS SF-4 depression scale, there will be 83% power to detect a difference in 
change scores of 2.5 between groups using a two-sample t-test with Type I error of 5%.  
The minimally important difference for this instrument is 2.2.79   
4. CESSATION PATTERNS AND TREATMENT. At baseline we will explore pre-treatment 
combustible tobacco use patterns (STU Q6a and Q6b), quitting behaviors (STU Q13), 
behavioral program utilization (STU Q11) and oncology provider support (5As, STU Q12), 
and smoking cessation medication use (STU Q10). At follow-up we will explore post-
treatment combustible tobacco use patterns (STU Q3a-Q3e), quitting behaviors (STU Q9), 
behavioral program utilization (STU, Q7) and oncology provider support (5As, STU Q8), and 
smoking cessation medication use (STU Q6). We will explore the effects of 
sociodemographic and cancer treatment factors on these variables. We will examine 
associations of quitting behaviors and behavioral and medication utilization with tobacco use 
status (as outlined in the section of CHANGES IN SMOKING STATUS AND EXPOSURE) at 
baseline and on respective 3 and 6 month tobacco outcomes. These analyses will be 
descriptive in nature. Summary statistics (frequency, proportions, and 95% confidence 
intervals) will be used. 
5. TRIAL OUTCOMES. We will compare treatment duration between smokers and non-
smokers and between patients with environmental tobacco exposure and those without 
exposure. Cumulative incidence/competing risk methods will be used to estimate time to 
treatment discontinuation for adverse events, disease progression, completion per protocol, 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
201 
or other causes. Gray’s test will be used to test for differences in the cumulative incidence 
distributions.78 Differences in the distribution of reasons for discontinuation of treatment will 
be examined using exact tests. Relative dose intensity is defined as the ratio of actually 
delivered dose intensity to the planned dose intensity. The effects of tobacco use and 
exposure on relative dose intensity (≥ 90% vs. < 90%) will be explored using logistic 
regression. Differences in the primary endpoint and important secondary endpoints will be 
examined using log rank test and exact test (as appropriate). 
Data collected in the tobacco use project will support a range of analyses. Precise estimates of 
power will depend on the prevalence of smoking at baseline among study participants, the 
proportion whose smoking status changes, and the duration and adequacy of follow-up. 
References 
1. Garces YI, Yang P, Parkinson J, Zhao X, Wampfler JA, Ebbert JO, Sloan JA. The 
relationship between cigarette smoking and quality of life after lung cancer diagnosis. 
Chest. 2004; 126(6):1733-1741.doi: 10.1378/chest.126.6.1733. 
2. Gritz E. Rationale for Treating Tobacco Dependence in the Cancer Setting. Conference 
presentation at: Treating Tobacco Dependence at the National Cancer lnstitute's Cancer 
Centers. December 2009. 
3. Park ER, Japuntich SJ, Rigotti NA, Traeger L, He Y, Wallace RB, Malin JL, Zallen JP, 
Keating NL. A snapshot of smokers  after  lung and colorectal  cancer  diagnosis.  Cancer. 
2012;118(12):3153-3164. doi: 10.1002/cncr.26545. 
4. Bellizzi KM, Rowland JH, Jeffery DD, McNeel T. Health behaviors of cancer survivors: 
examining opportunities for cancer control intervention. J Clin Oneal Off J Am Soc Clin 
Oneal. 2005;23(34):8884- 8893. doi: 10.1200/JC0.2005.02.2343. 
5. Underwood JM, Townsend JS, Tai E, White A, Davis SP, Fairley TL. Persistent cigarette 
smoking and other tobacco use after a tobacco-related cancer diagnosis. J Cancer 
Surviv Res Pract. 2012;6(3):333- 344. doi: 10.1007/s11764-012-0230-1. 
6. Dresler CM. Is it more important to quit smoking than which chemotherapy is used? 
Lung Cancer Arnst Neth. 2003;39(2): 119-124. 
7. Shen T, Le W, Yee A, Kamdar 0, Hwang PH, Upadhyay D. Nicotine induces resistance 
to chemotherapy in nasal epithelial cancer. Am J Rhino/ Allergy. 2010;24(2):e73-77. 
doi:10.2500/ajra.2010.24.3456. 
8. Chen AM, Chen LM, Vaughan A, Sreeraman R, Farwell DG, Luu Q, Lau DH, Stuart K, 
Purdy JA, Vijayakumar S. Tobacco smoking during radiation therapy for head-and-neck 
cancer is associated with unfavorable outcome. Int J Radiat Oneal Biol Phys. 
2011;79(2):414-419. doi: 10.1016/j.ijrobp.2009.10.050. 
9. Garces YI, Schroeder DR, Nirelli LM, Croghan GA, Croghan IT, Foote RL, Hurt RD. Second 
primary tumors following tobacco dependence treatments among head and neck cancer 
patients. Am J Clin Oneal. 2007;30(5):531-539. doi: 10.1097/COC.Ob013e318059adfc. 
10. Richardson GE, Tucker MA, Venzon DJ, Linnoila RI, Phelps R, Phares JC, Edison M, Ihde 
DC,  Johnson BE. Smoking cessation after successful treatment of small-cell lung cancer is 
associated with fewer smoking-related second primary cancers. Ann Intern Med. 
1993;119(5):383-390. 
11. Tucker MA, Murray N, Shaw EG, Ettinger OS, Mabry M, Huber MH, Feld R, Shepherd 
FA, Johnson DH, Grant SC, Aisner J, Johnson BE. Second primary cancers related to 
smoking and treatment  of small-cell lung cancer. Lung Cancer Working Cadre. J Natl 
Cancer Inst. 1997;89(23): 1782-1788. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
202 
12. Clinical Practice Guideline Treating Tobacco Use and Dependence 2008 Update Panel, 
Liaisons, and Staff. A clinical practice guideline for treating tobacco use and dependence: 
2008 update. A U.S. Public Health Service report. Am J Prev Med. 2008;35(2): 158-176. 
doi: 10.1016/j.amepre.2008.04.009. 
13. Land SR, Toll BA, Moinpour CM, Mitchell SA, Ostroff JS, Hatsukami DK, Duffy SA, Gritz 
ER, Rigotti NA, Brandon TH, Prindiville SA, Sarna LP, Schnall RA, Herbst RS, Cinciripini 
PM, Leischow SJ, Dresler CM, Fiore MC, Warren  GW. Research Priorities, Measures, and 
Recommendations  for Assessment  of   Tobacco Use in Clinical Cancer Research. Clin 
Cancer Res Off J Am Assoc Cancer Res. 2016;22(8):1907-1913. doi:10.1158/1078-
0432.CCR-16-0104. 
14. Nishihara R, Morikawa T, Kuchiba A, Lochhead P, Yamauchi M, Liao X, Imamura Y, Nosho 
K, Shima K, Kawachi I, Qian ZR, Fuchs CS, Chan AT, Giovannucci E, Ogino S. A 
prospective study of duration of smoking cessation and colorectal cancer risk by 
epigenetics-related tumor classification. Am J Epidemiol. 2013;178(1):84-100. 
doi:10.1093/aje/kws431. 
15. Yang H-K, Shin D-W, Park J-H, Kim S-Y, Eom C-S, Kam S, Choi J-H, Cho B-L, Seo H-
G. The association between perceived social support and continued smoking in cancer 
survivors. Jpn J Clin Oneal. 2013;43(1 ):45-54.  doi:10.1093/jjco/hys182. 
16. Tseng T-S, Lin H-Y, Moody-Thomas S, Martin M, Chen T. Who tended to continue smoking 
after cancer diagnosis: the national health and nutrition examination survey 1999-2008. 
BMC Public Health.2012; 12:784.  doi: 10.1186/1471-2458-12-784. 
17. Joshu CE, Mondul AM, Meinhold CL, Humphreys EB, Han M, Walsh PC, Platz EA. Cigarette  
smoking and prostate cancer recurrence after prostatectomy. J Natl Cancer Inst. 2011 
;103(10):835-838.doi: 10.1093/jnci/djr124. 
18. Fleshner N, Garland J, Moadel A, Herr H, Ostroff J, Trambert R, O'Sullivan M, Russo P. 
Influence of smoking status on the disease-related outcomes of patients with tobacco-
associated superficial transitional cell carcinoma of the bladder. Cancer. 1999;86(11):2337-
2345. 
19. Rice D, Kim H-W, Sabichi A, Lippman S, Lee JJ, Williams B, Vaporciyan A, Smythe WR, 
Swisher S, Walsh G, Putnam JB, Hong WK, Roth J. The risk of second primary tumors after 
resection of stage I nonsmall cell lung cancer. Ann Thorac Surg. 2003;76(4):1001-1007-
1008. 
20. Do K-A, Johnson MM, Doherty DA, Lee JJ, Wu XF, Dong Q, Hong WK, Khuri FR, Fu KK, 
Spitz MR. Second primary tumors in patients with upper aerodigestive tract cancers: joint 
effects of smoking and alcohol (United States). Cancer Causes Contra/ CCC. 
2003;14(2):131-138. 
21. National Center for Chronic Disease Prevention and Health Promotion (US) Office on 
Smoking and Health. The Health Consequences of Smoking-50 Years of Progress: A 
Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention 
(US); 2014. http://www.ncbi.nlm.nih.gov/books/NBK179276/. Accessed July 8, 2016. 
22. Gritz ER, Fingeret MC, Vidrine DJ, Lazev AB, Mehta NV, Reece GP. Successes and 
failures of the teachable moment: smoking cessation in cancer patients. Cancer. 
2006;106(1):17-27. doi:10.1002/cncr.21598. 
23. Parsons A, Daley A, Begh R, Aveyard P. Influence of smoking cessation after diagnosis of 
early stage lung cancer on prognosis: systematic review of observational studies with meta-
analysis. BMJ. 2010;340:b5569. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
203 
24. Yang B, Jacobs EJ, Gapstur SM, Stevens V, Campbell PT. Active smoking and 
mortality among colorectal cancer survivors: the Cancer Prevention Study II nutrition 
cohort. J Clin Oneal Off J Am Soc Clin Oneal. 2015;33(8):885-893. doi: 
10.1200/JC0.2014.58.3831. 
25. Daniel M, Keefe FJ, Lyna P, Peterson B, Garst J, Kelley M, Bepler G, Bastian LA. 
Persistent smoking after a diagnosis of lung cancer is associated with higher reported pain 
levels. J Pain Off J Am Pain Soc. 2009; 10(3):323-328. doi: 10.1016/j.jpain.2008.10.006. 
26. Danson SJ, Rowland C, Rowe R, Ellis S, Crabtree C, Horsman JM, Wadsley J, Hatton MQ, 
Woll PJ, Eiser C. The relationship between smoking and quality of life in advanced lung 
cancer patients: a prospective longitudinal study. Support Care Cancer Off J Multinatl Assoc 
Support Care Cancer. 2016;24(4): 1507- 1516.  doi: 10.1007/s00520-015-2928-x. 
27. McBride CM, Ostroff JS. Teachable moments for promoting smoking cessation: the context 
of cancer care and survivorship. Cancer Control J Moffitt Cancer Cent. 2003;10(4):325-333. 
28. Zhang J, Kamdar 0, Le W, Rosen GD, Upadhyay D. Nicotine induces resistance to 
chemotherapy by modulating mitochondrial signaling in lung cancer. Am J Respir Cell 
Mo/ Biol. 2009;40(2): 135-146. doi: 10.1165/rcmb.2007-02770C. 
29. Tsurutani J, Castillo SS, Brognard J, Granville CA, Zhang C, Gills JJ, Sayyah J, 
Dennis PA. Tobacco components stimulate Akt-dependent proliferation and NFkappaB-
dependent survival in lung cancer cells. Carcinogenesis. 2005;26(7): 1182-1195. doi: 
10.1093/carcin/bgi072. 
30. Zevallos JP, Mallen MJ, Lam CY, Karam-Hage M, Blalock J, Wetter OW, Garden AS, 
Sturgis EM, Cinciripini PM. Complications of radiotherapy in laryngopharyngeal 
cancer: effects of a prospective smoking cessation program. Cancer. 
2009;115(19):4636-4644. doi:10.1002/cncr.24499. 
31. Vaporciyan AA, Merriman KW, Ece F, Roth JA, Smythe WR, Swisher SG, Walsh  GL, 
Nesbitt JC,  Putnam JB. Incidence of major pulmonary morbidity after pneumonectomy: 
association with timing of smoking cessation. Ann Thorac Surg. 2002;73(2):420-425-
426. 
32. Xu J, Huang H, Pan C, Zhang B, Liu X, Zhang L. Nicotine inhibits apoptosis induced 
by cisplatin in human oral cancer cells. Int J Oral Maxillofac Surg. 2007;36(8):739-7 44. 
doi: 10.1016/j.ijom.2007 .05.016. 
33. Kelemen LE, Warren GW, Koziak JM, Kobel M, Steed H. Smoking may modify the 
association between neoadjuvant chemotherapy and survival from ovarian cancer. 
Gynecol Oneal. 2016;140(1):124-130.doi: 10.1016/j.ygyno.2015.11.008. 
34. Jung KH, Kim SM, Choi MG, Lee JH, Noh JH, Sohn TS, Bae JM, Kim S. 
Preoperative smoking cessation can reduce postoperative complications in gastric 
cancer surgery. Gastric Cancer Off J Int Gastric Cancer Assoc Jpn Gastric Cancer 
Assoc. 2015;18(4):683-690. doi:10.1007/s10120-014-0415-6. 
35. Rigotti NA. The future of tobacco treatment in the health care system. Ann Intern 
Med. 2009; 150(7):496- 497. 
36. Geller AC, Brooks DR, Powers CA, Brooks KR, Rigotti NA, Bognar B, McIntosh S, 
Zapka J. Tobacco cessation and prevention practices reported by second and fourth 
year students at US medical schools.  J Gen Intern Med. 2008;23(7):1071-1076. 
doi:10.1007/s11606-008-0526-z. 
37. Albers AB,  Biener L, Siegel M, Cheng OM, Rigotti N. Household smoking  bans and 
adolescent   antismoking attitudes and smoking initiation: findings from a longitudinal 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
204 
study of a Massachusetts youth cohort. Am J Public Health. 2008;98(10):1886-1893. 
doi:10.2105/AJPH.2007.129320. 
38. Thorndike AN, Regan S, Rigotti NA. The treatment of smoking by US physicians during 
ambulatory visits: 1994 2003. Am J Public Health. 2007;97(10): 1878-1883. doi: 
10.2105/AJPH.2006.092577. 
39. Public Law 111-5. The American Recovery and Reinvestment Act of 2009. 
2009;155:115-521. 
40. Blumenthal D, Tavenner M. The "meaningful use" regulation for electronic health 
records. N Engl J Med. 2010;363(6):501-504.   doi: 10.1056/NEJMp1006114. 
41. Toll BA, Brandon TH, Gritz ER, Warren GW, Herbst RS, AACR Subcommittee on 
Tobacco and Cancer. Assessing tobacco use by cancer patients and facilitating 
cessation: an American Association for Cancer Research policy statement. Clin Cancer 
Res Off J Am Assoc Cancer Res. 2013;19(8):1941-1948. doi:10.1158/1078-0432.CCR-
13-0666. 
42. Quality Oncology Practice Initiative (QOPI®) I ASCO Institute For Quality. 
http://www.instituteforquality.org/quality-oncology-practice-initiative-qopi. Accessed July 8, 
2016. 
43. Shields PG. New NCCN Guidelines: Smoking Cessation for Patients With Cancer. J 
Natl Compr Cancer Netw JNCCN. 2015; 13(5 Suppl):643-645. 
44. de Moor JS, Elder K, Emmons KM. Smoking prevention and cessation interventions 
for cancer survivors. Semin Oneal Nurs. 2008;24(3):180-192.  
doi:10.1016/j.soncn.2008.05.006. 
45. Gritz ER, Nisenbaum R, Elashoff RE, Holmes EC. Smoking behavior following diagnosis in 
patients with stage I non-small cell lung cancer. Cancer Causes Control CCC. 
1991;2(2):105-112. 
46. Dresler CM, Bailey M, Roper CR, Patterson GA, Cooper JD. Smoking cessation and lung 
cancer resection. Chest. 1996;110(5):1199-1202. 
47. Sanderson Cox L, Patten CA, Ebbert JO, Drews AA, Croghan GA, Clark MM, Wolter TD, 
Decker  PA, Hurt RD. Tobacco use outcomes among patients with lung cancer treated 
for nicotine dependence. J Clin Oneal Off J Am Soc C/in Oneal. 2002;20(16):3461-3469. 
48. Schnoll RA, Zhang B, Rue M, Krook JE, Spears WT, Marcus AC, Engstrom PF. Brief 
physician-initiated quit-smoking strategies for clinical oncology settings: a trial coordinated 
by the Eastern Cooperative Oncology Group. J Clin Oneal Off J Am Soc Clin Oneal. 
2003;21 (2):355-365. 
49. Sarna L. Smoking behaviors of women after diagnosis with lung cancer. Image-- J Nurs 
Scholarsh.1995;27(1):35-41. 
50. Cooley ME, Emmons KM, Haddad R, Wang Q, Posner M, Bueno R, Cohen T-J, Johnson 
BE. Patient- reported receipt of and interest in smoking-cessation interventions after a 
diagnosis of cancer. Cancer. 2011; 117(13):2961-2969. doi: 10.1002/cncr.25828. 
51. Cancer Facts and Statistics I American Cancer Society. 
http://www.cancer.org/research/cancerfactsstatistics/. Accessed January 27, 2016. 
52. de Dios MA, Anderson BJ, Stanton C, Audet DA, Stein M. Project Impact: a 
pharmacotherapy pilot trial investigating the abstinence and treatment adherence of Latino 
light smokers. J Subst Abuse Treat. 2012;43(3):322-330. doi: 10.1016/j.jsat.2012.01.004. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
205 
53. Park ER, Japuntich SJ, Traeger L, Cannon S, Pajolek H. Disparities between blacks and 
whites in tobacco and lung cancer treatment. The Oncologist. 2011 ;16(10):1428-1434.doi: 
10.1634/theoncologist.2011-0114. 
54. Warren GW, Marshall JR, Cummings KM, Toll B, Gritz ER, Hutson A, Dibaj S, Herbst R, 
Dresler C, IASLC Tobacco  Control and Smoking  Cessation  Committee.  Practice patterns 
and perceptions   of thoracic oncology providers on tobacco use and cessation in cancer 
patients. J Thorac Oneal Off Pub/ Int Assoc  Study  Lung  Cancer.  2013;8(5):543-548.  
doi:10.1097/JTO.Ob013e318288dc96. 
55. Warren GW, Marshall JR, Cummings KM, Toll BA, Gritz ER, Hutson A, Dibaj S, Herbst R, 
Mulshine JL, Hanna N, Dresler CA. Addressing tobacco use in patients with cancer: a 
survey of American Society of Clinical Oncology members. J Oneal Pract Am Soc Clin 
Oneal. 2013;9(5):258-262. doi:10.1200/JOP.2013.001025. 
56. Goldstein AO, Ripley-Moffitt CE, Pathman DE, Patsakham KM. Tobacco use treatment 
at the U.S. National Cancer lnstitute's designated Cancer Centers. Nicotine Tob Res Off 
J Soc Res Nicotine Tob. 2013;15(1 ):52-58. doi:10.1093/ntr/nts083. 
57. Warren GW, Dibaj S, Hutson A, Cummings KM, Dresler C, Marshall JR. Identifying 
Targeted Strategies to Improve Smoking Cessation Support for Cancer Patients. J 
Thorac Oneal Off Pub/ Int Assoc Study Lung Cancer. 2015;10(11 ):1532-1537. 
doi:10.1097/JT0.0000000000000659. 
58. Bjurlin MA, Goble SM, Hollowell CMP. Smoking cessation assistance for patients with 
bladder cancer: a national survey of American urologists. J Ural. 2010; 184(5):1901-1906. 
doi: 10.1016/j.juro.2010.06.140. 
59. Weaver KE, Danhauer SC, Tooze JA, Blackstock AW, Spangler J, Thomas L, Sutfin EL. 
Smoking cessation  counseling  beliefs and behaviors of outpatient  oncology  providers.  
The Oncologist.  2012; 17(3):455-462. doi: 10.1634/theoncologist.2011-0350. 
60. Simmons VN, Litvin EB, Unrod M, Brandon TH. Oncology healthcare providers' 
implementation of  the 5A's model of brief intervention for smoking cessation: patients' 
perceptions. Patient Educ Couns. 2012;86(3):414-419. doi: 10.1016/j.pec.2011.06.016. 
61. Peters EN, Torres E, Toll BA, Cummings KM, Gritz ER, Hyland A, Herbst RS, Marshall 
JR, Warren GW. Tobacco assessment in actively accruing National Cancer Institute 
Cooperative Group Program Clinical Trials. J Clin Oncol Off J Am Soc Clin Oncol. 
2012;30(23):2869-2875. doi: 10.1200/JC0.2011.40.8815. 
62. Park ER, Japuntich S, Temel J, Lanuti M, Pandiscio J, Hilgenberg J, Davies D, 
Dresler C, Rigotti NA. A smoking cessation intervention for thoracic surgery and 
oncology clinics: a pilot trial. J Thorac Oncol Off Pub/ Int Assoc Study Lung Cancer. 
2011;6(6):1059-1065. doi:10.1097/JTO.Ob013e318215a4dc. 
63. Haas JS, Linder JA, Park ER, Gonzalez  I, Rigotti NA, Klinger EV, Kontos EZ, 
Zaslavsky  AM,  Brawarsky P, Marinacci LX, St Hubert S, Fleegler EW, Williams DR. 
Proactive tobacco cessation outreach to smokers of low socioeconomic status: a 
randomized clinical trial. JAMA Intern Med. 2015; 175(2):218-226. doi:  
10.1001/jamainternmed.2014.6674 
64. Park ER, Puleo E, Butterfield RM, Zorn M, Mertens AC, Gritz ER, Li FP, Emmons 
KM. A process evaluation of a telephone-based peer-delivered smoking cessation 
intervention for adult survivors of childhood cancer: the partnership for health study. 
Prev Med. 2006;42(6):435-442.doi: 10.1016/j.ypmed.2006.03.004. 
65. Emmons KM, Puleo E, Park E, Gritz ER, Butterfield RM, Weeks JC, Mertens A, Li 
FP. Peer-delivered smoking counseling for childhood cancer survivors increases 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
206 
rate of cessation: the partnership for health study. J Clin Oncol Off J Am Soc Clin 
Oncol. 2005;23(27):6516-6523. doi:10.1200/JC0.2005.07.048. 
66. Fisch MJ, Zhao  F, Manola J, Miller AH,  Pirl WF, Wagner  LI. Patterns and predictors of 
antidepressant   use in ambulatory cancer patients with common solid tumors. 
Psychooncology. 2015;24(5):523-532.doi: 10.1002/pon.3606. 
67. Sanford SD, Zhao F, Salsman JM, Chang VT, Wagner LI, Fisch MJ. Symptom burden 
among young adults with breast or colorectal cancer. Cancer. 2014; 120(15):2255-
2263. doi: 10.1002/cncr.28297. 
68. Hamann HA, Lee J-W, Schiller JH, Horn L, Wagner LI, Chang VT-S, Fisch MJ. 
Clinician perceptions of care difficulty, quality of life, and symptom reports for lung 
cancer patients: an analysis from the Symptom Outcomes and Practice patterns 
(SOAPP) study. J Thorac Oncol Off Pub/ Int Assoc Study Lung Cancer. 
2013;8(12):1474-1483. doi:10.1097/01.JT0.0000437501.83763.5d. 
69. Wagner LI, Robinson D, Weiss M, Katz M, Greipp P, Fonseca R, Cella D. Content 
development for the Functional Assessment of Cancer Therapy-Multiple Myeloma 
(FACT-MM): use of qualitative and quantitative methods for scale construction. J Pain 
Symptom Manage. 2012;43(6):1094-1104.doi: 10.1016/j.jpainsymman.2011.06.019. 
70. A. Cmelak, Li S, Zhao W, Westra W, Chung C, Gillison M, Gilbert J, Bauman J, 
Wagner L, Ferris R, Trevarthen D, Colevas A, Jahagirdar B, Burtness B. Reduced-
dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal 
squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction 
chemotherapy (IC). 2014. 
71. Lewandowski RJ, Andreoli JM, Hickey R, Kallini JR, Gabr A, Baker T, Kircher S, 
Salem R, Kulik L. Angiogenic Response following Radioembolization: Results from a 
Randomized Pilot Study of Yttrium-90 with or without Sorafenib. J Vase lnterv Radio/ 
JVIR. June 2016. doi: 10.1016/j.jvir.2016.03.043. 
72. Mouli S, Hickey R, Thornburg B, Sato KT, Desai K, Gabr A, Kallini JR, Niemeri H, 
Kircher S, Mulcahy MF, Benson Iii AB, Gupta R, Salem R, Lewandowski RJ. Single- 
versus Triple-Drug Chemoembolization for Hepatocellular Carcinoma: Comparing 
Outcomes by Toxicity, Imaging Response, and Survival.  J  Vase lnterv Radio/ JVIR. 
April 2016. doi: 10.1016/j.jvir.2016.01.135. 
73. Hickey R, Lewandowski RJ, Prudhomme T, Ehrenwald E, Baigorri B, Critchfield J, Kallini 
J, Gabr A, Gorodetski B, Geschwind J-F, Abbott A, Shridhar R, White SB, Rilling WS, 
Boyer B, Kauffman S, Kwan S, Padia SA, Gates VL, Mulcahy M, Kircher S, Nimeiri H, 
Benson AB, Salem R. 90Y Radioembolization of Colorectal Hepatic Metastases Using Glass 
Microspheres: Safety and Survival Outcomes from  a 531- Patient Multicenter Study. J Nucl 
Med Off Pub/ Soc Nucl Med. 2016;57(5):665-671.doi: 10.2967/jnumed.115.166082. 
74. Lewandowski RJ, Memon K, Mulcahy MF, Hickey  R, Marshall K, Williams  M, Salzig  K, 
Gates VL, Atassi B, Vouche M, Atassi R, Desai K, Hohlastos E, Sato K, Habib A, Kircher 
S, Newman SB, Nimeiri H, Benson AB, Salem R. Twelve-year experience of 
radioembolization for colorectal hepatic metastases  in 214 patients: survival by era and 
chemotherapy. Eur J Nucl Med Mo/ Imaging. 2014;41(10):1861-1869. doi: 10.1007/s00259-
014-2799-2. 
75. Hickey R, Mulcahy MF, Lewandowski RJ, Gates VL, Vouche M, Habib A, Kircher S, 
Newman S, Nimeiri H, Benson AB, Salem R. Chemoradiation of hepatic malignancies: 
prospective, phase 1 study of full-dose capecitabine with escalating doses of yttrium-90 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
207 
radioembolization.  Int J Radiat Oneal Biol Phys.  2014;88(5): 1025-1031. doi: 
10.1016/j.ijrobp.2013.12.040. 
76. Gonzalez A, Japuntich S, Keating NL, Wallace R, He Y, Streck JM, Park ER. Pain 
experiences among a population-based cohort of current, former, and never regular 
smokers with lung and colorectal cancer. Cancer. 2014; 120(22):3554-3561. doi: 
10.1002/cncr.28893. 
77. Park ER, Streck JM, Gareen IF, Ostroff JS, Hyland KA, Rigotti NA, Pajolek H, Nichter M. 
A qualitative study of lung cancer risk perceptions and smoking beliefs among national 
lung screening trial participants. Nicotine Tob Res Off J Soc Res Nicotine Tob. 2014; 
16(2):166-173. doi: 10.1093/ntr/ntt133. 
78. Gray RJ. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a 
Competing Risk. Ann Stat. 1988;16(3):1141-1154. 
79. Kroenke K, Yu Z, Wu J, Kean J, Monahan PO. Operating Characteristics of PROMIS 
Four-Item Depression and Anxiety Scales in Primary Care Patients with Chronic Pain. Pain 
Med. 2014;15(11):1892- 1901. doi: 10.1111/pme.12537. 
80. Park ER, Gareen IF, Japuntich S, Lennes I, Hyland K, DeMello S, Sicks JD, Rigotti NA. 
Primary Care Provider-Delivered Smoking Cessation Interventions and Smoking Cessation 
Among Participants in the National Lung Screening Trial. JAMA Intern Med. 
2015;175(9):1509-1516. doi: 10.1001/jamainternmed.2015.2391.  
81. Fife BL, Wright ER. The dimensionality of stigma: a comparison of its impact on the self of 
persons with HIV/AIDS and cancer. J Health Soc Behav. 2000;41 (1):50-67. 
 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
208 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix XIV 
 
Predictive Biomarker Development in Patients with BRAF Mutant Melanoma Enrolled 
on EA6134 
The following study was submitted and approved in response to the Request for Applications 
(RFA) for Administrative Supplements to Support Biomarker Studies Associated with NCI-
supported Clinical Trials of Immunotherapy. The applications were administratively reviewed 
internally by NCI and reviewed and approved by DCTD/CTEP Protocol Review Committee 
separate from a protocol amendment. 
Based on discussions with the NIH grant oversight committee, we have made several 
changes to the aims and research plans. However, we maintain the same initial hypothesis 
that an integrated predictive biomarker approach can divide patients with advanced BRAF 
mutant melanoma into four subgroups: (1) patients who benefit most from immunotherapy, (2) 
patients who benefit most from targeted therapy, (3) patients who benefit equally from either 
immunotherapy or targeted therapy, and (4) patients who will not benefit from either 
immunotherapy or targeted therapy. All patients enrolled in the EA6134 protocol are required 
to submit a baseline tumor specimen (block or >15 unstained slides plus a core biopsy) 
obtained prior to initiation of systemic therapy. These will be interrogated for biomarker 
development and correlated to baseline clinical prognostic variables. Given the grant duration 
is for a 1-2 year period, correlations to efficacy endpoints will be conducted under a future 
grant mechanism. 
Aim 1: To perform immune biomarker assays on baseline tumor specimens from 
patients with BRAF mutant melanoma treated with nivo/ipi or D/T on EA6134.  
The ECOG-ACRIN Central Biorepository Pathology Facility at MD Anderson will review H&E 
stained slides of each tumor specimen and prepare/ship this slide and 3 contiguously 
sectioned unstained slides for IHC and 10 additional unstained to the Histopathology and 
Tissue Shared Resource (HTSR) at the Georgetown Lombardi. IHC for PD-L1 and CD8 will 
be performed by the HTSR using established methods. PD-L1 status will be assessed by 
standard techniques (scoring system of 0 to 3+) and by those utilized by the nivo/ipi studies 
(threshold cutoff of 5%). CD-8+ T-cell infiltration/density will also be scored using a scoring 
system of 0 to 3+ and automated density measures. In addition, the Genomics and 
Epigenomics Shared Resource (GESR) at Georgetown-Lombardi will isolate RNA and DNA 
using the 10 FFPE tumor slides and/or equivalent tumor blocks using established approaches. 
RNA will be analyzed for immune gene expression on the Nanostring platform using the 
PanCancer Immune Profiling Kit (770 genes). DNA will be stored for future whole exome 
sequencing (WES) once additional funding is available. Raw data will be provided to the 
Bioinformatics team in the Innovation Center for Biomedical Informatics (ICBI) at Georgetown 
University. 
Aim 2: To integrate and analyze immune biomarker data sets with clinical prognostic 
factors from patients on EA6134 using the Georgetown Database of Cancer (G-DOC) 
G-DOC includes a broad collection of bioinformatics and systems biology tools for analysis 
and visualization of four major "omics" types: DNA, mRNA, microRNA, and metabolites. 
Molecular data will be processed using signal extraction and normalization pipelines in 
Bioconductor packages as well as our pipelines for pre-processing. Pre-processed data 
Rev. Add10 
Rev. Add13 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
209 
matrices for each type will be used for bio-statistical and systems biology analyses. 
Specifically, we will use the R package NanoStringNorm to pre-process, run diagnostics, and 
visualize NanoString expression data. Further analyses including class comparison, machine 
learning and systems biology analysis will be performed. We will use the Recursive Feature 
Elimination (RFE) based on Random Forest (RF) machine learning approach to assess 
relationship of biomarkers. We will perform the model construction using 100 patient 
specimens for biomarker discovery. Additional specimens will be used for validation purposes; 
however the validation specimens will likely not be available after September 2017; thus 
requiring on no-cost extension of this grant. Data from WES/NGS will be incorporated once 
available – this system readily facilitates updated modeling with the introduction of new data. 
Subsequently data provided by ECOG-ACRIN on patient baseline clinical variables known to 
be associated with improved melanoma survival (LDH, number of disease sites, BRAF 
mutation (V600E vs V600K), stage of disease, age < 65, and sex) will be entered into the G-
DOC database. It will then be determined if biomarkers are associated with these baseline 
clinical variables. The biomarker variables will be PD-L1 status (> 5% positive tumor cells vs 
<5% positive tumor cells), CD8+ T cell density (IHC score of 2-3 vs 0-1), interferon-gamma 
gene expression signature (present or absent). Further optimized cutoffs or continuous 
variables may be utilized for association testing. Fisher’s exact testing (categorical variables) 
and regression models (continuous variables) will be performed to determine associations 
between biomarker results and clinical variables. 
Aim 3 (Future plans): To determine if mutational burden and/or profile can be combined 
with an immune biomarker profile to more accurately predict durable clinical benefit 
from nivo/ipi vs D/T in patients on EA6134 
As WES/NGS studies are not included in the approved budget for this P30 supplement grant 
and the efficacy endpoints will not be available during the 1-2 year grant period, we will apply 
for additional funding sources to complete these research plans over the following 2-3 year 
period. These biomarker and bioinformatic plans remain unchanged.

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
211 
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a 
Phase III Trial 
 
Appendix XVI 
 
Assessment of serum based biomarkers of efficacy and adverse events due to 
treatment with immune checkpoint inhibitors 
Exploratory Correlative Study Design 
As part of this correlative study, we will evaluate and attempt to establish biomarkers of 
efficacy and adverse events due to treatment with immune checkpoint inhibitors. For this we 
plan to study serial blood samples obtained from patients in the immune checkpoint inhibitor 
arms of this trial at regular intervals and as they develop irAEs and require 
immunosuppressive therapy and/or discontinuation of treatment. The sample collection 
schema is in Fig. 1. The molecular readouts from changes in mutation and methylation 
patterns of circulating cell-free DNA extracted from the serum samples will be compared with 
clinical observations of efficacy and toxicity. 
 
 
Main study sample collection times are indicated. In this substudy extra blood collection time 
points are added to monitor patients with irAEs during their course of immunosuppressive 
treatment. 
Specific Hypotheses 
Primary:  
We hypothesize that (a) a larger proportion of responders (compared to nonresponders) will 
have changes in ctDNA measurement after treatment, and (b) tumor status can be monitored 
during the course of the treatment or an irAE by quantifying the amount of tumor specific DNA 
(mutant ctDNA) in the blood and that prolonged immunosuppressive therapy may stunt and/or 
reverse any ongoing antitumor response (Aim 1). 
Fig. 1 Schema of EA6134 main clinical trial (top) and substudy for monitoring irAEs (bottom). In the 
substudy extra blood collection time points are added to monitor patients with irAEs during 
immunosuppressive treatment. 
Rev. Add21 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
212 
Secondary:  
We hypothesize that tissue injury due to irAEs directed against several tissues (liver, lung, 
heart, colon, pancreas etc.) will be reflected as changes in tissue-specific DNA methylation 
patterns in the blood that is shed as cell-free methylated DNA (cmeDNA) and that these 
changes will be detectable in the blood at onset and resolve to baseline as the irAE is 
successfully treated (Aim 2). 
We have established experimentally cmeDNA detection by amplicon sequencing of tissue-
specifically methylated genomic regions for heart, lung, brain, or liver. We also have recently 
established a tissue-agnostic epigenome-wide cmeDNA analysis that will circumvent 
generation of amplicons for each tissue of interest. We will use both approaches if high 
sensitivity of detection (low abundance of a signal) is required because the amplicon 
sequencing method is ~10-fold more sensitive than the unbiased, genome-wide capture-seq.  
Specific Aims  
Aim 1: To monitor tumor response by comparing changes in circulating cell-free mutant tumor 
DNA (ctDNA) as a readout of tumor burden (a) at week 12 relative to baseline before 
treatment in responders and non-responders; (b) before and during immunosuppressive 
treatment to control irAEs. 
Aim 2: To monitor organ-specific adverse events (irAEs) using circulating cell-free, tissue-
specific methylated DNA (cmeDNA) as a readout of tissue-specific toxicity (a) at the time of 
grade 3-4 irAE relative to baseline and control patients without irAEs; (b) during 
immunosuppressive treatment for irAEs. 
Background 
Treatment with Immune Checkpoint Inhibitors (ICIs) 
Therapeutic inhibition of immune checkpoints has demonstrated striking efficacy in a variety of 
cancers and is currently the standard of care in over a dozen cancer settings and are being 
studied in more than 2200 clinical trials in combination with other anti-cancer 
agents/regimens. Antibodies against the PD-1 pathway, pembrolizumab (pembro) and 
nivolumab (nivo), antibodies against the PDL-1 pathway, atezolizumab, avelumab and 
durvalumab have in particular revolutionized the treatment of patients with melanoma, lung, 
kidney, bladder, head and neck cancers and have produced long term durable responses 
(1,2) The combination of nivo with anti-CTLA-4, ipilimumab (ipi), produces tumor responses in 
approximately 60% of patients with metastatic melanoma (3) and 40% with advanced kidney 
cancer (4). These results have contributed to the FDA approval of these medications for 
melanoma, and clear cell kidney, non small cell lung, bladder, hepatocellular and head & neck 
cancers. Treatment with immune checkpoint inhibitors has shown efficacy in over 20 distinct 
cancer types and in addition FDA approval now includes a tissue-agnostic indication, i.e. any 
cancer with DNA repair deficiency.  
Immune-Related Adverse Events (irAE) 
Immune checkpoint blockade frequently causes inflammatory and immune-related adverse 
effects (irAEs) due to the disruption of self-tolerance protection by normal tissues. These 
irAEs can be severe, leading to discontinuation of immune checkpoint inhibitor therapy and 
the requirement for immunosuppressive treatment. Any tissue can be injured with the most 
frequent occurrences in the skin, gastro-intestinal tract, endocrine glands, liver, and lungs. 
Combined checkpoint blockade of PD-1 and CTLA-4 has higher toxicity than monotherapy 
and requires more frequent immunosuppressive treatment and/or discontinuation of therapy. 
Specifically, in a randomized multi-institutional trial involving the now FDA approved regimen 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
213 
of nivolumab (1 mg/kg) + ipilimumab 3 mg/kg IV q 3 weeks followed by nivo 3 mg/kg 
monotherapy q 2 weeks, treatment related grade 3-4 irAEs occurred in 59% of patients 
compared to 21% for nivolumab monotherapy (5). In particular 123/313 patients on nivo + ipi 
did not receive all 4 induction treatments (and thus no maintenance nivo) due to treatment 
related AEs requiring immunosuppressive therapy. Treatments for irAEs in a recent study 
were mostly corticosteroids (systemic >65%; topical 30%) and infliximab (6%) or 
mycophenolic acid (0.8%) for GI or hepatic irAEs. Although 67% of these patients remained 
alive at 3 years, suggesting that discontinuation of therapy and the application of 
immunomodulation did not compromise their survival, it is unclear if efficacy would have been 
further enhanced if nivo monotherapy had been provided once toxicity had resolved or if 
earlier, briefer or different immunomodulatory therapy had been used to control the irAEs.  
Although treatment with steroids and other immune modulators can reverse these irAEs, 
immunosuppression may compromise the anti-tumor activity of the immune checkpoint 
blockade. Thus, there is an unmet need for non-invasive biomarkers for real time prediction of 
irAEs and the impact of immune suppressive therapy on therapeutic efficacy to inform 
management of cancer patients treated with immune checkpoint inhibitors.  
A first step to detecting irAEs earlier is to determine whether one can identify blood-based 
patterns of specific organ damage in patients with clinically detectable irAEs and to assess if 
these alterations resolve with successful treatment of the irAE. Thus, we propose to collect 
blood samples to isolate cell-free DNA for analysis at the onset of irAE and follow that with 
serial blood samples at regular time points during and after the treatment of the irAE. Each 
patient's baseline blood sample at irAE onset will serve as their respective control. We 
propose to assess immune-related organ damage by monitoring changes in the abundance of 
a set of tissue-specific circulating cell-free methylated DNA (cmeDNA). The analysis of 
cmeDNA can be tailored to any organ or tissue that is possibly damaged by the autoimmune 
reaction to checkpoint inhibition and we will initially include 12 tissues in our analysis.   
In order to determine whether the immunosuppressive treatment of an irAE has an impact on 
the anti-tumor immune response, we propose to monitor changes in the circulating cell-free 
mutant tumor DNA (ctDNA) levels as readout of effect of treatment anti-tumor treatment 
efficacy.   
Background on cell free tumor DNA (ctDNA) 
Monitoring the molecular characteristics of cancer by serial analyses of circulating cell-free 
mutant tumor DNA (ctDNA) enables capture of emerging heterogeneity of the disease and 
may even support treatment decisions (6,7). ctDNA analysis has evolved since its inception 
with improvements in the technologies and detection limits (8,9) and now represents a set of 
research tools that appear poised to enter routine clinical care (10,11). The recent FDA 
approval of a ctDNA assay for the EGFR T790M mutation in lung cancer to assess suitability 
of treatment with osimertinib supports this notion (12). Also, it appears that ctDNA may be 
superior to tumor tissue DNA in the assessment of cancer heterogeneity and during disease 
progression with metastatic disease (13,14). We plan to monitor 263 mutations in 56 
frequently mutated cancer genes in ctDNA. We have established the assay and reported it 
recently (15). Monitoring for a panel of mutated genes in highly heterogeneous cancers can 
provide new qualitative insights into the changing molecular composition of the cancer during 
immune therapy (16). 
Background on DNA methylation and cmeDNA (circulating methylated DNA) 
DNA methylation is an important epigenetic regulation mechanism that consists of an addition 
of a methyl group to carbon 5 of cytosine residues in clusters of CpG islands. The effects of 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
214 
DNA methylation for each genomic locus is not fully understood, but it is widely accepted that 
DNA methylation can regulate gene expression (17), cellular differentiation and chromosomal 
stability. DNA methylation is tissue- and cell type-specific and can thus serve as a biomarker 
for specific tissues (18). One application of DNA-methylation profiling has been used to predict 
the tissue of origin of cancers with unknown primary lesions. This has also been applied in 
clinical diagnostics and histopathology (19,20).  
DNA methylation signatures of tissues or cells can be obtained from ever-growing methylome 
data bases such as the Human Epigenome Atlas (ftp://ftp.genboree.org/EpigenomeAtlas/) that 
is housed at Baylor College or from the published literature (21). In addition to isolation from 
cells and tissues, methylated DNA has been isolated from serum or plasma where it can be 
used to assess cancer progression, tissue transplant survival, prenatal diagnostics and other 
phenotypes (22,23) In addition to the detection of short fragments of methylated DNA in the 
circulation, other bio-fluids were also reported as sources: e.g. saliva was used to identify 
altered neurotransmission in attention-deficit/hyperactivity disorder children via methylated 
DNA analysis (24).  
In Figure 2 we show the approach to the analysis of circulating cell-free DNA methylation. The 
quantitative analysis is based on next-generation DNA sequencing (NGS). Figure 3 shows an 
analysis of the top 10 genomic loci that distinguish different tissues of interest. Analyses of 
these distinct methylation patterns are used to assign differentially methylated DNA fragments 
in the circulation to their tissue or origin. 
 
 
Figure 2. Overview of approach to detect to changes in cfDNA methylation patterns. For 
sequencing based detection of methylated CpGs DNA is treated with bisulfite that will convert non-
methylated C to U. Methylated Cs are resistant to the bisulfite conversion. Thus, methylated Cs are 
read as Cs whereas non-methylated Cs are read as Ts in conventional DNA sequencing. For the 
detection of tissue-specific cfDNA we select genomic regions that contain 4 to 8 CpGs within <150 
nucleotides and show distinct methylation when comparing across a range of tissues. Figure 5 (below) 
shows a line-up of distinct genomic regions across a range of tissues. PCR primers outside the CpGs 
are then used to amplify bisulfite treated cfDNA. Deep sequencing provides the patterns of methylated 
and non-methylated DNA fragments. Only fragments where all CpGs selected are either methylated or 
non-methylated are considered as a positive signal to avoid false signals due to random methylation or 
de-methylation. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
215 
 
 
Of significance for this proposal, recent work has shown that after different modes of normal 
tissue damage by inflammation (multiple sclerosis, pancreatitis), trauma (traumatic brain 
injury) or hypoxia (cardiac arrest) dying cells in the CNS, pancreas, heart etc. will release their 
DNA as short fragments into the circulation. This will lead to an increased abundance of 
tissue-specific DNA and the DNA methylation patterns can be used to identify the tissue or 
cellular origin of the circulating methylated DNA (cmeDNA) (21).  
We plan to apply cmeDNA analysis to monitor tissue damage due to irAEs during immune 
checkpoint inhibitor (ICI) treatment in patients with clinically detected irAEs. Towards this goal 
we have established a highly sensitive assay for detection of methylation patterns in CpG 
islands of tissue-specific genes using cell-free DNA from serum samples. Figure 4 shows an 
example of such an analysis and provides the details in the legend. From amplicon 
sequencing we achieve at least 10,000 reads per amplicon and can thus detect as few as 
1/1,000 distinctly methylated DNA fragments in a serum samples using this approach. 
Figure 3. Tissue-specific DNA methylation. Top 10 genomic loci that contain tissue-specific distinct 
hypo- or hyper-methylated DNA segments. The analysis used data generated by Sun et al. (PNAS 
2015).25 Markers were defined as genomic loci with methylation densities that deviate 3 SDs below or 
above in only one tissue compared with the mean level of the other tissues. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
216 
 
 
We have recently established an experimental work flow that is agnostic towards detection of 
tissue-specific cell-free DNA in the circulation (cfDNA). In this approach bisulfite treated 
cfDNA fragments that contain CpG regions (~3% of the genome) are captured and then 
subjected to NGS. Analysis of serially collected samples then can reveal changes over time. 
We have described this approach and the data analysis recently (25). 
Number of subjects: We anticipate for EA6134 as a whole that 150 subjects will receive 
nivo/ipi as initial therapy (Arm A, Fig. 1) and that another 100 subjects will receive nivo/ipi on 
Arm D (Fig. 1) after exhibiting disease progression on D/T. Based on consent and submission 
compliance rates as of July 2020, it is projected that 75% to 80% of the subjects in this study 
will consent to the collection of and have submitted serum samples which are requested q 6-
week blood until off study and, if applicable, weekly following an irAE. The amendment to 
collect additional samples following an irAE was approved in mid 2018. Of the 250 patients 
estimated to receive I/O therapy as part of this study, about 35 subjects on Arm A and 15 on 
Arm D had already stopped treatment due to either toxicity or disease progression by the time 
the amendment (=substudy) to the protocol to collect the specimens detailed in this research 
proposal was activated leaving around 200 subjects potentially available for the substudy. In 
the substudy, we will obtain weekly blood draws after the onset of grade 3-4 toxicities to allow 
for more frequent measurements of ctDNA and cmeDNA. The intervals of blood draws in 
those patients that have already enrolled are 6 weeks. The incidence of grade 3-4 irAEs with 
nivo/ipi is around 50%; therefore we anticipate data relevant to toxicity to be available in about 
125 subjects from the whole study and up to 100 from the substudy. The remainder of 
subjects with less toxicity (~125 from the whole study and ~100 from the substudy) will serve 
as controls. Response data should be available on all 250 subjects from the whole study with 
roughly 50% anticipated to be responders by week 12 and 60% by week 24. Available 
samples have been assessed based on the samples submitted as of July 2020 and the 
Figure 4. Heart specific methylated cfDNA analysis. A) Biotracer reading of cfDNA fragment size 
(~150bp) and cfDNA level in a patient serum after DNA extraction. Peaks from size markers spiked in 
with the sample serve as a reference (arrows). B) Gel image of amplicons using primers adjacent to 
the FAM101A locus. The predicted size of the amplicon was 189 bp. Positive control DNA samples 
analyzed were genomic heart and cardiomyocyte DNA (commercially available), patient RT02 and 
RT05 cfDNA were from an ongoing radiation trial. H20 is a negative control for DNA contamination. C) 
Independent repeat measurements of samples from two patients RT-05 and RT-02, were run 
independently from serum extractions to sequencing analysis to test reproducibility. Abundance of 
cardiac-specific DNA is provided in genome equivalents calculated based on the amount of DNA 
extracted. 35,000 to 74,000 reads generated from the cfDNAs were obtained for the amplicons 
analyzed shown here. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
217 
sample size calculation has been updated in the Statistical Design and Analysis Plan section 
below. 
Blood samples: As mentioned above all participants in EA6134 have consented to have 2 x 
10cc red top tubes of blood collected at baseline and every 6 weeks for both initial and 
crossover treatments and at time of progression. Substudy: In amendment 10 we proposed 
more frequent biomarker measurements during the period of management of grade 3-4 irAEs. 
Thus, the EA6134 protocol was amended to have additional 2 x 10 cc red top tubes of blood 
collected at weekly visits in those subjects with grade 3-4 irAEs until irAEs resolve to grade 1 
and then at their regularly scheduled visits (q 2-3 weeks) until they are tapered off of 
immunosuppressive agents. Following that they will resume q 6-week blood collections until 
off study.  
All specimens are shipped to the ECOG-ACRIN Blood Specimen Core (IMCPL) located at the 
Pittsburgh Cancer Institute for storage. In our NCI approved R01 grant we proposed that 
aliquoted samples collected from patients who have either completed protocol participation or 
cleared the 24 week CT scan and blood drawn on either Arm A or D during the preceding 3 
month interval will be shipped quarterly to the R01 grant co-PI (Wellstein’s) lab at 
Georgetown-Lombardi for measurements of ctDNA and cmeDNA. Serial samples from a given 
patient are to be analyzed together as defined in the Aims. We will initially have a complete 
set of samples available from the 140 patients that have entered the trial as of July, 2018. 
That set of samples will be sufficient to establish the cmeDNA assays and test the existing 
ctDNA assays.  
Samples to analyze: The serum samples to analyze will either be from Arm A (=nivo/ipi 
treatment first) or Arm D (=switched to nivo/ipi due to progressive disease after 
dabrafenib/trametinib first; see Fig. 1). For Arm A (nivo/ipi first) we will use 0, 6, 12, 18 and 
24-week samples collected for all patients at the trial-prescribed intervals. These time points 
should capture specimens from 90% of patients with tumor response (median time to 
response 2.76 months or 12 weeks) and 90% of the patients experiencing irAEs: The 
observed time course of grade 3-4 irAEs in a recently published study co-authored by MB 
Atkins (5) is reproduced in Fig. 5 with the trial collection times of 0, 6, 12, 18 and 24 weeks 
overlayed for illustration purposes. For Arm D (D/T first) we will use the baseline sample 
before initiation of D/T treatment as an additional control (see Fig. 1, above). 
 
 
Fig 5. Incidence of grade 3-4 AEs. From Sznol et al: "Pooled Analysis Safety Profile of Nivolumab and 
Ipilimumab Combination Therapy" (5). The percent of patients who experienced at least one grade 3-4 
irAE at the respective times (total n=448) are shown [from the original Figure in Ref. (5)]. Arrows: time 
points of blood collection in the current study. 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
218 
Statistical Design and Analysis Plan  
Sample Avaialibility Assessed as of July 2020 
Overall 90% of the patients consented to participate in the correlative study. We summarized 
inventory for patients enrolled as of 12/31/19 (as our assessment requires at least 24 weeks 
of follow-up time) and projected the numbers for the remaining patients. 
Aim 1a: Based on the data as of 12/31/19, 90% of the enrolled patients consented to 
participate in the correlative study. Of the consented pateints, 90% had baseline samples and 
86% (of the cases submitted baseline samples) had samples on at least one FU time point. At 
the completion of the study, approximately 104 patients (150X.9X.9X.86) will provide samples 
for the analysis proposed in Aim 1a. The crossover rate (to arm C or D) was lower than 
anticipated, but could not be assessed accurately at this point as the study is still being 
conducted. We project at least 46 patients crossed over to arm D will provide samples for Aim 
1a. Therefore, the overall sample size for Aim 1a will be approximately 150 patients. 
Aims 1b and 2: As of 12/31/19, approximately 50% of the patients in arm A or D had grade 3 
or higher irAEs and submitted samples. Therefore, we project approximately 75 patients will 
have consented and submitted irAE samples when accrual is completed. The remainder of 
subjects with less toxicity (~75) will serve as controls.  
Study Design and Analysis 
Aim 1: (a) We will first correlate the ctDNA analyses with clinical measurements of treatment 
responses and efficacy. Changes in the ctDNA measure from the baseline will be compared 
between the responders and non-responders. The relative abundance of ctDNA will be 
measured at each time point (baseline, weeks 6, 12, 18 and 24) by [ctDNA / (ctDNA+wtDNA)], 
resulting in a number between 0 and 1. The difference in the relative adundance of ctDNA 
between post-treatment time point (weeks 6, 12, 18 and 24) and baseline will be evaluated. 
The difference will range from -1 to 1. The difference of > 0 will be considered as a positive 
change (change = yes) and the rest will be considered as no change.  
The initial analysis will be based on week 12 samples as these will be available on the 
majority of patients. Scan reports out to 24 weeks and if necessary blood samples out to the 
same time will be used to attempt to distinguish temporally related discrepancies. Changes in 
ctDNA measurements between pre- and post-treatment will be compared in responders vs. 
non-responders. For the primary endpoint, we first present a power calculation based on a 
binary formulation of ctDNA and then as a continuous measure.  
Of the 150 patients treated with Ipi/Nivo, it is assumed 90 (60%) patients will achieve a 
response. It is hypothesized that a larger proportion of responders will have changes in ctDNA 
measurement after treatment. If the difference in proportion of patients with changes in the 
pre- and post-treatment ctDNA measurements among responders vs. non-responders is at 
least 25% (suh as 55% vs. 30%, 65% vs. 40%, 75% vs. 50%), the sample size of 90 
responders and 60 non responders will provide at least 82% power. This is based on Fisher’s 
exact test with a two-sided type I error rate of 0.05. The distribution of changes in the ctDNA 
measure between pre- and post- time points will be evaluated and compared between the 
responders and non-responders. If the standardized difference between the responders and 
non-reponders are at least 0.5, there will be at least 85% power based on the two-sample t-
test. We will evaluate the distribution of the changes. If non-parametric test is more 
appropriate, Wilcoxon’s rank-sum test will be used to compare the difference in the changes.   
(b) Tumor status can be monitored during the course of the treatment or an irAE by 
quantifying the amount of tumor specific DNA (mutant ctDNA) in the blood and that prolonged 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
219 
immunosuppressive therapy may stunt and/or reverse any ongoing antitumor response (Aim 
1). We will evaluate the changes in ctDNA (from baseline) in patients who experienced at 
least grade 3 irAEs (n=75) vs. no irAEs (n=75). There will be multiple time points while 
experiencing irAEs up to week 24. The majority of the patients experiencing irAEs will be on 
immunosupressive treatement (n=75). In order to determine whether the immunosuppressive 
treatment of an irAE has an impact on the anti-tumor immune response, we will monitor 
changes in the ctDNA levels as readout of effect of treatment anti-tumor treatment efficacy. 
We will evaluate the trend of ctDNA levels while on immonosupressive treatment using 
descriptive statistics. Patterns of the changes in ctDNA during the immunosuppressive 
treatment will be summarized.  
Aim 2: (a) We will correlate the cmeDNA analyses with clinical measurements of irAEs. 
Differences from baseline in patients who experience irAEs relative to those that do not for the 
estimated 150 patients treated with nivo/ipi in the study as a whole will be evaluated. Changes 
in cmeDNA measurements between pre- and post-treatment will be compared in patients with 
vs. without grade 3,4 irAEs. It is assumed 75 (50%) patients have grade 3,4 irAEs. Post-
treatment time point of week 12 will be used for patients without grade 3,4 irAEs and various 
time points for patients with grade 3,4 irAEs.  
Organ-specific, circulating cell-free methylated DNA (cmeDNA) will be detected by bisulfite 
sequencing of DNA and quantitated from the sequence reads (Barefoot et al. 2020; Ref 25). It 
is expected that irAEs will result in an increase in cmeDNA from the affected organs relative to 
the baseline measurements. A >3–fold increase above baseline in cmeDNA after the onset of 
irAEs will be considered as a change. If organ-specific cmeDNA is not detectable at baseline, 
three or more sequence reads of organ-specific cmeDNA will be considered as a positive 
signal and a change from baseline. cmeDNA will be followed in serial samples over the time of 
irAE treatment and scored accordingly. It is hypothesized that a larger proportion of patients 
with grade 3,4 irAEs will have changes in cmeDNA measurement after treatment. If the 
difference in proportion of patients with changes in the pre- and post-treatment cmeDNA 
measurements with vs. without grade 3,4 irAEs is at least 25% (such as 30% vs. 55%, 40% 
vs. 65%, 50% vs. 75%), the sample size of 75 in each group will provide at least 85% power. 
This is based on Fisher’s exact test with a two-sided type I error rate of 0.05. Given the 
exploratory nature of this study, type I errors will not be adjusted for multiple comparisons. 
Changes in organ-specific cmeDNA measurements between pre- and post-treatment will be 
evaluated in patients with or without grade 3,4 irAEs. 
(b). We anticipate 75 patients with serial samples during the immunosuppressive therapy. We 
will evaluate changes in signatures of specific organ toxicities during the immunosuppressive 
therapy relative to baseline and summarize the data using descriptive statistics. Changes in 
cmeDNA measurements will be evaluated by immunosuppressive treatment. Proportion of 
patients with cmeDNA measurement return to the baseline measurement will be compared by 
treatment type using Fisher’s exact test. 
Additional References 
1. Weber, Jeffrey S., et al. Nivolumab versus Chemotherapy in Patients with Advanced 
Melanoma Who Progressed after anti-CTLA-4 Areatment (CheckMate 037): A 
Randomised, Controlled, Open-label, Phase 3 Trial. Lancet Onc 16.4 (2015): 375-384. 
2. Rosenberg, J.E., et al., Atezolizumab in patients with locally advanced and metastatic 
urothelial carcinoma who have progressed following treatment with platinum-based 
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet, 2016. 387(10031): p. 1909-
20 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
220 
3. Postow, Michael A., et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated 
Melanoma. N Eng J Med 372.21 (2015): 2006-2017. 
4. Motzer RJ, Tannir NM, McDermott DF et al. Nivolumab plus Ipilimumab versus Sunitinib in 
Advance Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290 
5. Sznol M et al. (2017) Pooled Analysis Safety Profile of Nivolumab and Ipilimumab 
Combination Therapy in Patients With Advanced Melanoma. J Clin Oncol 
JCO.2016.2072.2116. 
6. Schiavon G et al. (2015) Analysis of ESR1 mutation in circulating tumor DNA 
demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med 
7:313ra182. 
7. Garcia-Murillas I et al. (2015) Mutation tracking in circulating tumor DNA predicts relapse 
in early breast cancer. Science Translational Medicine 7:302ra133. 
8. Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, Diaz LA, Goodman SN, David KA, 
Juhl H, Kinzler KW, Vogelstein B (2005) Detection and quantification of mutations in the 
plasma of patients with colorectal tumors. Proceedings of the National Academy of 
Sciences of the United States of America 102:16368-16373. 
9. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, 
Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA (2008) Circulating mutant DNA to 
assess tumor dynamics. Nature medicine 14:985-990. 
10. Crowley E, Nicolantonio FD, Loupakis F, Bardelli A (2013) Liquid biopsy: monitoring 
cancer-genetics in the blood. Nature Publishing Group 10:472-484. 
11. Haber DA, Velculescu VE (2014) Blood-based analyses of cancer: circulating tumor cells 
and circulating tumor DNA. Cancer Discovery 4:650-661. 
12. Rosell R, Karachaliou N (2016) Lung cancer: Using ctDNA to track EGFR and KRAS 
mutations in advanced-stage disease. Nature Reviews Clinical Oncology 13:401-402 
13. Rapisuwon S, Vietsch EE, Wellstein A (2016) Circulating Biomarkers to Monitor Cancer 
Progression and Treatment. Computational and Structural Biology Journal 14:211-222. 
14. Vietsch EE, van Eijck CH, Wellstein A (2015) Circulating DNA and Micro-RNA in Patients 
with Pancreatic Cancer. Pancreatic Disorders & Therapy 5:1-11. 
15. Vietsch EE, Graham GT, McCutcheon JN, Javaid A, Giaccone G, Marshall JL, Wellstein A 
(2017) Circulating cell-free DNA mutation patterns in early and late stage colon and 
pancreatic cancer. Cancer Genetics 218-219:39-50. 
16. Smith MP et al. (2016) Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage 
Strategy for Targeted Melanoma Therapy. Cancer Cell 29:270-284. 
17. Yin Y et al. (2017) Impact of cytosine methylation on DNA binding specificities of human 
transcription factors. Science (New York, NY) 356:eaaj2239 
18. Crowley E, Nicolantonio FD, Loupakis F, Bardelli A (2013) Liquid biopsy: monitoring 
cancer-genetics in the blood. Nature Publishing Group 10:472-484. 
19. Moran S, Martínez-Cardús A, Boussios S, Esteller M (2017) Precision medicine based on 
epigenomics: the paradigm of carcinoma of unknown primary. Nature Reviews Clinical 
Oncology 14:682-694 

ECOG-ACRIN 
EA6134 
Cancer Research Group 
Version Date: July 30, 2025 
 
Update Date: July 13, 2015 
221 
20. Guo S, Diep D, Plongthongkum N, Fung H-L, Zhang K, Zhang K (2017) Identification of 
methylation haplotype blocks aids in deconvolution of heterogeneous tissue samples and 
tumor tissue-of-origin mapping from plasma DNA. Nature Genetics 49:635-642. 
21. Lehmann-Werman R et al. (2016) Identification of tissue-specific cell death using 
methylation patterns of circulating DNA. PNAS PMID: 26976580 
22. Sun K et al. (2015) Plasma DNA tissue mapping by genome-wide methylation sequencing 
for noninvasive prenatal, cancer, and transplantation assessments. PNAS 112:E5503-
5512. PMID: 26392541 
23. Lo YMD, Lam WKJ (2016) Tracing the tissue of origin of plasma DNA-feasibility and 
implications. Annals of the New York Academy of Sciences 1376:14-17. 
24. Wilmot B, Fry R, Smeester L, Musser ED, Mill J, Nigg JT (2016) Methylomic analysis of 
salivary DNA in childhood ADHD identifies altered DNA methylation in VIPR2. J Child 
Psychol Psychiatry 57:152-160. PMID: 26304033 
25. Barefoot ME, Lindberg MR, Wellstein A (2020) Decoding the Tissue of Origin of Cellular 
Damage From Cell-Free DNA in Liquid Biopsies. Reference Module in Biomedical 
Sciences. Elsevier.  https://doi.org/10.1016/B978-0-12-801238-3.11669-1